KR100894713B1 - 4-arylpiperazin-1-ylpiperidine derivatives inhibiting beta-secretase's activity or pharmaceutical compositions containing the same and composition for prevention and treatment of neurodegenerative diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a piperidine compound substituted with an aryl piperazine inhibiting the activity of beta-secretase, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient. Since the piperidine derivatives substituted with aryl piperazine according to the present invention have excellent beta-secretase inhibitory activity, they may be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome.

Alzheimer's disease, piperidine compounds, beta-secretase, aging, neurodegenerative diseases, beta-amyloid

Description

A piperidine derivative substituted with aryl piperazine that inhibits the activity of beta-secretase, or a pharmaceutically acceptable salt thereof and a composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient {(4-arylpiperazin- 1-yl) piperidine derivatives inhibiting beta-secretase's activity or pharmaceutical compositions containing the same and composition for prevention and treatment of neurodegenerative diseases containing the same as an active ingredient}

The present invention provides a novel aryl piperazine-substituted piperidine derivative that inhibits the activity of beta-secretase and a composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient, or an inhibitor of beta-secretase activity It is about.

In recent years, due to the rapid economic growth and the development of new medical technology, the longevity of humans is being realized, and the elderly welfare policy is increasing in importance in the process of transition to an aging society. In particular, the socio-economic burden on Alzheimer's dementia disease, a neurodegenerative disease that is most problematic for the elderly, is gradually increasing, and countermeasures are urgently needed. Therefore, the development of Alzheimer's disease treatment may be one of the most direct solutions to solve these problems.

Alzheimer's disease (AD) is a neurodegenerative disorder that is closely related to aging characterized by loss of memory, cognition, reasoning, judgment and coping due to neuronal damage. Pathological characteristics of Alzheimer's disease include intracellular accumulation of nerve fiber bundles and extracellular deposition of senile plaques consisting of beta-amyloid (Aβ) peptides in areas related to cognitive activity of the brain. Indicates. Aβ proteins consisting of 39-43 amino acids are known to exhibit neuronal toxicity.

Aβ peptides, a major component of the senile plaques that are common in Alzheimer's dementia patients, are derived from the amyloid precursor protein (APP) 695, 751, 770. In most cases, this APP is cleaved by proteases called α-secretase and γ-secretase to release P3 peptides and water-soluble proteins called sAPPα out of cells. Specifically, in patients with Alzheimer's dementia, β-secretase and γ-secretase are activated to release Aβ peptide and a protein called sAPPβ out of the cell. Among Alzheimer's dementia patients, most of the mutations in APP genes are mutations in the cognitive regions of α, β, and γ-secretases. These mutations alter the structure of the protein, resulting in β and γ-secretase. It has been shown that exposure to the chromophore results in higher amounts of Αβ peptide than normal individuals. Aβ peptides have insoluble properties consisting of 42 amino acid residues and are known to be deposited in brain regions associated with memory and recognition, leading to apoptosis of brain cells. According to recent reports, the mutation of APP gene factor acts as a substrate of the apoptotic protease caspase-6 and caspase-3, and the cleaved APP is cleaved by β- and γ-secretase. It is known to form Aβ easily. It has been reported that APP overexpressing transgenic mice overexpressing APP mutant genes in Alzheimer's dementia resulted in a decrease in the senile plaques and dementia-specific spatial perceptual learning in patients with dementia. Taken together, these reports suggest that mutations in APP genes in Alzheimer's dementia patients are closely related to the production of Aβ peptides and play an important role in the development of Alzheimer's disease.

Thus, the β-secretase enzyme, also called BACE, Asp or Memapsin ((a) Tang, J. et al., Proc . Natl . Acad . Sci . USA 2000 , 97 , 1456. ( b) Hussain, I. et al., Mol . Cell Neurosci . 1999 , 14 , 419. (c) Yan, R. et al., Nature 1999 , 402 , 533. (d). Sinha, S, et al., Nature 1999 , 402 , 537. (e) Inhibitors that inhibit the activity of Vassar, R. et al., Science 1999 , 286 , 735.) prevent the prophylactic and underlying pathogenesis of Alzheimer's disease. It is recognized as a treatable drug, and many pharmaceutical companies are investing huge research funds to develop new inhibitors.

There are many reports on the development of β-secretase inhibitors, most of which have peptide bonds using mainly natural amino acids. Recently, inhibitors with different structures from peptide compounds derived from natural amino acids have been reported ((a) Stachel, SJ et al., J. Med . Chem . 2004 , 47 , 6447. (b) Huang, D. et al. ., J. Med. Chem. 2005 , 48, 5108. (c) Bhisetti, GR et al., PCT Int. Appl. WO 02/088101, 2002. (d) Garino, C. et al., Bioorg. Med . Chem. Lett. 2006, 16 , 1995.).

Accordingly, the present inventors have tried to develop a beta-secretase inhibitor that is excellent in inhibiting the activity of beta-secretase, and as a result, the piperidine derivative in which aryl piperazine is substituted for piperidine derivatives is substituted for beta-secret. It was confirmed that the efficacy of inhibiting the activity of thease is excellent and completed the present invention.

An object of the present invention is to provide a piperidine derivative substituted with a novel aryl piperazine and a pharmaceutically acceptable salt thereof.

Another object of the present invention to provide a composition for preventing and treating neurodegenerative diseases using the derivative as an active ingredient.

In order to achieve the above object, the present invention provides a piperidine derivative and a pharmaceutically acceptable salt thereof substituted with a novel aryl piperazine.

The present invention also provides a composition or a beta-secretase inhibitor for the prevention and treatment of neurodegenerative diseases using the derivative as an active ingredient.

The piperidine derivative substituted with aryl piperazine represented by the following Chemical Formula 1 according to the present invention has excellent beta-secretase inhibitory activity, and thus may be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome. have.

The present invention provides a piperidine derivative substituted with an aryl piperazine represented by Formula 1 below, and a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

을 나타내고, 이때 R⁴는 C_{6 - 10}아릴C_{1 - 4}알킬기, C_{6 - 12}아릴, C_{1 - 5}알콕시 또는 C_{6 - 12}아릴옥시가 치환된 C_{6 - 12}아릴기이고, Z는 수소, 할로겐, C_{1 -4} 직쇄 또는 측쇄 알킬기 또는 C_{1 - 5}알콕시기이고, R ¹ And R ² is independently —O—CO—R ⁴ or

A represents, wherein R ⁴ is C _{6 - 10} aryl C _{1 - 4} alkyl group, C _{6 - 12} aryl, C _{1 - 5} alkoxy or C _{6 - 12} aryloxy-substituted C _{6 -} and ₁₂ aryl group, Z is hydrogen ₅ is an alkoxy group, _- a halogen, C _{1 -4} alkyl group or a linear or branched C ₁

R ³ is hydrogen, -CO-NH- (CH ₂ ) _m -R ⁵ Or ^{-CO-NH-C (R 6} ) (R 7) - (CH 2) m -COO-R 8 , and wherein R ⁵ is 1 to 2 C _{1 -4} straight or branched alkyl or C _{1 - 5} alkoxy or halogen-substituted C _{6 - 12} aryl group, and, m is an integer of 0 to 2, R ⁶ And R ⁷ is independently hydrogen, C _{1 -4} straight or branched alkyl group or benzyl group, R ⁸ is a C _{1 -4} straight or branched alkyl group.

Preferably said R ⁴ according to the invention is naphthyl, biphenyl or phenoxybenzyl, Z is hydrogen, halogen, methyl or methoxy,

R ³ is

It is any one selected from the group consisting of.

More specifically exemplified by the piperidine derivative represented by Formula 1 are as follows.

(1) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(2) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(3) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(4) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(5) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;

(6) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;

(7) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;

(8) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;

(9) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;

(10) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;

(11) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;

(12) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-2-naphthoate;

(13) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(14) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(15) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(16) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;

(17) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;

(18) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;

(19) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;

(20) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;

(21) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;

(22) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;

(23) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(24) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(25) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;

(26) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(27) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(28) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;

(29) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(30) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(31) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate;

(32) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(33) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(34) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;

(35) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(36) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(37) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;

(38) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(39) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(40) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate;

(41) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(42) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;

(43) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;

(44) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(45) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;

(46) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;

(47) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(48) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;

(49) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate;

(50) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate;

(51) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-2 Naphthoate;

(52) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate;

(53) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate;

(54) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-bi Phenyl-4-carboxylate;

(55) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate;

(56) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate;

(57) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(58) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(59) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(60) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(61) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(62) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;

(63) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(64) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(65) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(66) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(67) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(68) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(69) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(70) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;

(71) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(72) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(73) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(74) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(75) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;

(76) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(77) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;

(78) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;

(79) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(80) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;

(81) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(82) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(83) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;

(84) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate;

(85) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate;

(86) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate ;

(87) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;

(88) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;

(89) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(90) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(91) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;

(92) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;

(93) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;

(94) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;

(95) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(96) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(97) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(98) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(99) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;

(100) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;

(101) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine -4-yl-biphenyl-3-carboxylate;

(102) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;

(103) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(104) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(105) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(106) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;

(107) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;

(108) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;

(109) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;

(110) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;

(111) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(112) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;

(113) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate;

(114) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate;

(115) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-1 Naphthoate;

(116) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate;

(117) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate;

(118) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-bi Phenyl-3-carboxylate;

(119) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate;

(120) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate;

(121) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(122) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(123) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(124) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(125) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(126) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(127) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(128) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(129) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(130) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(131) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(132) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(133) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(134) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate;

(135) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(136) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(137) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(138) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(139) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;

(140) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(141) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;

(142) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate;

(143) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(144) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;

(145) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(146) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(147) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(148) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;

(149) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;

(150) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate ;

(151) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate;

(152) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate;

(153) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(154) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(155) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight;

(156) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;

(157) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car Carboxylates;

(158) 1- (3-Chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3 Carboxylates;

(159) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;

(160) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight;

(161) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; And

(162) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car Carboxylate.

The present invention includes not only piperidine derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates, racemates or stereoisomers that can be prepared therefrom.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

In addition, the present invention, as shown in Scheme 1,

Preparing a compound of Chemical Formula 3 (3a or 3b) by ring opening the tricyclic ring of the compound of Chemical Formula 2 as an aryl piperazine compound (Step 1);

Preparing a compound of formula 4 (4a or 4b) by esterifying the compound of formula 3 prepared in step 1 (step 2); And

It provides a method for preparing an aryl piperazine substituted piperidine derivative comprising the step (step 3) of preparing a compound of Formula 1 (1a or 1b) by deprotecting the compound of Formula 4 prepared in step 2. .

(Wherein R ⁴ And Z is as defined in Chemical Formula 1, wherein Chemical Formula 1a and Chemical Formula 1b are included in the derivative of Chemical Formula 1 of the present invention).

Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.

Step 1: ring opening reaction

Step 1 according to the present invention is a step of preparing a compound of formula 3a or 3b by ring opening reaction by attacking the aryl piperazine compound in the triangular ring position of the formula (2) which is a starting material.

The starting compound of Formula 2 can be obtained from commercially available 1,2,3,6-tetrahydropyridine using known methods [Heterocycles 1994, 39, 163].

The aryl piperazine compound may attack carbon 3 or 4 constituting the triangular ring in Formula 2 to form a racemate in which the compound of Formula 3a and the compound of Formula 3b are produced in a ratio of 1: 1 Can be. At this time, the phenyl group of the aryl piperazine compound may include an electron withdrawing substituent such as halogen, methoxy group.

In general, the compound of Chemical Formula 3a or 3b of Step 1 according to the present invention may be prepared by the following method.

General manufacturing method A

After dissolving the compound of Formula 2 in acetonitrile, LiClO ₄ and aryl piperazine were added and stirred under reflux for 5-6 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with distilled water, and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 2: 1) to give a compound of formula 3a or 3b.

General manufacturing method B

After dissolving the compound of Formula 2 in acetonitrile, LiClO ₄ and aryl piperazine were added and heated at 130 ° C. for 15-30 minutes using microwave. The reaction was diluted with ethyl acetate, washed with 0.1 N aqueous hydrochloric acid solution and water, and then the organic layer was concentrated under reduced pressure with sodium sulfate. The residue is purified by column chromatography (hexane / ethyl acetate = 2/1) to give the compound of formula 3a or 3b.

General manufacturing method C

The compound of Formula 2 and aryl piperazine are dissolved in anhydrous ethanol and stirred under reflux for 36 to 50 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with distilled water, and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 2: 1) to give a compound of formula 3a or 3b.

Step 2: ester reaction

Step 2 according to the present invention is a step of obtaining a compound of formula 4a or 4b by esterification of the hydroxyl group of the compound (3a, 3b) of formula 3 prepared in step 1 with an organic acid chloride.

The ester reaction can be carried out without particular limitation by the ester reaction conditions known in the art.

Specifically, it may be prepared by the following method.

General manufacturing method A

A mixture of the formulas 3a and 3b, an organic acid chloride, triethyla and 4-N, N-dimethylaminopyridine (DMAP) are dissolved in tetrahydrofuran, and then stirred under reflux for 50 to 60 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with 1N sodium hydroxide and distilled water, and then the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 4: 1) to give the compound of formula 4a or 4b, respectively.

General manufacturing method B

After dissolving the mixture of Formulas 3a and 3b in pyridine, organic acid chloride (1.1 equiv) is added and heated at 150 ° C. for 3 minutes using microwave. The reaction was diluted with ethyl acetate, washed with aqueous hydrochloric acid solution and water, and then the organic layer was concentrated under reduced pressure after removing moisture with sodium sulfate. The residue is purified by column chromatography (hexane / ethyl acetate = 1/1) to give the compound of formula 4a or 4b, respectively.

Step 3: Deprotection  step

Step 3 according to the present invention is a step of preparing a compound of Formula 1 (1a or 1b) by deprotecting the compound of Formula 4 prepared in Step 2.

The deprotection may be carried out by a method commonly used, and may be preferably deprotected by removing t-butoxycarbonyl group using a trifluoroacetic acid solution, dichloromethane or a mixed solution thereof.

Specifically, dichloromethane-trifluoroacetic acid solution (1: 1) is added to the compound of Formula 4a or Formula 4b at 0 ° C., followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium carbonate and water, and then the organic layer was concentrated under reduced pressure with sodium sulfate. The residue can be purified by column chromatography (hexane / ethyl acetate = 1/2) to afford the compound of formula 1 (1a or 1b) according to the present invention.

In addition, the compound of formula 1 (1a or 1b) prepared in step 3 further comprises the step of preparing a derivative (1c and 1d) of formula 1 by reacting with an isocyanate derivative as shown in Scheme 2 (step 4) can do.

(R ³ , R ⁴ in Scheme 2 above) And Z is as defined in Formula 1, wherein the compounds of Formulas 1c and 1d are included in the derivative of Formula 1 of the present invention.)

In this case, as the isocyanate derivative used, 2-isocyanato methyl ester, aryl isocyanate and the like can be used, and these can be prepared by a known method [Nowich, JS et al, J. Org . Chem . , 1992 , 57, 7364-7366.

The method for preparing the compound of Formula 1 according to the present invention is not limited to the above scheme, and may be prepared using known organic chemical reactions.

Furthermore, the present invention provides a beta-secretase inhibitor containing an aryl piperazine-substituted piperidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a composition for the prevention and treatment of neurodegenerative diseases containing aryl piperazine-substituted piperidine derivatives or pharmaceutically acceptable salts thereof as an active ingredient.

Beta-amyloid (Aβ) peptide, which plays an important role in the development of Alzheimer's disease, has insoluble properties consisting of 42 amino acid residues and is deposited in brain regions related to memory and recognition, leading to apoptosis of brain cells. It is known. These Αβ peptides are produced by the amyloid precursor protein (APP), which is a precursor metabolic protein. The cleaved APP is known to form Aβ more easily by β-secretase.

Therefore, inhibiting the activity of β-secretase can inhibit the production of Aβ peptides that cause Alzheimer's disease. Thus, β-secretase activity inhibitors are recognized as drugs that can prevent and treat the underlying causes of Alzheimer's disease. [(A) Tang, J. et al., Proc . Natl . Acad . Sci . USA 2000 , 97 , 1456. (b) Hussain, I. et al., Mol . Cell Neurosci . 1999 , 14 , 419. (c) Yan, R. et al., Nature 1999 , 402 , 533. (d). Sinha, S, et al., Nature 1999 , 402 , 537. (e) Vassar, R. et al., Science 1999 , 286 , 735].

Meanwhile, the piperidine derivative substituted with the aryl piperazine represented by Chemical Formula 1 according to the present invention has about 10 to 20 times higher inhibitory activity than the conventional piperazine derivative in an activity inhibition experiment with beta-secretase enzyme. Indicated.

Therefore, the composition containing the piperidine derivative substituted with the aryl piperazine represented by the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient inhibits the activity of beta-secretase to inhibit the Aβ peptide. It can be used as a treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Down's syndrome and the like caused by Aβ peptide by inhibiting the production of.

When using the composition of the present invention as a medicine, the pharmaceutical composition containing the piperidine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient may be various oral or parenteral It may be formulated in a dosage form and administered, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

The pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, the piperidine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

As an active ingredient, the derivative of formula 1 may be used orally once a day or in divided doses in an amount of 0.1 to 500 mg / kg body weight, preferably 0.5 to 100 mg / kg body weight, for mammals including humans. Or by parenteral routes.

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples.

< Example  1> 4- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

Step 1: t-butyl 4- (4- (4- Fluorophenyl Piperazin-1-yl) -3- Hydroxypiperidine -1-carboxyl Rate Manufacture

After dissolving the compound of Formula 2 (5 mmol) in acetonitrile (10 mL), LiClO ₄ (5.5 mmol) and 1- (4-fluorophenyl) piperazine (5.5 mmol) were added and stirred under reflux for 5-6 hours. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-fluorophenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 90%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.46 (br.s, 18H), 1.76-1.82 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.39 (m, 2H), 2.42 -2.73 (m, 8H), 2.86-2.92 (m, 2H), 2.97-3.04 (m, 2H), 3.06-3.18 (m, 8H), 3.40-3.49 (m, 1H), 3.57-3.65 (m, 2H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.54 (m, 1H), 6.84-6.90 (m, 4H), 6.92-7.00 (m, 4H)

Step 2: Preparation of t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidine-1-carboxylate

T-butyl-4- (4- (4-fluorophenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate (2 mmol) and 2-prepared in step 1 Naphthoic acid chloride (4 mmol), triethylamine (4 mmol) and 4-N, N-dimethylaminopyridine (DMAP, 0.2 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred under reflux for 50-60 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), washed with 1N sodium hydroxide (2 x 10 mL), distilled water (20 mL), and then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 4: 1) to give t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl ) Piperidine-1-carboxylate was obtained (yield: 46%).

¹ H NMR (CDCl ₃ , 200 MHz): δ1.50 (s, 9H), 1.70-1.90 (m, 1H), 2.10-2.30 (m, 1H), 2.65-2.85 (m, 3H), 2.90-3.12 (m, 8H), 3.95-4.20 (m, 2H), 5.34-5.46 (m, 1H), 6.74-6.93 (m, 4H), 7.50-7.64 (m, 2H), 7.85-7.90 (m, 2H) , 7.93-7.97 (m, 1 H), 8.02-8.07 (m, 1 H), 8.59 (s, 1 H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.4, 30.0, 41.6, 42.6, 49.3, 50.6, 63.8, 70.5, 79.9, 115.0, 115.5, 117.7, 125.1, 126.6, 127.6, 127.7, 128.1, 128.2, 129.2 , 131.0, 132.4, 135.5, 147.8, 154.6, 159.3, 165.9.

Step 3: 4- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoei Manufacturing

Dichloromethane in t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidine-1-carboxylate prepared in step 2 above Trifluoroacetic acid solution (1: 1) was added at 0 ° C. and stirred for 15 minutes, followed by stirring at room temperature for 2-4 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with saturated sodium carbonate (50 mL) and water (50 mL), and the organic layer was concentrated under reduced pressure with sodium sulfate. The residue was purified by column chromatography (hexane / ethyl acetate = 1/2) to give 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphtho The yield was obtained (yield: 98%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 2.00-2.20 (m, 1H), 2.30-2.50 (m, 1H), 2.74-2.85 (m, 3H), 2.92-3.22 (m, 8H), 3.44- 3.58 (m, 2H), 5.41-5.51 (m, 1H), 6.70-6.79 (m, 2H), 6.81-6.91 (m, 2H), 7.52-7.65 (m, 2H), 7.87-7.89 (m, 2H ), 7.96- 8.00 (m, 1H), 8.02-8.07 m, 1H), 8.61 (s, 1H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 27.8, 42.2, 43.5, 49.2, 50.4, 53.3, 61.7, 68.4, 115.0, 115.4, 117.5, 117.7, 124.9, 126.7, 126.9, 127.6, 128.3, 128.4, 129.3 , 131.2, 132.3, 135.5, 147.6, 147.6, 154.5, 159.3, 165.6.

< Example  2> 4- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

Step 1: t-butyl-4- (4- (3- Chlorophenyl Piperazin-1-yl) -3- Hydroxypiperidine -1-carboxyl Rate Manufacture

After dissolving the compound of Formula 2 (5 mmol) in acetonitrile (10 mL), LiClO ₄ (5.5 mmol) and 1- (3-chlorophenyl) piperazine (5.5 mmol) were added and stirred under reflux for 5-6 hours. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (3-chlorophenyl) piperazin-1-yl) -3-hydroxypiperidine- 1-carboxylate was obtained (yield: 90%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.46 (br.s, 18H), 1.70-1.80 (m, 1H), 2.03-2.09 (m, 1H), 2.30-2.43 (m, 2H), 2.50 -2.75 (m, 8H), 2.80-2.89 (m, 2H), 2.95-3.01 (m, 2H), 3.10-3.26 (m, 8H), 3.40-3.47 (m, 1H), 3.57-3.65 (m, 2H), 4.00- 4.16 (m, 1H), 4.18-4.34 (m, 1H), 4.36-4.50 (m, 1H), 6.74-6.84 (m, 4H), 6.86 (br.s, 2H), 7.15 ( t, J = 8 Hz, 2H).

Step 2: t-butyl-3- (2- Naphthoyloxy ) -4- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidine-1-carboxyl Rate  Produce

Example 1 in t-butyl-4- (4- (3-chlorophenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate (2 mmol) prepared in step 1 In the same manner as in step 2 of t-butyl3- (2-naphthoyloxy) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidine-1-carboxylate Obtained (yield 51%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H) , 7.87 (m, 2 H), 7.92-7.96 (m, 1 H), 8.01-8.07 (m, 1 H), 8.57 (s, 1 H).

Step 3: 4- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

In the same manner as in Step 3 of Example 1, 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 99 %).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.60-1.85 (m, 1H), 1.90-2.20 (m, 1H), 2.60-2.72 (m, 2H), 2.75-2.84 (m, 2H), 2.85- 2.95 (m, 2H), 3.00-3.10 (m, 4H), 3.15-3.35 (m, 1H), 3.40-3.65 (m, 1H), 3.70-4.05 (m, 1H), 5.25-5.40 (m, 1H ), 6.66-6.77 (m, 3H), 7.08 (t, J = 8.0 Hz, 1H), 7.50-7.60 (m, 2H), 7.87-7.92 (m, 2H), 7.95-8.00 (m, 1H), 8.01-8.07 (m, 1 H), 8.61 (s, 1 H).

< Example  3> 4- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

Step 1: t-butyl-4- (4- (4- Methoxyphenyl Piperazin-1-yl) -3- Hydroxypiperidine -1-carboxyl Rate Manufacture

Compound (5 mmol) and 1- (2-methoxyphenyl) piperazine (5.5 mmol) in Chemical Formula 2 were dissolved in anhydrous ethanol (10 mL) and stirred under reflux for 36 to 50 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 77%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.44 (m, 2H), 2.50 -2.75 (m, 8H), 2.84-2.94 (m, 2H), 2.96-3.16 (m, 10H), 3.38-3.50 (m, 1H), 3.56-3.67 (m, 2H), 3.76 (br.s, 6H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.56 (m, 1H), 6.80-6.93 (m, 8H).

Step 2: t-butyl-3- (2- Naphthoyloxy ) -4- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidine-1-carboxyl Rate  Produce

T-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate prepared in step 1 was added to pyridine (3 mL). After dissolving, 2-naphthoic acid chloride (1.1 equiv) was added and heated at 150 ° C. for 3 minutes using microwave. The reaction was diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous hydrochloric acid solution (50 mL) and water (50 mL), and then the organic layer was concentrated under reduced pressure with Na ₂ SO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to give t-butyl-3- (2-naphthoyloxy) -4- (4- (4-methoxyphenyl) piperazin-1- I) piperidine-1-carboxylate was obtained (yield: 57%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.50 (s, 9H), 1.68-1.84 (m, 1H), 2.14-2.24 (m, 1H), 2.65-2.82 (m, 3H), 2.90-3.11 (m, 8H), 3.72 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.25 (m, 1H), 5.36-5.43 (m, 1H), 6.74-6.82 (m, 4H), 7.51 -7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.07 (m, 1H), 8.59 (s, 1H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.4, 30.0, 42.5, 49.5, 51.2, 55.5, 63.9, 68.0, 70.5, 79.9, 114.3, 118.0, 125.2, 126.6, 127.7, 128.1, 128.2, 129.3, 131.0 , 132.4, 135.5, 145.6, 153.7, 154.6, 166.0

Step 3: 4- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

In the same manner as in Step 3 of Example 1, 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 97%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.62-1.90 (m, 1H), 2.10-2.35 (m, 1H), 2.60-2.85 (m, 3H), 2.90-3.00 (m, 8H), 3.20- 3.40 (m, 1H), 3.70 (s, 3H), 5.28-5.45 (m, 1H), 6.64-6.82 (m, 4H), 7.48-7.61 (m, 2H), 7.84-7.88 (m, 2H), 7.90-8.00 (m, 1 H), 8.02-8.07 (m, 1 H), 8.59 (s, 1 H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 31.9, 44.2, 45.5, 49.2, 50.9, 55.1, 65.3, 70.9, 113.9, 117.6, 125.0, 126.3, 127.4, 127.7, 127.8, 128.9, 130.6, 132.1, 135.1 , 145.4, 153.2, 165.6.

< Example  4> 4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

Step 1: t-butyl-4- (4- (2- Methoxyphenyl Piperazin-1-yl) -3- Hydroxypiperidine 1-carboxyl Rate Manufacture

Dissolve compound (5 mmol) in acetonitrile (10 mL) and add LiClO ₄ (5.5 mmol) and 1- (2-methoxyphenyl) piperazine (5.5 mmol). The reaction was carried out for a minute. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 77%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.15 (m, 1H), 2.30-2.44 (m, 2H), 2.55 -2.80 (m, 8H), 2.89-2.98 (m, 3H), 3.00-3.20 (m, 9H), 3.38-3.50 (m, 1H), 3.56-3.66 (m, 1H), 3.68-3.82 (m, 2H), 3.87 (br.s, 6H), 4.20-4.36 (m, 2H), 4.38-4.56 (m, 2H), 6.84-6.90 (m, 2H), 6.92-6.97 (m, 4H), 6.98- 7.05 (m, 2 H).

Step 2: t-butyl-3- (2- Naphthoyloxy ) -4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidine-1-carboxyl Rate  Produce

T-butyl-4- (4- (2-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate prepared in Step 1 was prepared according to Example 3 In the same manner as in t-butyl-3- (2-naphthoyloxy) -4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidine-1-carboxylate (Yield 39%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.49 (s, 9H), 1.71-1.86 (m, 1H), 2.15-2.24 (m, 1H), 2.65-2.83 (m, 3H), 2.87-2.98 ( m, 4H), 3.00-3.15 (m, 4H), 3.79 (s, 3H), 3.90-4.05 (m, 1H), 4.10-4.22 (m, 1H), 5.35-5.44 (m, 1H), 6.78- 6.87 (m, 3H), 6.90-6.96 (m, 1H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 1H), 8.04-8.08 (m, 1H), 8.60 (s, 1H).

Step 3: 4- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-2- Naphthoate  Produce

In the same manner as in Step 3 of Example 1, 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 99%)

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.98-2.13 (m, 1H), 2.35-2.45 (m, 1H), 2.75-2.85 (m, 2H), 2.90-3.17 (m, 9H), 3.40- 3.50 (m, 1H), 3.54-3.60 (m, 1H), 3.76 (s, 3H), 5.45-5.52 (m, 1H), 6.76-6.86 (m, 3H), 6.90-6.96 (m, 1H), 7.52-7.63 (m, 2H), 7.87-7.91 (m, 2H), 7.95-8.01 (m, 1H), 8.04-8.07 (m, 1H), 8.62 (s, 1H).

< Example  5> 4- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

Step 1

It was carried out in the same manner as step 1 of Example 1.

Step 2

The target compound was obtained in the same manner as Step 2 of Example 1, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 46%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 9H), 1.60-1.81 (m, 1H), 2.10-2.22 (m, 1H), 2.65-2.83 (m, 3H), 2.90-3.09 (m, 8H), 3.90-4.20 (m, 2H), 5.30-5.41 (m, 1H), 6.76-6.95 (m, 4H), 7.38-7.51 (m, 3H), 7.59-7.67 (m, 4H) , 8.03-8.12 (m, 2 H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.2, 29.8, 41.4, 42.4,49.2, 50.4, 63.6, 70.2, 79.7, 114.9, 115.3, 117.4, 117.5, 126.5, 126.8, 127.0, 127.9, 128.7, 128.9, 129.9, 130.1, 139.6, 145.4, 147.7, 154.4, 159.1, 165.4.

Step 3

The same procedure as in Step 3 of Example 1 was carried out to yield 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate (Yield 86%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.62-1.81 (m, 1H), 2.03-2.25 (m, 1H), 2.64-2.82 (m, 5H), 2.93-2.97 (m, 6H), 3.09- 3.16 (m, 1H), 3.22-3.35 (m, 1H), 5.24-5.35 (m, 1H), 6.75-6.94 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.68 (m, 4H ), 8.08-8.13 (dd, J = 7.0 Hz & 2.0 Hz, 2H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 26.2, 45.2, 48.6, 50.4, 65.6, 70.0, 114.8, 115.2, 117.1, 117.3, 126.7, 126.9, 127.8, 128.6, 129.1, 129.8, 139.6, 145.1, 147.7, 147.8, 154.2, 158.9, 165.4.

< Example  6> 4- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-3-yl- Biphenyl -4-carboxyl re Manufacture of wight

Step 1

It was carried out in the same manner as step 1 of Example 2.

Step 2

The target compound was obtained in the same manner as Step 2 of Example 2, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 51%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 9H), 1.65-1.85 (m, 1H), 2.10--2.25 (m, 1H), 2.60-2.85 (m, 3H), 2.93- 3.15 (m, 8H), 3.95-4.18 (m, 2H), 5.28-5.40 (m, 1H), 6.63-6.81 (m, 3H), 7.10 (t, J = 7.8 Hz, 1H), 7.38-7.52 ( m, 3H), 7.58-7.69 (m, 4H), 8.06-8.12 (m, 2H).

Step 3

The same method as in Step 3 of Example 2 was carried out to obtain 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate ( Yield: 98%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.90-2.05 (m, 1H), 2.25--2.40 (m, 1H), 2.65-2.80 (m, 3H), 2.89-3.10 (m, 8H), 3.30 -3.55 (m, 2H), 5.30-5.45 (m, 1H), 6.66-6.80 (m, 3H), 7.09 (t, J = 8.2 Hz, 1H), 7.39-7.51 (m, 3H), 7.59-7.70 (m, 4H), 8.10 (d, J = 8.2 Hz, 2H).

< Example  7> 4- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl- Biphenyl -4-carboxyl re Manufacture of wight

Step 1

It was carried out in the same manner as Step 1 of Example 3.

Step 2

The target compound was obtained in the same manner as Step 2 of Example 3, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 41%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.66-3.07 (m, 3H), 2.95-3.07 ( m, 8H), 3.73 (s, 3H), 3.95-4.02 (m, 1H), 4.04-4.20 (m, 1H), 5.31-5.38 (m, 1H), 6.77-6.85 (m, 4H), 7.36- 7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.4, 30.0, 41.4, 42.7, 49.5, 51.1, 55.5, 63.9, 70.5, 79.9, 114.3, 117.9, 126.8, 127.0, 127.2, 128.1, 128.9, 129.2, 130.1 , 140.0, 145.7, 153.6, 154.6, 165.7.

Step 3

The same procedure as in Step 3 of Example 3 was carried out to obtain 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate. (Yield 98%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.64-1.81 (m, 1H), 2.13-2.24 (m, 1H), 2.64-2.83 (m, 5H), 2.90-3.00 (m, 6H), 3.08- 3.22 (m, 1H), 3.26-3.31 (m, 1H), 3.72 (s, 3H), 5.24-5.34 (m, 1H), 6.75-6.84 (m, 4H), 7.34-7.51 (m, 3H), 7.60-7.67 (m, 4H), 8.11 (d, J = 8.6 Hz, 2H).

< Example  8> 4- (4- (2- Methoxyphenyl Preparation of Piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate

Step 1

It was carried out in the same manner as step 1 of Example 4.

Step 2

The target compound was obtained in the same manner as Step 2 of Example 4, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 36%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.60-2.74 (m, 1H), 2.75-2.85 ( m, 2H), 2.90-3.13 (m, 8H), 3.81 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.20 (m, 1H), 5.31-5.39 (m, 1H), 6.80- 6.86 (m, 3H), 6.89-6.97 (m, 1H), 7.37-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.09-8.12 (m, 2H).

Step 3

The same procedure as in Step 3 of Example 4 was conducted to obtain 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate. (Yield 97%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.83-2.07 (m, 1H), 2.24-2.43 (m, 1H), 2.72-2.88 (m, 2H), 2.90-3.14 (m, 9H), 3.36- 3.60 (m, 2H), 3.79 (s, 3H), 5.32-5.48 (m, 1H), 6.76-6.88 (m, 3H), 6.89-6.99 (m, 1H), 7.35-7.52 (m, 3H), 7.60-7. 07 (m, 4 H), 8.09-8.13 (m, 2 H).

< Example  9> 4- (4- (4- Fluorophenyl Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate

Step 1

It was carried out in the same manner as step 1 of Example 1.

Step 2

A target compound was obtained in the same manner as Step 2 of Example 1, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 62%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 9H), 1.60-1.80 (m, 1H), 2..09--2.20 (m, 1H), 2.60-2.77 (m, 3H) , 2.85-3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.24-5.35 (m, 1H), 6.76-7..08 (m, 8H), 7.15-7.26 (m, 1H), 7.31 -7.42 (m, 2 H), 7.95-8.02 (m, 2 H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.2, 29.8, 41.4, 42.6, 49.2, 50.4, 63.6, 70.1, 79.6, 114.9, 115.3, 117.2, 119.8, 124.5, 131.5, 147.7, 154.3, 155.3, 159.0, 161.6, 164.9.

Step 3

The same procedure as in Step 3 of Example 1 was carried out to obtain 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield) : 99%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.80-2.00 (m, 1H), 2..25--2.40 (m, 1H), 2.70-2.81 (m, 3H), 2.85-3.05 (m, 8H ), 3.29-3.45 (m, 2H), 5.26-5.40 (m, 1H), 6.75-7.10 (m, 8H), 7.15-7.23 (m, 1H), 7.32-7.44 (m, 2H), 7.96-8.03 (m, 2 H). ¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.9, 42.8, 44.3, 49.3, 50.5, 62.6, 68.9, 115.1, 115.5, 117.2, 117.5, 117.7, 120.1, 124.0, 124.5, 129.9, 131.7, 147.6, 147.7, 155.3, 162.0, 164.9.

< Example  10> 4- (4- (3- Chlorophenyl Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate

Step 1

It was carried out in the same manner as step 1 of Example 2.

Step 2

A target compound was obtained in the same manner as Step 2 of Example 2, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 49%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 9H), 1.61-1.74 (m, 1H), 2.09--2.17 (m, 1H), 2.63-2.76 (m, 3H), 2.90- 3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.25-5.33 (m, 1H), 6.70-6.84 (m, 3H), 6.95-7.02 (m, 2H), 7.04-7.22 (m, 4H ), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H).

Step 3

The same procedure as in Step 3 of Example 2 was carried out to yield 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield: 74%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.65-1.85 (m, 1H), 2.15-2.30 (m, 1H), 2.71-2.82 (m, 6H), 2.85-2.96 (m, 2H), 3.00- 3.07 (m, 3H), 3.10-3.25 (m, 1H), 3.28-3.33 (m, 1H), 5.21-5.35 (m, 1H), 6.66-6.81 (m, 3H), 6.95-7.02 (m, 2H ), 7.04-7.11 (m, 2H), 7.15-7.23 (m, 2H), 7.32-7.43 (m, 2H), 7.96-8.02 (m, 2H).

< Example  11> 4- (4- (4- Methoxyphenyl Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate

Step 1

It was carried out in the same manner as Step 1 of Example 3.

Step 2

A target compound was obtained in the same manner as Step 2 of Example 3, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 46%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 9H), 1.50-1.95 (m, 1H), 2.10--2.12 (m, 1H), 2.16-2.81 (m, 3H), 2.95- 3.07 (m, 8H), 3.74 (s, 3H), 3.93-4.25 (m, 2H), 5.26-5.31 (m, 1H), 6.77-6.86 (m, 4H), 6.94-7.15 (m, 4H), 7.17-7.22 (m, 1 H), 7.33-7.42 (m, 2 H), 7.96-8.03 (m, 2 H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 28.2, 29.8, 41.3, 42.6, 49.3, 50.9, 55.2, 63.6, 70.2, 79.6, 114.1, 117.1, 117.7, 119.8, 124.2, 124.6, 129.8, 131.5, 145.5 , 153.4, 154.4, 155.4, 161.6, 165.0.

Step 3

The same procedure as in Step 3 of Example 3 was carried out to yield 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield) : 99%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.66-1.86 (m, 1H), 2.17--2.26 (m, 1H), 2.71-2.83 (m, 3H), 2.90-3.00 (m, 8H), 3.05 -3.25 (m, 1H), 3.30-3.35 (m, 1H), 3.74 (s, 3H), 5.22-5.33 (m, 1H), 6.75-6.85 (m, 4H), 6.95-7.09 (m, 4H) , 7.14-7.22 (m, 1 H), 7.32-7.44 (m, 2 H), 7.96-8.03 (m, 2H).

¹³ C NMR (CDCl ₃ , 200 MHz): δ 30.9, 43.8, 45.8, 45.3, 49.5, 51.1, 55.4, 64.4, 70.2, 114.2, 117.2, 117.8, 119.9, 124.4, 124.6, 129.9, 131.6, 145.6, 153.5 , 155.5, 161.7, 165.1.

< Example  12> 3- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

Step 1

The target compound was obtained by the same method as the step 1 of Example 1 (yield: 42%).

Step 2

The desired compound was obtained in the same manner as Step 2 of Example 1, except that 1-naphthoic acid chloride was used (yield: 52%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H) , 7.87 (m, 2 H), 7.92-7.96 (m, 1 H), 8.01-8.07 (m, 1 H), 8.57 (s, 1 H).

Step 3

The same procedure as in Step 3 of Example 1 was followed to obtain 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 99%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.85-2.04 (m, 1H), 2.05-2.30 (m, 1H), 2.64-2.74 (m, 2H), 2.75-2.90 (m, 3H), 2.95- 3.15 (m, 6H), 3.22-3.42 (m, 1H), 3.50-3.80 (m, 1H), 5.40-5.60 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.93 (m, 2H ), 7.47-7.59 (m, 2H), 7.79-7.87 (m, 2H), 7.89-7.92 (m, 1H), 8.02-8.05 (m, 1H), 8.62 (s, 1H).

< Example  13> 3- (4- (3- Chlorophenyl Preparation of Piperazin-1-yl) piperidin-4-yl-1-naphthoate

Step 1

It was carried out in the same manner as step 1 of Example 2.

Step 2

The desired compound was obtained in the same manner as Step 2 of Example 2, except that 1-naphthoic acid chloride was used (yield: 47%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.75 (m, 3H), 2.80-3.15 ( m, 8H), 4.00-4.15 (m, 1H), 4.20-4.35 (m, 1H), 5.15-5.30 (m, 1H), 6.66-6.79 (m, 3H), 7.09 (t, J = 8.2 Hz, 1H), 7.44-7.62 (m, 2H), 7.85-7.89 (m, 2H), 7.92-7.97 (m, 1H), 8.01-8.06 (m, 1H), 8.58 (s, 1H).

Step 3

The same procedure as in Step 3 of Example 2 was carried out to yield 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 98 %).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.90-2.10 (m, 1H), 2.30-2.50 (m, 1H), 2.65-2.85 (m, 2H), 2.90-3.20 (m, 7H), 3.30- 3.60 (m, 2H), 5.00-5.30 (m, 2H), 5.40-5.50 (m, 1H), 6.64-6.75 (m, 3H), 7.07 (t, J = 8.0 Hz, 1H), 7.50-7.65 ( m, 2H), 7.84-7.87 (m, 2H), 7.96-8.00 (m, 1H), 8.02-8.07 (m, 1H), 8.61 (s, 1H).

< Example  14> 3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

Step 1

It was carried out in the same manner as Step 1 of Example 3.

Step 2

Except for using 1-naphthoic acid chloride in the same manner as in Step 2 of Example 3 to obtain the target compound (yield: 45%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.45 (s, 9H), 1.60-1.78 (m, 1H), 1.90-2.00 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.02 (m, 7H), 3.05-3.20 (m, 1H), 3.72 (s, 3H), 4.00-4.10 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.27 (m, 1H), 6.75 -6.83 (m, 4H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.58 (s, 1H) .

Step 3

The same procedure as in Step 3 of Example 3 was carried out to yield 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 92%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.53-1.71 (m, 1H), 1.93-2.01 (m, 1H), 2.59-2.85 (m, 3H), 2.90-3.05 (m, 8H), 3.05- 3.25 (m, 1H), 3.35-3.48 (m, 1H), 3.71 (s, 3H), 5.15-5.27 (m, 1H), 6.72-6.82 (m, 4H), 7.48-7.62 (m, 2H), 7.84-7.88 (m, 2H), 7.92-7.97 (m, 1H), 8.02-8.07 (m, 1H), 8.59 (s, 1H).

< Example  15> 3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-1- Naphthoate  Produce

Step 1

It was carried out in the same manner as step 1 of Example 4.

Step 2

The desired compound was obtained in the same manner as Step 2 of Example 4, except that 1-naphthoic acid chloride was used (yield: 44%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.45 (s, 9H), 1.62-1.78 (m, 1H), 1.92-2.04 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.05 (m, 7H), 3.10-3.25 (m, 1H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.25 (m, 1H), 6.79 -6.87 (m, 3H), 6.91-6.97 (m, 1H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.94 (m, 1H), 8.04-8.07 (m, 1H) , 8.59 (s, 1 H).

Step 3

The same procedure as in Step 3 of Example 4 was followed to obtain 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-1-naphthoate (yield: 99%).

¹¹ H NMR (CDCl ₃ , 300 MHz): δ 1.75-1.95 (m, 1H), 2.00-2.25 (m, 1H), 2.65-2.82 (m, 3H), 2.85-3.10 (m, 8H), 3.20- 3.35 (m, 1H), 3.52-3.57 (m, 1H), 3.81 (s, 3H), 5.33-5.44 (m, 1H), 6.79-6.89 (m, 3H), 6.91-6.98 (m, 1H), 7.48-7.59 (m, 2H), 7.82-7.86 (m, 2H), 7.93-7.96 (m, 1H), 8.05-8.09 (m, 1H), 8.65 (s, 1H).

< Example  16> 3- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl Preparation of 3-carboxylate

Step 1

It carried out in the same manner as Step 1 of Example 12.

Step 2

The target compound was obtained in the same manner as Step 2 of Example 12, except that biphenyl-3-carboxylic acid chloride was used instead of 1-naphthoic acid chloride (yield: 52%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 9H), 1.55-1.77 (m, 1H), 1.91--2.00 (m, 1H), 2.60-2.80 (m, 3H), 2.88- 3.15 (m, 8H), 3.95-4.11 (m, 1H), 4.15-4.30 (m, 1H), 5.13-5.24 (m, 1H), 6.77-6.96 (m, 4H), 7.35-7.51 (m, 3H ), 7.58-7.67 (m, 4 H), 8.06-8.12 (m, 2 H).

Step 3

The same procedure as in Step 3 of Example 12 was conducted to obtain 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 97%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.75 (m, 1H), 1.85--2.10 (m, 1H), 2.15-2.45 (m, 2H), 2.55-2.80 (m, 4H), 2.89 -2.99 (m, 5H), 3.10-3.20 (m, 1H), 3.30-3.55 (m, 1H), 5.15-5.21 (m, 1H), 6.76-6.82 (m, 2H), 6.86-6.94 (m, 2H), 7.35-7.48 (m, 3H), 7.58-7.66 (m, 4H), 8.08-8.11 (m, 2H).

< Example  17> 3- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl Preparation of 3-carboxylate

Step 1

It was carried out in the same manner as Step 1 of Example 13.

Step 2

Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 13 to obtain the target compound (yield: 48%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.46 (s, 9H), 1.55-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.60-2.78 (m, 3H), 2.80-2.95 (m, 2H), 2.99-3.08 (m, 6H), 3.95-4.10 (m, 1H), 4.15-4.35 (m, 1H), 5.12-5.23 (m, 1H), 6.65-6.81 (m, 3H) , 7.11 (t, J = 8.2 Hz, 1H), 7.38-7.51 (m, 3H), 7.58-7.67 (m, 4H), 8.02-8.12 (m, 2H).

Step 3

Example 13 steps 3 and performing the same method of 3 - (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate was obtained ( Yield: 99%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.65-1.90 (m, 1H), 1.95-2.15 (m, 1H), 2.63-2.77 (m, 3H), 2.80-2.92 (m, 3H), 3.00- 3.09 (m, 4H), 3.15-3.35 (m, 1H), 3.45-3.60 (m, 1H), 4.65-4.90 (m, 1H), 5.25-5.40 (m, 1H), 6.77-6.81 (m, 3H ), 7.11 (t, J = 8.2 Hz, 1H), 7.37-7.50 (m, 3H), 7.56-7.67 (m, 4H), 8.10 (d, J = 8.6 Hz , 2H).

< Example  18> 3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3- Carboxylate  Produce

Step 1

It carried out in the same manner as Step 1 of Example 14.

Step 2

Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 14 to obtain the target compound (yield: 27%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.85-1.97 (m, 1H), 2.62-2.76 (m, 3H), 2.85-3.97 (m, 8H), 3.74 (s, 3H), 3.95-4.06 (m, 1H), 4.18-4.35 (m, 1H), 5.14-5.22 (m, 1H), 6.77-6.85 (m, 4H), 7.37 -7.49 (m, 3H), 7.61-7.66 (m, 4H), 8.08 (d, J = 8.3 Hz , 2H).

Step 3

The same procedure as in Step 3 of Example 14 was followed to obtain 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 66%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.57-1.70 (m, 1H), 1.90-2.00 (m, 1H), 2.58-2.82 (m, 5H), 2.90-3.00 (m, 6H), 3.10- 3.20 (m, 1H), 3.36-3.44 (m, 1H), 3.73 (s, 3H), 5.09-5.22 (m, 1H), 6.75-6.85 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.66 (m, 4H), 8.07-8.11 (dd, J = 6.4 Hz & 2 Hz , 2H).

< Example  19> 3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

Step 1

It was carried out in the same manner as Step 1 of Example 15.

Step 2

Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 15 to obtain the target compound (yield: 40%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.45 (s, 9H), 1.63-1.79 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.74 (m, 3H), 2.85-3.05 (m, 7H), 3.06-3.20 (m, 1H), 3.82 (s, 3H), 3.95-4.03 (m, 1H), 4.17-4.30 (m, 1H), 5.15-5.22 (m, 1H), 6.80 -6.90 (m, 3H), 6.91-6.98 (m, 1H), 7.36-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.08-8.11 (m, 2H).

Step 3

The same procedure as in Step 3 of Example 15 was followed to obtain 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 99%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72-1.96 (m, 1H), 2.00-2.22 (m, 1H), 2.64-2.80 (m, 3H), 2.82-3.08 (m, 8H), 3.36- 3.60 (m, 2H), 3.28-3.36 (m, 1H), 3.48-3.64 (m, 1H), 3.82 (s, 3H), 5.30-5.42 (m, 1H), 6.80-6.89 (m, 3H), 6.90-7.01 (m, 1H), 7.34-7.49 (m, 3H), 7.57-7.66 (m, 4H), 8.12-8.16 (m, 2H).

< Example  20> Preparation of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate

Step 1

It carried out in the same manner as Step 1 of Example 12.

Step 2

The desired compound was obtained in the same manner as Step 2 of Example 12, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 46%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.80--2.00 (m, 1H), 2.55-2.75 (m, 3H), 2.80- 3.15 (m, 8H), 3.95-4.10 (m, 1H), 4.15-4.30 (m, 1H), 5.05-5.20 (m, 1H), 6.77-7..07 (m, 8H), 7.15-7.26 ( m, 1H), 7.35-7.42 (t, J = 7.8 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H).

Step 3

The same procedure as in Step 3 of Example 12 was carried out to yield 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield) : 98%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.68-1.90 (m, 1H), 1.95--2.10 (m, 1H), 2.60-2.75 (m, 3H), 2.80-2.90 (m, 2H), 2.95 -3.10 (m, 6H), 3.15-3.30 (m, 1H), 3.45-3.54 (m, 1H), 5.22-5.33 (m, 1H), 6.77-6.86 (m, 4H), 6.88-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.43 (m, 2H), 7.98-8.05 (m, 2H).

< Example  21> 3- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-4-yl-4- Phenoxybenzoate Manufacture

Step 1

It was carried out in the same manner as Step 1 of Example 13.

Step 2

A target compound was obtained in the same manner as Step 2 of Example 13, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 33%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.45 (s, 9H), 1.63-1.70 (m, 1H), 1.85-1.95 (m, 1H), 2.58-2.74 (m, 3H), 2.84-2.96 (m, 2H), 3.02-3.08 (m, 6H), 3.90-4.07 (m, 1H), 4.15-4.30 (m, 1H), 5.11-5.20 (m, 1H), 6.71-6.81 (m, 3H) , 6.94-7.00 (m, 2H), 7.04-7.22 (m, 4H), 7.35-7.42 (m, 2H), 7.96-8.05 (m, 2H).

Step 3

The same procedure as in Step 3 of Example 13 was followed to obtain 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 63%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.50-1.70 (m, 1H), 1.85-2.02 (m, 1H), 2.56-2.78 (m, 6H), 2.84-2.96 (m, 2H), 3.00- 3.08 (m, 3H), 3.10-3.20 (m, 1H), 3.35-3.45 (m, 1H), 5.05-5.20 (m, 1H), 6.69-6.81 (m, 3H), 6.95-7.01 (m, 2H ), 7.04-7.20 (m, 4H), 7.38 (t, J = 8.1 Hz, 2H), 7.96-8.00 (dd, J = 8.7 Hz & 1.7 Hz, 2H).

< Example  22> 3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-4- Of phenoxybenzoate  Produce

Step 1

It carried out in the same manner as Step 1 of Example 14.

Step 2

The desired compound was obtained in the same manner as Step 2 of Example 14, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 33%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.45 (s, 9H), 1.55-1.80 (m, 1H), 1.85--2.04 (m, 1H), 2.64-2.75 (m, 3H), 2.86- 3.96 (m, 8H), 3.74 (s, 3H), 3.98-4.05 (m, 1H), 4.17-4.20 (m, 1H), 5.08-5.17 (m, 1H), 6.77-6.94 (m, 4H), 6.95-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.33-7.42 (m, 2H), 7.93-8.00 (m, 2H).

Step 3

The same procedure as in Step 3 of Example 14 was followed to obtain 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield) : 98%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.55-1.75 (m, 1H), 1.90-2.05 (m, 1H), 2.30-2.50 (m, 2H), 2.60-2.80 (m, 4H), 2.84- 3.00 (m, 5H), 3.05-3.20 (m, 1H), 3.35-3.45 m, 1H), 3.74 (s, 3H), 5.08-5.20 (m, 1H), 6.76-6.86 (m, 4H), 6.94 -7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.42 (m, 2H), 7.96-8.03 (m, 2H).

< Example  23> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-3-yl-2- Naphthoate  Produce

4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate (48 mg, 0.11 mmol) and triethylamine prepared in Example 1 ( 0.04 mL, 0.29 mmol) was dissolved in dichloromethane (1.5 mL). Known methods [Nowich, JS et al, J. Org . Chem , 1992, 57, 7364-7366] (S) -methyl 2-isocyanatophenylpropanoate (0.13 mmol) prepared from phenylalanine methylester was added to the reaction and stirred at room temperature for 3 hours. Dilute the reaction with ethyl acetate (10 mL), wash with water and then with Na ₂ SO ₄ . Water in the organic layer was removed. Then, the organic solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: hexane = 2: 3) to obtain the target compound (yield: 93%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.85 (m, 2H), 2.17-2.25 (m, 2H), 2.68-2.82 (m, 6H), 2.92-3.07 (m, 14H), 3.09- 3.25 (m, 4H), 3.75 (s, 6H), 3.80-4.05 (m, 4H), 4.77-4.85 (m, 2H), 4.94-4.99 (m, 2H), 5.34-5.43 (m, 2H), 6.72-6.79 (m, 4H), 6.84-6.92 (m, 4H), 7.71-7.15 (m, 4H), 7.22-7.32 (m, 6H), 7.52-7.62 (m, 4H), 7.86-7.90 (m , 4H), 7.91-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).

< Example  24> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane  -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 82%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.65-1.83 (m, 2H), 2.16-2.25 (m, 2H), 2.65-2.85 (m, 6H), 2.90-3.04 (m, 14H), 3.06 -3.21 (m, 4H), 3.74 (s, 6H), 3.75 (s, 6H), 3.77-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.94-4.97 (m, 2H), 5.34 -5.41 (m, 2H), 6.74-6.85 (m, 8H), 7.12-7.18 (m, 4H), 7.22-7.35 (m, 6H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.91-7.96 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H).

< Example  25> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-3-yl-2- Naphthoate  Produce

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23, the target compound was obtained (yield: 95%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.69-1.85 (m, 2H), 2.15-2.25 (m, 2H), 2.65- 2.85 (m, 4H), 2.90-2.98 (m, 4H), 3.01 -3.10 (m, 12H), 3.15-3.23 (m, 4H), 3.71 (s, 3H), 3.76 (s, 3H), 3.80-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.90 -5.00 (m, 2H), 5.30-5.45 (m, 2H), 6.65-6.80 (m, 4H), 7.05-7.16 (m, 6H), 7.21-7.35 (m, 8H), 7.52-7.62 (m, 4H), 7.87-7.90 (m, 4H), 7.95-7.98 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H).

< Example  26> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 23 to obtain the target compound (yield: 97% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.60-1.80 (m, 2H), 2.15-2.20 (m, 2H), 2.66-2.80 (m, 6H), 2.85-3.04 (m, 14H), 3.05 -3.23 (m, 4H), 3.75 (s, 6H), 3.80-4.02 (m, 4H), 4.75-4.85 (m, 2H), 4.95-5.00 (m, 2H), 5.30-5.40 (m, 2H) , 6.75-6.83 (m, 4H), 6.85-6.95 (m, 24H), 7.08-7.20 (m, 4H), 7.21-7.31 (m, 6H), 7.34-7.54 (m, 6H), 7.59-7.72 ( m, 8H), 8.08 (d, J = 8.5 Hz, 4H).

< Example  27> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane  -2 days Cabamo 1) piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 69%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.60-1.80 (m, 2H), 2.10-2.20 (m, 2H), 2.64-2.80 (m, 6H), 2.85-3.00 (m, 14H), 3.05- 3.22 (m, 4H), 3.73 (s, 6H), 3.75 (s, 6H), 3.80-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.95-5.05 (m, 2H), 5.30- 5.40 (m, 2H), 6.75-6.85 (m, 8H), 7.08-7.20 (m, 4H), 7.25-7.34 (m, 6H), 7.36-7.51 (m, 6H), 7.60-7.67 (m, 8H ), 8.09 (d, J = 8.4 Hz, 4H).

< Example  28> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2 days Cabamo 1) piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 35%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.60-1.80 (m, 2H), 2.14-2.25 (m, 2H), 2.64- 2.79 (m, 6H), 2.85-3.00 (m, 4H), 3.02 -3.10 (m, 10H), 3.13-3.23 (m, 4H), 3.76 (s, 6H), 3.78-4.14 (m, 4H), 4.76-4.84 (m, 2H), 4.91-4.97 (m, 2H) , 5.30-5.38 (m, 2H), 6.69-6.82 (m, 6H), 7.08-7.19 (m, 6H), 7.23-7.32 (m, 6H), 7.34-7.50 (m, 6H), 7.61-7.71 ( m, 8H), 8.09 (d, J = 8.6 Hz, 4H).

< Example  29> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (4-fluorophenyl) prepared in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 76%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.50-1.74 (m, 2H), 2.06-2.20 (m, 2H), 2.60-2.75 (m, 6H), 2.84-3.04 (m, 14H), 3.05- 3.24 (m, 4H), 3.74 (s, 6H), 3.75-4.00 (m, 4H), 4.75-4.85 (m, 2H), 4.93-5.00 (m, 2H), 5.25-5.35 (m, 2H), 6.75-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.03-7.09 (m, 4H), 7.11-7.23 (m, 6H), 7.24-7.36 (m, 6H), 7.38-7.42 (m , 4H), 7.95 -8.01 (m, 4H).

< Example  30> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 68%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.72 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.80 (m, 6H), 2.85-3.01 (m, 14H), 3.04 -3.25 (m, 4H), 3.70 (s, 6H), 3.74 (s, 6H), 3.76-4.00 (m, 4H), 4.75-4.85 (m, 2H), 4.93-5.00 (m, 2H), 5.25 -5.35 (m, 2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.04-7.19 (m, 8H), 7.20-7.33 (m, 8H), 7.36-7.41 (m, 4H), 7.95-8.01 (m, 4H).

< Example  31> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2 days Cabamo 1) piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (3-chlorophenyl) obtained in Example 10 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 97%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.75 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.75 (m, 6H), 2.84-2.96 (m, 4H), 2.98- 3.10 (m, 10H), 3.11-3.23 (m, 4H), 3.70 (s, 3H), 3.74 (s, 3H), 3.76-4.00 (m, 4H), 4.73-4.83 (m, 2H), 4.90- 4.96 (m, 2H), 5.23-5.33 (m, 2H), 6.67-6.81 (m, 6H), 6.95-7.02 (m, 4H), 7.04-7.35 (m, 18H), 7.36-7.42 (m, 4H ), 7.95-8.00 (m, 4H).

< Example  32> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method [Nowich] , JS et al, J. Org . Example 23, except that (S) -methyl 2-isocyanato-4-methylpentaneoate (0.13 mmol) prepared from leucine methylester was reacted with Chem, 1992, 57, 7364-7366. The target compound was obtained in the same manner as in (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.98-0.99 (m, 12H), 1.50-1.89 (m, 8H), 2.20-2.28 (m, 2H), 2.75-2.89 (m, 6H), 2.90 -3.14 (m, 14H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m, 2H), 4.90-4.95 (m, 2H) , 5.36-5.45 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m, 4H), 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.99 ( m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).

< Example  33> 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-jade Sopentane -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 32 to obtain the target compound (yield: 88%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.97 (d, J = 6.2 Hz, 12H), 1.50-1.78 (m, 8H), 2.20-2.27 (m, 2H), 2.78-2.89 (m, 6H) , 2.90-3.15 (m, 14H), 3.71 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.04-4.15 (m, 2H), 4.49-4.58 (m, 2H) , 4.90-5.00 (m, 2H), 5.37-5.45 (m, 2H), 6.74-6.81 (m, 8H), 7.52-7.61 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.99 ( m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).

< Example  34> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 32 to obtain the target compound (yield: 96%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.98 (d, J = 6.0 Hz, 12H), 1.50-1.89 (m, 8H), 2.20-2.26 (m, 2H), 2.75-2.90 (m, 6H) , 2.93-3.12 (m, 14H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m, 2H), 4.90-5.00 (m, 2H), 5.35-5.45 (m, 2H), 6.65-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz, 2H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H) , 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).

< Example  35> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane Preparation of 2-ylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32 to obtain the target compound (yield: 99% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.97 (d, J = 6.0 Hz, 12H), 1.50-1.80 (m, 8H), 2.19-2.35 (m, 2H), 2.74-2.90 (m, 6H) , 2.93-3.12 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m, 2H), 4.04-4.15 (m, 2H), 4.48-4.57 (m, 2H), 4.91-4.95 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.83 (m, 4H), 6.86-6.93 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).

< Example  36> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2 days Cabamo I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32 to obtain the target compound (yield: 76% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.93 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 6H), 1.50- 1.77 (m, 8H), 2.15-2.25 (m, 2H), 2.72-2.90 (m, 6H), 2.94-3.10 (m, 14H), 3.72 (s, 3H), 3.73 (m, 3H), 3.75 ( s, 6H), 3.85-3.95 (m, 2H), 4.00-4.10 (m, 2H), 4.45-4.58 (m, 2H), 4.90-4.95 (m, 2H), 5.30-5.40 (m, 2H), 6.76-6.84 (m, 8H), 7.35-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).

< Example  37> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2 days Cabamo I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32, the target compound was obtained (yield: 85%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.93 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.3 Hz, 6H), 1.50- 1.84 (m, 8H), 2.15-2.25 (m, 2H), 2.75-2.85 (m, 6H), 2.93-3.10 (m, 14H), 3.72 s, 3H), 3.76 (s, 3H), 3.85-3.95 (m, 2H), 4.00-4.10 (m, 2H), 4.45-4.60 (m, 2H), 4.94-5.00 (m, 2H), 5.31-5.39 (m, 2H), 6.68-6.80 (m, 6H) , 7.10 (t, J = 8.1 Hz, 2H), 7.35-7.54 (m, 6H), 7.59-7.71 (m, 8H), 8.07-8.11 (m, 4H).

< Example  38> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 96%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.96 (d, J = 6.3 Hz, 12H), 1.49-1.75 (m, 8H), 2.15-2.25 (m, 2H), 2.74-2.85 (m, 6H) , 2.90-3.09 (m, 14H), 3.72 s, 3H), 3.75 (s, 3H), 3.82-3.92 (m, 2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.90-4.95 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 6,95-7.00 (m, 4H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).

< Example  39> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl Preparation of -1-oxopentan-2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 93%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.96 (d, J = 6.4 Hz, 12H), 1.49-1.74 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H) , 2.93-3.10 (m, 14H), 3.74 (s, 12H), 3.85-3.93 (m, 2H), 3.95-4.06 (m, 2H), 4.45-4.58 (m, 2H), 4.89-4.93 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.03-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).

< Example  40> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl Preparation of -1-oxopentan-2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (3-chlorophenyl) obtained in Example 10 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 43%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.96 (d, J = 6.3 Hz, 12H), 1.50-1.80 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H) , 2.89-3.09 (m, 14H), 3.75 (s, 6H), 3.84-3.92 (m, 2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.85-4.93 (m, 2H), 5.24-5.34 (m, 2H), 6.69-6.80 (m, 6H), 6.96-00 (m, 4H), 7.05-7.22 (m, 8H), 7.36-7.42 (m, 4H), 7.95-8.01 (m, 4H).

< Example  41> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method [Nowich] , JS et al, J. Org . Chem, 1992, 57, 7364-7366], except that the reaction of (S) -methyl 2-isocyanato-4-methylbutanate (0.13 mmol) prepared from methyl esters valine with The target compound was obtained in the same manner (yield: 97%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.9 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 1.78-1.87 (m, 2H), 2.13-2.29 (m , 4H), 2.75-2.89 (m, 6H), 2.90-3.02 (m, 12H), 3.03-3.16 (m, 2H), 3.76 (s, 6H), 3.88-3.98 (m, 2H), 4.05-4.13 (m, 2H), 4.44-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.35-5.45 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m, 4H) , 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).

< Example  42> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Preparation of Piperidin-3-yl-2-naphthoate

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 41 to obtain the target compound (yield: 75%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.9 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.29 (m , 4H), 2.75-2.89 (m, 6H), 2.90-2.96 (m, 12H), 3.00-3.17 (m, 2H), 3.72 (s, 6H), 3.76 (s, 6H), 3.90-4.00 (m , 2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m, 2H), 5.02-5.06 (m, 2H), 5.36-5.44 (m, 2H), 6.74-6.82 (m, 8H), 7.52 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).

< Example  43> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane Preparation of 2-ylcarbamoyl) piperidin-3-yl-2-naphthoate

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 41, the target compound was obtained (yield: 84%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.28 (m , 4H), 2.73-2.88 (m, 6H), 2.90-3.14 (m, 14H), 3.77 (s, 6H), 3.90-4.00 (m, 2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.37-5.45 (m, 2H), 6.66-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz, 2H) ,, 7.52-7.62 ( m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).

< Example  44> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 41 to obtain the target compound (yield: 91% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H), 1.70-1.82 (m, 2H), 2.10-2.30 (m , 4H), 2.73-2.88 (m, 6H), 2.90-2.99 (m, 12H), 3.00-3.14 (m, 2H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.04-4.14 ( m, 2H), 4.44-4.50 (m, 2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.77-6.83 (m, 4H), 6.85-6.94 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.08-8.11 (m, 4H).

< Example  45> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 41 to obtain the target compound (yield: 87% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.98 (d, J = 6.8 Hz, 6H), 1.70-1.85 (m, 2H), 2.11-2.26 (m , 4H), 2.73-2.89 (m, 6H), 2.90-3.00 (m, 12H), 3.01-3.14 (m, 2H), 3.73 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.00-4.12 (m, 2H), 4.44-4.50 (m, 2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.76-6.84 (m, 8H), 6.85- 6.94 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J = 8.3 Hz, 4H).

< Example  46> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate, the procedure was carried out in the same manner as in Example 41, to obtain the target compound (yield: 77% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 6H), 1.73- 1.88 (m, 2H), 2.05-2.28 (m, 4H), 2.72-2.85 (m, 6H), 2.90-3.00 (m, 2H), 3.04-3.12 (m, 12H), 3.72 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m 2H), 4.02-4.13 (m, 2H), 4.39-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.32-5.40 (m, 2H) , 6.68-6.80 (m, 6H), 7.10 (t, J = 8.1 Hz, 2H), 7.36-7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.10 (m, 4H).

< Example  47> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Preparation of Piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 41 to obtain the target compound (yield: 82%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.93 (d, J = 6.8 Hz, 6H), 0.97 (d, J = 6.8 Hz, 6H), 1.68-1.80 (m, 2H), 2.11-2.20 (m , 4H), 2.70-2.82 (m, 6H), 2.93-3.11 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.50 ( m, 2H), 5.01-5.05 (m, 2H), 5.28-5.36 (m, 2H), 6.76-6.83 (m, 4H), 6.87-7.04 (m, 8H), 7.05-7.08 (m, 4H), 7.16-7.21 (m, 2H), 7.35-7.41 (m, 4H), 7.97-8.01 (m, 4H).

< Example  48> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxo Butane-2- Ilkaba Mole Piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 41 to obtain the target compound (yield: 80%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91 -0.98 (m, 12H), 1.65-1.76 (m, 2H), 2.11-2.21 (m, 4H), 2.70-2.85 (m, 6H), 2.90 -3.11 (m, 14H), 3.74 (s, 6H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.48 (m, 2H), 5.01- 5.05 (m, 2H), 5.28-5.38 (m, 2H), 6.76-6.84 (m, 8H), 6.95-7.00 (m, 4H), 7.05-7.08 (m, 4H), 7.15-7.21 (m, 2H ), 7.35-7.41 (m, 4H), 7.97-8.00 (m, 4H).

< Example  49> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-3-yl-2- Naphthoate  Produce

48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method (Nowich , JS et al, J. Org.Chem, 1992, 57, 7364-7366), except for reacting (S) -methyl 2-isocyanatopropanoate (0.13 mmol) prepared from alanine methylester. Was carried out in the same manner as in Example 23 to obtain the target compound (yield: 83%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.78-1.85 (m, 2H), 2.20-2.30 (m , 2H), 2.75-2.89 (m, 6H), 2.95-3.00 (m, 12H), 3.01-3.15 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.87-3.97 (m , 2H), 4.03-4.13 (m, 2H), 4.45-4.57 (m, 2H), 5.11-5.17 (m, 2H), 5.35-5.45 (m, 2H), 6.73-6.80 (m, 4H), 6.83 -6.91 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H) .

< Example  50> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2 days Cabamo I) piperidin-3-yl-2- Naphthoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 49 to obtain the target compound (yield: 88%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.75-1.85 (m, 2H), 2.20-2.30 (m , 2H), 2.75-2.89 (m, 6H), 2.94-2.96 (m, 12H), 2.99-3.16 (m, 2H), 3.71 (s, 6H), 3.77 (s, 6H), 3.87-3.97 (m , 2H), 4.03- 4.13 (m, 2H), 4.45-4.55 (m, 2H), 5.11-5.16 (m, 2H), 5.36-5.45 (m, 2H), 6.73-6.81 (m, 8H), 7.51 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).

.

< Example  51> 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Preparation of Piperidin-3-yl-2-naphthoate

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 49, the target compound was obtained (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.73-1.86 (m, 2H), 2.20-2.29 (m , 2H), 2.75-2.89 (m, 6H), 2.93-3.12 (m, 14H), 3.74 (s, 3H), 3.78 (s, 3H), 3.85-3.95 (m, 2H), 4.04-4.12 (m , 2H), 4.45-4.55 (m, 2H), 5.10-5.14 (m, 2H), 5.36-5.44 (m, 2H), 6.65-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz 2H) , 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).

< Example  52> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.70-1.83 (m, 2H), 2.15-2.28 (m , 2H), 2.74-2.86 (m, 6H), 2.91-3.13 (m, 14H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m, 2H), 4.02-4.08 (m , 2H), 4.45-4.56 (m, 2H), 5.10-5.12 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.82 (m, 4H), 6.86-6.93 (m, 4H), 7.36 -7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).

< Example  53> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2 days Cabamo I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49 to obtain the target compound (yield: 88% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.19-2.28 (m , 2H), 2.75-2.85 (m, 6H), 2.90-3.14 (m, 14H), 3.73 (s, 6H), 3.77 (s, 6H), 3.85-3.95 (m, 2H), 4.00-4.08 (m , 2H), 4.45-4.56 (m, 2H), 5.08-5.13 (m, 2H), 5.30-5.40 (m, 2H), 6.76-6.84 (m, 8H), 7.36-7.49 (m, 6H), 7.60 -7.67 (m, 8 H), 8.08-8.11 (m, 4H).

< Example  54> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2 days Cabamo 1) piperidin-3-yl- Biphenyl -4-carboxyl Rate  Produce

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49, the target compound was obtained (yield: 100%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.17-2.28 (m , 2H), 2.78-2.85 (m, 6H), 2.90-3.03 (m, 4H) 3.04-3.11 (m, 10H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m, 2H), 4.02-4.10 (m, 2H), 4.45-4.56 (m, 2H), 5.10-5.15 (m, 2H), 5.31-5.38 (m, 2H), 6.88-6.80 (m, 6H), 7.10 ( t, J = 8.1 Hz, 2H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.07-8.11 (m, 4H).

< Example  55> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 49 to obtain the target compound (yield: 84%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.17-2.21 (m , 2H), 2.75-2.81 (m, 6H), 2.90-3.07 (m, 14H) 3.74 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m, 2H), 4.00-4.07 (m, 2H), 4.45-4.55 (m, 2H), 5.09-5.13 (m, 2H), 5.26-5.35 (m, 2H), 6.78-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.04- 7.09 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).

< Example  56> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxopropane-2- Ilkaba Mole Piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 49 to obtain the target compound (yield: 95%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.15-2.25 (m , 2H), 2.72-2.84 (m, 6H), 2.88-3.07 (m, 14H) 3.73 (s, 3H), 3.74 (s, 6H), 3.76 (s, 3H), 3.85-3.95 (m, 2H) , 3.91-4.05 (m, 2H), 4.45-4.53 (m, 2H), 5.09-5.14 (m, 2H), 5.26-5.35 (m, 2H), 6.78-6.85 (m, 8H), 6.95-7.01 ( m, 4H), 7.04-7.09 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).

< Example  57> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamo I) piperidin-3-yl-2- Naf Preparation of Toate

48 mg (0.11 mmol) and 2-fluorophenyl of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 A target compound was obtained in the same manner as in Example 23, except that 18 mg (0.13 mmol) of isocyanate was reacted (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.83-1.96 (m, 1H), 2.27-2.36 (m, 1H), 2.78-2.96 (m, 3H), 2.97-3.03 (m, 6H), 3.14- 3.28 (m, 2H), 3.96-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.52 (m, 1H), 6.71 (d, J = 3.8 Hz, 1H), 6.73-6.80 ( m, 2H), 6.84-6.92 (m, 2H), 6.94-7.05 (m, 1H), 7.07-7.15 (m, 2H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 (m, 1 H), 8.03-8.11 (m, 2 H), 8.60 (s, 1 H).

< Example  58> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl-2- Naf Preparation of Toate

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 57 to obtain the target compound (yield: 100%).

¹ H ¹ H NMR (CDCl ₃ , 300 MHz): δ 1.82- 1.96 (m, 1H), 2.27-2.37 (m, 1H), 2.81-2.86 (m, 2H), 2.89-3.05 (m, 7H) , 3.14-3.29 (m, 2H), 3.71 (s, 3H), 3.94-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.42-5.52 (m, 1H), 6.70 (d, J = 4.1 Hz, 1H), 6.73-6.82 (m, 4H), 6.94-7.15 (m, 3H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H) , 8.03-8.12 (m, 2H), 8.60 (s, 1H).

< Example  59> 4- (4- (3- Chlorophenyl ) Piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2- Naf Preparation of Toate

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 57, the target compound was obtained (yield: 75%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.82-1.96 (m, 1H), 2.26-2.37 (m, 1H), 2.78-2.89 (m, 3H), 2.90-2.99 (m, 2H), 3.02- 3.10 (m, 4H), 3.14-3.27 (m, 2H), 3.95-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.50 (m, 1H), 6.66-6.80 (m, 4H ), 6.95-7.15 (m, 4H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.12 (m, 2H), 8.60 (s , 1H).

< Example  60> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl- Bype Preparation of Neyl-4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.77-1.91 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.89 (m, 3H), 2.95-3.07 (m, 6H), 3.12- 3.26 (m, 2H), 3.95-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.37-5.45 (m, 1H), 6.71 (d, J = 4.1 Hz, 1H), 6.75-6.83 ( m, 2H), 6.86-6.91 (m, 2H), 6.92-7.15 (m, 3H), 7.36-7.49 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H).

< Example  61> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl- Bype Preparation of Neyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.78-1.90 (m, 1H), 2.25-2.32 (m, 1H), 2.80-2.90 (m, 4H), 2.95-3.07 (m, 5H), 3.12 -3.27 (m, 2H), 3.73 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.37-5.44 (m, 1H), 6.70 (d, J = 3.8 Hz , 1H), 6.75-6.84 (m, 4H), 6.96-7.15 (m, 3H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H).

< Example  62> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl- Biphenyl -4- Carboxylate  Produce

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57, the target compound was obtained (yield: 86%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.77-1.90 (m, 1H), 2.24-2.33 (m, 1H), 2.75-2.84 (m, 3H), 2.86-3.03 (m, 2H), 2.86- 3.03 (m, 2H), 3.06-3.10 (m, 4H), 3.12- 3.25 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.37-5.44 (m, 1H ), 6.68-6.80 (m, 4H), 6.95-7.15 (m, 4H), 7.36-7.49 (m, 3H), 7.60-7.68 (m, 4H), 8.04-8.11 (m, 3H).

< Example  63> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl-4- Phenyl Preparation of benzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenylbenzoate in the same manner as in Example 57 to obtain the target compound (yield: 80%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.73- 1.86 (m, 1H), 2.23-2.32 (m, 1H), 2.77-2.90 (m, 4H), 2.92-3.08 (m, 5H), 3.10 -3.24 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.32-5.42 (m, 1H), 6.68 (d, J = 3.7 Hz, 1H), 6.78-6.83 (m, 2H), 6.87-7.26 (m, 8H), 7.39 (t, J = 7.8 Hz, 4H), 7.97-8.09 (m, 3H).

< Example  64> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-3-yl-4- Phenyl Preparation of benzoate

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenylbenzoate in the same manner as in Example 57 to obtain the target compound (yield: 100%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72- 1.85 (m, 1H), 2.23-2.32 (m, 1H), 2.78-2.90 (m, 6H), 2.92-3.05 (m, 6H), 3.10- 3.24 (m, 2H), 3.74 (s, 3H), 3.93-4.04 (m, 1H), 4.08-4.15 (m, 1H), 5.32-5.41 (m, 1H), 6.68 (d, J = 3.8 Hz, 1H), 6.78-6.85 (m, 4H), 6.95-7.01 (m, 3H), 7.03-7.14 (m, 4H), 7.15-7.22 (m, 1H), 7.35-7.42 (m, 2H), 7.97 -8.09 (m, 3 H).

< Example  65> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl-2- Naphthoate  Produce

48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and 3-methoxyphenyl A target compound was obtained in the same manner as in Example 23, except that 20 mg (0.13 mmol) of isocyanate was reacted (yield: 93%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.80- 1.91 (m, 1H), 2.25-2.35 (m, 1H), 2.77-3.03 (m, 9H), 3.08-3.22 (m, 2H), 3.79 ( s, 3H), 3.95-4.05 (m, 1H), 4.13-4.20 (m, 1H), 5.40-5.48 (m, 1H), 6.56-6.65 (m, 2H), 6.73-6.81 (m, 2H), 6.83-6.93 (m, 3H), 7.13-7.28 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.60 (s, 1H ).

< Example  66> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl-2- Naphtho Manufacture of Eight

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 65 except for using the piperazin-1-yl) piperidin-3-yl-2-naphthoate (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.80- 1.90 (m, 1H), 2.22-2.33 (m, 1H), 2.78-3.05 (m, 9H), 3.07-3.22 (m, 2H), 3.71 ( s, 3H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.59-6.64 (m, 2H), 6.73- 6.81 (m, 4H), 6.85-6.90 (m, 1H), 7.13-7.21 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.97 (m, 1H ), 8.02-8.06 (m, 1 H), 8.59 (s, 1 H).

< Example  67> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl-2- Naphtho Manufacture of Eight

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 65, the target compound was obtained (yield: 70%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.80- 1.93 (m, 1H), 2.24-2.32 (m, 1H), 2.75-2.81 (m, 2H), 2.82-2.99 (m, 3H), 3.00 -3.08 (m, 4H), 3.09-3.20 (m, 2H), 3.80 (s, 3H), 3.97-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H) , 6.58-6.80 (m, 5H), 6.85-6.89 (m, 1H), 7.04-7.30 (m, 3H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).

< Example  68> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl- Biphenyl Preparation of 4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65 to obtain the target compound (yield: 97% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.72- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.77-2.88 (m, 3H), 2.90-3.01 (m, 6H), 3.02 -3.18 (m, 2H), 3.79 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.18 (m, 1H), 5.33-5.42 (m, 1H), 6.59-6.65 (m, 2H) , 6.74-6.82 (m, 2H), 6.85-6.94 (m, 3H), 7.12-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07-8.12 ( m, 2H).

< Example  69> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl- Biphenyl Preparation of 4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65 to obtain the target compound (yield: 96% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.73-1.87 (m, 1H), 2.20-2.32 (m, 1H), 2.75-2.90 (m, 3H), 2.92-3.00 (m, 6H), 3.01- 3.21 (m, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95-4.03 (m, 1H), 4.06-4.14 (m, 1H), 5.33-5.41 (m, 1H), 6.58- 6.63 (m, 2H), 6.76-6.88 (m, 5H), 7.13-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.60-7.67 (m, 4H), 8.10 (d, J = 8.1 Hz, 2H).

< Example  70> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65, the target compound was obtained (yield: 42%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.62- 1.85 (m, 1H), 2.24-2.32 (m, 1H), 2.79-2.90 (m, 3H), 2.91-2.98 (m, 2H), 3.05 -3.10 (m, 4H), 3.11-3.21 (m, 1H), 3.73 (s, 3H), 3.81 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.17 (m, 1H), 4.25 -4.35 (m, 1H), 5.35-5.43 (m, 1H), 6.48 (s, 1H), 6.60-6.64 (m, 1H), 6.69-6.80 (m, 3H), 6.83-6.88 (m, 1H) , 7.07-7.22 (m, 3H), 7.37-7.54 (m, 3H), 7.59-7.73 (m, 4H), 8.07-8.12 (m, 2H).

< Example  71> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Preparation of Piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 65 to obtain the target compound (yield: 73%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.70- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.75-2.90 (m, 3H), 2.91-2.99 (m, 6H), 3.02 -3.18 (m, 2H), 3.79 (s, 3H), 3.94-4.02 (m, 1H), 4.06-4.16 (m, 1H), 5.30-5.38 (m, 1H), 6.52 (s, 1H), 6.58 -6.63 (m, 1H), 6.77-7.00 (m, 7H), 7.03-7.10 (m, 2H), 7.11-7.22 (m, 3H), 7.35-7.42 (m, 2H), 7.96-8.02 (m, 2H).

< Example  72> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 65 to obtain the target compound (yield: 89%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.69-1.82 (m, 1H), 2.17-2.27 (m, 1H), 2.74-2.87 (m, 3H), 2.90-2.97 (m, 6H), 3.01- 3.18 (m, 2H), 3.74 (s, 3H), 3.79 (s, 3H), 3.94-4.04 (m, 1H), 4.05-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.57- 6.64 (m, 2H), 6.77-6.88 (m, 5H), 6.95-7.00 (m, 2H), 7.04-7.08 (m, 2H), 7.11-7.21 (m, 3H), 7.34-7.42 (m, 2H ), 7.96-8.02 (m, 2 H).

< Example  73> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-3-yl-2- Naf Preparation of Toate

48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and 4-fluorophenyl Except for reacting 18 mg (0.13 mmol) of isocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 74%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.80- 1.93 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.08 -3.23 (m, 2H), 3.93-4.05 (m, 1H), 4.12-4.18 (m, 1H), 5.41-5.48 (m, 1H), 6.51 (s, 1H), 6.72-6.80 (m, 2H) , 6.84-6.91 (m, 2H), 6.96-7.05 (m, 2H), 7.29-7.35 (m, 2H), 7.52-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 ( m, 1H), 8.03-8.07 (m, 1H), 8.60 (s, 1H).

< Example  74> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-3-yl-2- Naf Preparation of Toate

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 73 to obtain the target compound (yield: 95%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.80- 1.92 (m, 1H), 2.24-2.33 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.05 -3.21 (m, 2H), 3.70 (s, 3H), 3.94-4.06 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.66 (s, 1H), 6.73 -6.81 (m, 4H), 6.96-7.03 (m, 2H), 7.28-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.06 (m, 1H), 8.59 (s, 1H).

< Example  75> 4- (4- (3- Chlorophenyl ) Piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2- Naf Preparation of Toate

4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 73, the target compound was obtained (yield: 71%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.76- 1.89 (m, 1H), 2.25-2.32 (m, 1H), 2.74-2.84 (m, 2H), 2.85-3.00 (m, 3H), 3.02 -3.08 (m, 4H), 3.10-3.21 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.53 (s, 1H) , 6.65-6.79 (m, 3H), 6.97-7.10 (m, 3H), 7.29-7.37 (m, 2H), 7.51-7.63 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).

< Example  76> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-3-yl- Bype Preparation of Neyl-4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 73, except that the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate was used (yield: 88%) ).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.72- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05 -3.19 (m, 2H), 3.92-4.04 (m, 1H), 4.06-4.17 (m, 1H), 5.34-5.42 (m, 1H), 6.59 (s, 1H), 6.76-6.82 (m, 2H) , 6.86-6.94 (m, 2H), 6.95-7.04 (m, 2H), 7.28-7.34 (m, 2H), 7.36-7.49 (m, 3H), 7.59-7.69 (m, 4H), 8.07-8.12 ( m, 2H).

< Example  77> 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamo Work Piperidin-3-yl- Bype Preparation of Neyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 73, except that the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate was used (yield: 86% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.73-1.87 (m, 1H), 2.23-2.31 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05- 3.22 (m, 2H), 3.73 (s, 3H), 3.93-4.04 (m, 1H), 4.06-4.15 (m, 1H), 5.35-5.43 (m, 1H), 6.53 (s, 1H), 6.76- 6.84 (m, 4H), 6.95-7.04 (m, 2H), 7.28-7.35 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H ).

< Example  78> 4- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Preparation of Piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 73, the target compound was obtained (yield: 75%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ1.74- 1.88 (m, 1H), 2.22-2.31 (m, 1H), 2.75-2.89 (m, 3H), 2.90-3.00 (m, 2H), 3.02 -3.18 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.34-5.42 (m, 1H), 6.53 (s, 1H), 6.68-6.80 (m, 3H) , 6.97-7.04 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.69 (m, 4H), 8.07 -8.11 (m, 2 H).

< Example  79> 4- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-3-yl-4- Phenoxy Preparation of Cibenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 73 to obtain the target compound (yield: 80%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.82 (m, 1H), 2.17-2.28 (m, 1H), 2.76-2.88 (m, 3H), 2.90-3.04 (m, 6H), 3.05 -3.17 (m, 2H), 3.91-4.02 (m, 1H), 4.06-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.56 (s, 1H), 6.76-6.83 (m, 2H) , 6.87-6.91 (m, 2H), 6.92-7.02 (m, 4H), 7.04-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.26-7.33 (m, 2H), 7.35-7.41 ( m, 2H), 7.96-8.02 (m, 2H).

< Example  80> 4- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamo 1) piperidin-3-yl-4- Phenoxy Preparation of Cibenzoate

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 73 to obtain the target compound (yield: 89%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.81 (m, 1H), 2.17-2.27 (m, 1H), 2.75-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.04 -3.16 (m, 2H), 3.74 (s, 3H), 3.93-4.03 (m, 1H), 4.05-4.12 (m, 1H), 5.29-5.37 (m, 1H), 6.63 (s, 1H), 6.77 -6.84 (m, 4H), 6.93-7.02 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.25-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H).

< Example  81> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (4- Fluorophenyl Preparation of Piperazin-1-yl) piperidin-3-yl-2-naphthoate

48 mg (0.11 mmol) and 3,5-dichloro 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 A target compound was obtained in the same manner as in Example 23, except that 25 mg (0.13 mmol) of phenylisocyanate was reacted (yield: 80%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.78-1.92 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.94-3.04 (m, 6H), 3.08 -3.23 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.17 (m, 1H), 5.40-5.48 (m, 1H), 6.72-6.79 (m, 2H), 6.81-6.91 (m, 3H), 7.02 (t, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz ,, 2H), 7.51-7.63 (m, 2H), 7.86-7.90 (m, 2H), 7.93-7.96 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).

< Example  82> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (4- Methoxyphenyl Preparation of Piperazin-1-yl) piperidin-3-yl-2-naphthoate

4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 81 to obtain the target compound (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.77-1.90 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.93-3.02 (m, 6H), 3.06 -3.24 (m, 2H), 3.71 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.16 (m, 1H), 5.40-5.46 (m, 1H), 6.51 (s, 1H), 6.73 -6.80 (m, 4H), 6.87 (s, 1H), 7.02 (t, J = 1.8 Hz ,, 1H), 7.35 (d, J = 1.8 Hz ,, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).

< Example  83> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-3-yl-2- I Preparation of Ptoate

4- (4- (3-chlorophenyl) obtained in Example 4 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 81 to obtain the target compound (yield: 70%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.78-1.90 (m, 1H), 2.23-2.34 (m, 1H), 2.72-2.81 (m, 2H), 2.82-2.98 (m, 3H), 3.00 -3.08 (m, 4H), 3.09-3.19 (m, 2H), 3.95-4.06 (m, 1H), 4.09-4.18 (m, 1H), 5.38-5.46 (m, 1H), 6.64-6.76 (m, 3H), 6.87 (s, 1H), 6.87 (s, 1H), 7.01-7.03 (t, J = 1.8 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 1.8 Hz, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.01-8.05 (m, 1H), 8.59 (s, 1H).

< Example  84> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-3-yl- bar Preparation of Diphenyl-4-carboxylate

4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 81 to obtain the target compound (yield: 96% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.72- 1.86 (m, 1H), 2.22-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.02 (m, 6H), 3.04 -3.18 (m, 2H), 3.95-4.04 (m, 1H), 4.08-4.17 (m, 1H), 5.33-5.42 (m, 1H), 6.75-6.81 (m, 2H), 6.85-6.95 (m, 3H), 7.01 (t, J = 1.8 Hz, 1H), 7.33 (d, J = 1.8 Hz ,, 2H), 7.36-7.50 (m, 3H), 7.58-7.68 (m, 4H), 8.06-8.11 ( m, 2H).

< Example  85> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (4- Methoxyphenyl Preparation of Piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate

4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained by the same method as Example 81 except for using the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate (yield: 99). %).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70- 1.85 (m, 1H), 2.20-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.01 (m, 6H), 3.02- 3.18 (m, 2H), 3.72 (s, 3H), 3.95-4.04 (m, 1H), 4.07-4.17 (m, 1H), 5.33-5.41 (m, 1H), 6.75-6.82 (m, 4H), 7.01 (t [singlet overlapped triplet], J = 1.8 Hz, 2H), 7.33 (d, J = 1.8 Hz ,, 2H), 7.35-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06- 8.10 (m, 2 H).

< Example  86> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- ( 3-chlorophenyl ) Piperazin-1-yl) piperidin-3-yl- bye Preparation of Phenyl-4-carboxylate

4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 81, the target compound was obtained (yield: 81%). .

¹ H NMR (CDCl ₃ , 300 MHz): δ1.70- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.74-2.88 (m, 3H), 2.89-2.99 (m, 2H), 3.02 -3.19 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.35-5.42 (m, 1H), 6.67-6.80 (m, 4H), 7.02 (t, J = 1.8 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 1.8 Hz, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07 -8.10 (m, 2 H).

< Example  Preparation of 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate

4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 81 to obtain the target compound (yield: 89%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.89 (m, 1H), 2.19-2.27 (m, 1H), 2.74-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.03 -3.17 (m, 2H), 3.92-4.02 (m, 1H), 4.06-4.13 (m, 1H), 5.28-5.36 (m, 1H), 6.76-6.83 (m, 3H), 6.87-7.02 (m, 5H), 7.03-7.10 (m, 2H), 7.16-7.23 (m, 1H), 7.32 (d, d, J = 1.8 Hz, 2H), 7.34-7.42 (m, 2H), 7.95-8.01 (m , 2H).

< Example  88> 1- (3,5- Dichlorophenylcarbamoyl ) -4- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-3-yl-4- Of phenoxybenzoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-43yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 81 to obtain the target compound (yield: 89%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.66- 1.78 (m, 1H), 2.16-2.25 (m, 1H), 2.74-2.84 (m, 3H), 2.86-3.03 (m, 6H), 3.04- 3.16 (m, 2H), 3.74 (s, 3H), 3.92-4.02 (m, 1H), 4.05-4.14 (m, 1H), 5.28-5.37 (m, 1H), 6.76-6.83 (m, 4H), 6.94-7.00 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.22 (m, 1H), 7.32 (d, J = 1.8 Hz, 2H), 7.33-7.42 (m, 2H), 7.95 -8.01 (m, 2 H).

< Example  89> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanatophenylpropanoate (0.13 mmol) (yield: 85%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.75 (m, 2H), 1.86-1.98 (m, 2H), 2.65-2.72 (m, 4H), 2.78-2.97 (m, 14H), 3.02- 3.22 (m, 6H), 3.68 (s, 3H), 3.73 (s, 3H), 3.80-4.15 (m, 4H), 4.72-5.04 (m, 2H), 5.05-5.15 (m, 2H), 5.16- 5.26 (m, 21H), 6.75-6.80 (m, 4H), 6.89 (t, J = 8.7 Hz, 4H), 7.12-7.33 (m, 10H), 7.52-7.62 (m, 4H), 7.86-7.89 ( m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).

< Example  90> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2 days Cabamo 1) piperidin-4-yl-1- Naphthoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 89 to obtain the target compound (yield: 93%).

¹ H NMR is shown in Table 2 below.

< Example  91> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3-phenylpropane-2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

4- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 89, the target compound was obtained (yield: 93%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.62-2.73 (m, 4H), 2.76-2.92 (m, 6H), 2.94 -3.22 (m, 14H), 3.69 (s, 3H), 3.73 (s, 3H), 3.80-4.05 (m, 2H), 4.06-4.20 (m, 2H), 4.70-4.90 (m, 2H), 5.00 -5.10 (m, 2H), 5.12-5.25 (m, 2H), 6.67-6.78 (m, 6H), 7.06-7.18 (m, 6H), 7.21-7.33 (m, 6H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H).

< Example  92> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

4- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 89 to obtain the target compound (yield: 90%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.50-1.75 (m, 2H), 1.85-2.00 (m, 2H), 2.64-2.82 (m, 6H), 2.84-2.92 (m, 4H), 2.93 -3.02 (m, 10H), 3.04-3.22 (m, 4H), 3.70 (s, 3H), 3.73 (s, 3H), 3.80-4.13 (m, 4H), 4.71-4.85 (m, 2H), 4.99 -5.05 (m, 2H), 5.08-5.21 (m, 2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 7.11-7.18 (m, 4H), 7.19-7.34 (m, 6H), 7.37-7.50 (m, 6H), 7.61-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.3 Hz & 1.0 Hz, 4H).

< Example  93> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3-phenylpropane-2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 89 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m, 6H), 2.83-2.92 (m, 4H), 2.93 -3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m, 4H), 4.71-4.85 (m, 2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m, 2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H) , 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.6 Hz & 1.2 Hz, 4H).

< Example  94> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3-phenylpropane-2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 89, the target compound was obtained (yield: 100%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m, 6H), 2.83-2.92 (m, 4H), 2.93 -3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m, 4H), 4.71-4.85 (m, 2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m, 2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H) , 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.6 Hz & 1.2 Hz, 4H).

< Example  95> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3- Phenylpropane -2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 89 to obtain the target compound (yield: 85%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.50-1.69 (m, 2H), 1.80-1.92 (m, 2H), 2.60-2.78 (m, 6H), 2.80-2.89 (m, 4H), 2.90 -3.03 (m, 10H), 3.05-3.20 (m, 4H), 3.70 (s, 3H), 3.72 (s, 3H), 3.80-4.13 (m, 4H), 4.71-4.83 (m, 2H), 4.99 -5.17 (m, 4H), 6.75-6.82 (m, 4H), 6.78-6.83 (m, 4H), 6.87-7.00 (m, 8H), 7.04-7.32 (m, 16H), 7.35-7.42 (m, 4H), 7.96-8.00 (m, 4H).

< Example  96> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -1-oxo-3-phenylpropane-2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 89 to obtain the target compound (yield: 90%).

¹¹ H NMR (CDCl ₃ , 300 MHz): δ 1.55-1.70 (m, 2H), 1.85-1.95 (m, 2H), 2.65-2.78 (m, 6H), 2.80-2.90 (m, 4H), 2.91- 3.02 (m, 10H), 3.03-3.13 (m, 4H), 3.70 (s, 3H), 3.72 (m, 3H), 3.74 (s, 6H), 3.80-4.13 (m, 4H), 4.70-4.83 ( m, 2H), 5.00-5.15 (m, 4H), 6.78-6.86 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.20 (m, 8H), 7.21-7.33 (m, 8H), 7.35-7.41 (m, 4 H), 7.95-8.01 (m, 4 H).

< Example  97> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2 days Cabamo 1) piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanato-4-methylpentaneoate (0.13 mmol) (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.87 (d, J = 6.5 Hz 6H), 0.97 (d, J = 6.5 Hz 6H), 1.48-1.78 (m, 8H), 1.95-2.01 (m, 2H ), 2.67-2.80 (m, 4H), 2.83-3.05 (m, 14H), 3.08-3.17 (m, 2H), 3.70 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m, 2H ), 4.10-4.18 (m, 2H), 4.44-4.57 (m, 2H), 4.97-5.04 (m, 2H), 5.18-5.27 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.92 (m, 4H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.59 (s, 2H).

< Example  98> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -1-oxopentan-2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoA in the same manner as in Example 97 to obtain the target compound (yield: 59%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.85 (d, J = 6.4 Hz 6H), 0.97 (d, J = 6.4 Hz 6H), 1.50-1.80 (m, 8H), 1.95-2.03 (m, 2H ), 2.68-2.80 (m, 4H), 2.83-3.02 (m, 14H), 3.03-3.19 (m, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m, 2H), 4.10-4.20 (m, 2H), 4.45-4.55 (m, 2H), 4.96-5.02 (m, 2H), 5.19-5.30 (m, 2H ), 6.74-6.83 (m, 8H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.95 (m, 2H), 8.02-8.05 (m, 2H), 8.59 (s , 2H).

< Example  99> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane - 2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphate , the same procedure as in Example 97 was carried out to obtain the target compound (yield: 81%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.89 (d, J = 6.5 Hz, 6H), 0.97 (d, J = 6.5 Hz, 6H), 1.49-1.75 (m, 8H), 1.90-2.05 (m , 2H), 2.64-2.74 (m, 4H), 2.80-2.92 (m, 6H), 2.94-3.16 (m, 10H), 3.71 (s, 3H), 3.74 (s, 3H), 3.95-4.07 (m , 2H), 4.10-4.18 (m, 2H), 4.46-4.57 (m, 2H), 4.99-5.05 (m, 2H), 5.19-5.30 (m, 2H), 6.66-6.79 (m, 6H), 7.05 -7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).

< Example  100> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97 to obtain the target compound (yield: 75% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H) 0.97 (d, J = 6.4 Hz, 6H), 1.49-1.76 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 4H), 2.83-2.94 (m, 4H), 2.97-3.03 (m, 10H), 3.04-3.13 (m, 2H) , 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m, 2H), 4.10-4.16 (m, 2H), 4.46-4.56 (m, 2H), 4.97-5.03 (m, 2H) , 5.12-5.25 (m, 2H), 6.77-6.85 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.08 (d, J = 8.0 Hz, 4H).

< Example  101> 3- (4- (4- Methoxylophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97 to obtain the target compound (yield: 96% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H) 0.97 (d, J = 6.5 Hz, 6H), 1.50-1.77 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 6H), 2.83-2.94 (m, 4H), 2.95-3.01 (m, 8H), 3.04-3.14 (m, 2H) , 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m, 2H), 4.08-4.15 (m, 2H), 4.45-4.56 (m, 2H), 4.98-5.04 (m, 2H), 5.15-5.25 (m, 2H), 6.77-6.86 (m, 8H), 7.35-7.49 (m, 6H), 7.58-7.67 (m, 8H), 8.07-8.10 (m, 4H).

< Example  102> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -1-oxopentan-2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97, the target compound was obtained (yield: 81%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91-0.98 (m, 12H), 1.45-1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.82 (m, 4H), 2.84 -2.91 (m, 6H), 2.95-3.12 (m, 10H), 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.06 (m, 2H), 4.08-4.15 (m, 2H), 4.45 -4.56 (m, 2H), 4.97-5.06 (m, 2H), 5.10-5.25 (m, 2H), 6.69-6.84 (m, 6H), 7.08-7.15 (m, 2H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.07 (d, J = 8.0 Hz, 4H).

< Example  103> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -One- Oxopentane -2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate A target compound was obtained in the same manner as in Example 97 except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 63%). .

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.92 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H), 1.45- 1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.85 (m, 6H), 2.86-2.94 (m, 4H), 2.97-3.02 (m, 8H), 3.04-3.10 (m, 2H ), 3.72 (s, 3H), 3.73 (s, 3H), 3.90-4.00 (m, 2H), 4.02-4.11 (m, 2H), 4.43-4.55 (m, 2H), 4.95-5.03 (m, 2H) ), 5.09-5.19 (m, 2H), 6.78-6.85 (m, 4H), 6.88-7.01 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).

< Example  104> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -4- methyl -1-oxopentan-2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 97 to obtain the target compound (yield: 62%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.92 (d, J = 6.3 Hz, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.96 (d, J = 6.3 Hz, 6H), 1.50- 1.78 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.80 (m, 6H), 2.83-2.92 (m, 4H), 2.95-3.04 (m, 8H), 3.05-3.10 (m, 2H ), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H), 3.90-4.00 (m, 2H), 4.02-4.13 (m, 2H), 4.42-4.55 (m, 2H), 4.95-5.02 (m, 2H), 5.07-5.20 (m, 2H), 6.78-6.86 (m, 8H), 6.98 (d, J = 8.8 Hz, 4H), 7.07 (d, J = 8.3 Hz, 4H), 7.19 (t, J = 7.4 Hz, 2H 2H), 7.35-7.42 (m, 4H), 7.97-8.01 (m, 4H).

< Example  105> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except that 2-isocyanato-3-methylbutanoate (0.13 mmol) was reacted (yield: 78%).

H NMR (CDCl ₃ , 300 MHz): δ 0.90-1.00 (m, 12H), 1.65-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68- 2.78 (m, 4H), 2.80-2.94 (m, 2H), 2.96-3.04 (m, 12H), 3.08-3.18 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.99- 4.12 (m, 2H), 4.13-4.21 (m, 2H), 4.40-4.49 (m, 2H), 5.10-5.15 (m, 2H), 5.18-5.30 (m, 2H), 6.74-6.82 (m, 4H ), 6.86-6.92 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m ,, 2H), 8.59 ( s, 2H).

< Example  106> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -1-oxobutane-2 Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 105 to obtain the target compound (yield: 84%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.98-1.00 (m, 12H), 1.65-1.81 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68 -2.78 (m, 4H), 2.80-3.00 (m, 12H), 3.01-3.20 (m, 4H), 3.69 (s, 3H), 3.73 (s, 6H), 3.74 (s, 3H), 3.95-4.11 (m, 2H), 4.13-4.20 (m, 2H), 4.40-4.49 (m, 2H), 5.08-5.13 (m, 2H), 5.18-5.30 (m, 2H), 6.75-6.82 (m, 8H) , 7.51-7.62 (m, 4H), 7.85-7.89 (m, 4H), 7.94-7.7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).

< Example  107> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -1-oxobutane-2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 105, the target compound was obtained (yield: 82%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.98-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.95-2.05 (m, 2H), 2.09-2.19 (m, 2H), 2.65 -2.78 (m, 4H), 2.80-2.95 (m, 6H), 2.96-3.07 (m, 8H), 3.09-3.17 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.95 -4.09 (m, 2H), 4.10-4.22 (m, 2H), 4.41-4.49 (m, 2H), 5.09-5.15 (m, 2H), 5.18-5.29 (m, 2H), 6.67-6.79 (m, 6H), 7.05-7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-8.01 (m, 2H), 8.02-8.05 (m, 2H), 8.58 ( s, 2H).

< Example  108> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 105 to obtain the target compound (yield: 88% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.90-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.70 -2.84 (m, 4H), 2.85-2.95 (m, 4H), 2.96-3.04 (m, 10H), 3.05-3.13 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95 -4.05 (m, 2H), 4.10-4.18 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.15 (m, 2H), 5.17-5.25 (m, 2H), 6.77-6.84 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.09 (d, J = 8.1 Hz, 4H).

< Example  109> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -1-oxobutane-2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 105 to obtain the target compound (yield: 82% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.92-2.01 (m, 2H), 2.10-2.20 (m, 2H), 2.69 -2.80 (m, 4H), 2.82-2.92 (m, 4H), 2.96-3.02 (m, 10H), 3.04-3.14 (m, 2H), 3.71 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.95-4.05 (m, 2H), 4.08-4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.13 (m, 2H), 5.16-5.22 (m, 2H) , 6.77-6.86 (m, 8H), 7.37-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J = 8.1 Hz, 4H).

< Example  110> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -1-oxobutane-2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3- carboxylate in the same manner as in Example 105, the target compound was obtained (yield: 77%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.91-1.00 (m, 12H), 1.65-1.73 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.66 -2.77 (m, 4H), 2.78-2.92 (m, 6H), 2.94-3.12 (m, 10H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.06 (m, 2H), 4.08 -4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.14 (m, 2H), 5.16-5.22 (m, 2H), 6.70-6.84 (m, 6H), 7.08-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.08 (d, J = 8.0 Hz, 4H).

< Example  111> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -One- Oxobutane -2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 105 to obtain the target compound (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.90-0.99 (m, 12H), 1.65-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.67 -2.80 (m, 6H), 2.81-2.92 (m, 4H), 2.93-3.01 (m, 8H), 3.05-3.09 (m, 2H), 3.72 (s, 3H), 3.74 (s, 3H), 3.95 -4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.07-5.12 (m, 2H), 5.13-5.20 (m, 2H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).

< Example  112> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -3- methyl -1-oxobutane-2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 105 to obtain the target compound (yield: 58%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.92-0.99 (m, 12H), 1.63-1.78 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.69 -2.80 (m, 6H), 2.82-2.90 (m, 4H), 2.95-3.00 (m, 8H), 3.01-3.10 (m, 2H), 3.72 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.94-4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.05-5.11 (m, 2H), 5.12-5.20 (m, 2H) , 6.78-6.86 (m, 8H), 6.96-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.25 (m, 2H), 7.36-7.42 (m, 4H), 7.96-8.01 ( m, 4H).

< Example  113> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2-ylcarbamoyl) piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanatopropaneoate (0.13 mmol) (yield: 85%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.65-1.75 (m, 2H), 1.95-2.05 (m , 2H), 2.68-2.78 (m, 4H), 2.80-3.02 (m, 14H), 3.05-3.15 (m, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.95-4.08 (m , 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.17-5.28 (m, 4H), 6.74-6.81 (m, 4H), 6.84-6.92 (m, 4H), 7.51 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.84-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.59 (s, 2H).

< Example  114> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 113 to give the target compound (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.95-2.05 (m , 2H), 2.65-2.78 (m, 4H), 2.80-3.00 (m, 14H), 3.01-3.16 (m, 2H), 3.71 (s, 6H), 3.72 (s, 3H), 3.75 (s, 3H ), 3.95-4.08 (m, 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.71-6.83 (m, 8H), 7.49-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.95-7.99 (m, 2H), 8.00-8.05 (m, 2H), 8.59 (s, 2H).

< Example  115> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 113, the target compound was obtained (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.00 (m , 2H), 2.65-2.75 (m, 4H), 2.80-3.00 (m, 6H), 3.01-3.09 (m, 8H), 3.10-3.17 (m, 2H), 3.72 (s, 3H), 3.75 (s , 3H), 3.95-4.08 (m, 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.66-6.80 (m, 6H), 7.05 -7.11 (m, 2H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H) .

< Example  116> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane 2-ylcarbamoyl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.02 (m , 2H), 2.65-2.86 (m, 6H), 2.88-2.94 (m, 4H), 2.95-3.11 (m, 10H), 3.73 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m , 2H), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.11-5.25 (m, 4H), 6.77-6.84 (m, 4H), 6.86-6.95 (m, 4H), 7.36 -7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.06-8.11 (m, 4H).

< Example  117> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.78 (m, 2H), 1.93-2.00 (m , 2H), 2.66-2.83 (m, 6H), 2.86-3.11 (m, 14H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m, 2H ), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.13-5.25 (m, 4H), 6.77-6.85 (m, 8H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8 H), 8.06-8.10 (m, 4 H).

< Example  118> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113, the target compound was obtained (yield: 95%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.62-1.76 (m, 2H), 1.91-1.98 (m , 2H), 2.63-2.75 (m, 4H), 2.76-2.90 (m, 6H), 2.91-3.09 (m, 10H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H ), 3.95-4.08 (m, 2H), 4.10-4.18 (m, 2H), 4.42-4.54 (m, 2H), 5.16-5.24 (m, 4H), 6.70-6.81 (m, 6H), 7.07-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.06-8.10 (m, 4H).

< Example  119> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2-ylcarbamoyl) piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 113 to obtain the target compound (yield: 87%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.62-1.73 (m, 2H), 1.90-1.98 (m , 2H), 2.65-2.80 (m, 6H), 2.81-2.89 (m, 4H), 2.92-3.06 (m, 10H), 3.73 (s, 3H), 3.75 (s, 3H), 3.93-4.04 (m , 2H), 4.05-4.15 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.21 (m, 4H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04 -7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.36-7.41 (m, 4H), 7.96-8.01 (m, 4H).

< Example  120> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (1- Methoxy -One- Oxopropane -2- Ilkaba Mole Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate A target compound was obtained by the same method as Example 113 except for using the piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 92%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.62-1.78 (m, 2H), 1.90-1.99 (m , 2H), 2.65-2.78 (m, 6H), 2.82-2.91 (m, 4H), 2.92-3.05 (m, 10H), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H ), 3.93-4.00 (m, 2H), 4.02-4.15 (m, 2H), 4.43-4.51 (m, 2H), 5.10-5.20 (m, 4H), 6.77-6.87 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.95-8.01 (m, 4H).

< Example  121> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and 2-fluorophenyl of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 Except for reacting 18 mg (0.13 mmol) of isocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 95%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.74-1.90 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.80 (m, 2H), 2.82-3.05 (m, 7H), 3.13- 3.29 (m, 2H), 4.02-4.12 (m, 1H), 4.22-4.32 (m, 1H), 5.25-5.35 (m, 1H), 6.71-6.81 (m, 3H), 6.83-7.02 (m, 3H ), 7.04-7.08 (m, 2H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.59 (s, 1H).

< Example  122> 3- (4- (4- Methoxylophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 121 to obtain the target compound (yield: 100%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.75-1.89 (m, 1H), 2.01-2.12 (m, 1H), 2.71-2.80 (m, 2H), 2.82-2.94 (m, 3H), 2.95 -3.00 (m, 4H), 3.12-3.34 (m, 2H), 3.73 (s, 3H), 4.05-4.10 (m, 1H), 4.22-4.30 (m, 1H), 5.26-5.34 (m, 1H) , 6.75-6.85 (m, 5H), 6.91-7.11 (m, 3H), 7.50-7.61 (m, 2H), 7.84-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.58 (s, 1H).

< Example  123> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 121, the target compound was obtained (yield: 95%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.72-1.86 (m, 1H), 2.00-2.08 (m, 1H), 2.65-2.76 (m, 2H), 2.83-2.93 (m, 3H), 3.02 -3.10 (m, 4H), 3.11-3.32 (m, 2H), 4.05-4.15 (m, 1H), 4.24-4.32 (m, 1H), 5.25-5.33 (m, 1H), 6.68-6.80 (m, 4H), 6.91-7.00 (m, 1H), 7.01-7.12 (m, 3H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.01-8.09 (m, 2H), 8.58 ( s, 1 H).

< Example  124> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.73-1.88 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.78 (m, 2H), 2.80-2.98 (m, 3H), 3.00 -3.10 (m, 4H), 3.11-3.28 (m, 2H), 4.03-4.13 (m, 1H), 4.21-4.26 (m, 1H), 5.25-5.29 (m, 1H), 6.74 (d, J = 3.8 Hz, 1H), 6.79-6.85 (m, 2H), 6.87-7.12 (m, 5H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H) .

< Example  125> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121 to obtain the target compound (yield: 100% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.74-1.88 (m, 1H), 2.01-2.10 (m, 1H), 2.71-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.93- 3.02 (m, 4H), 3.12-3.29 (m, 2H), 3.73 (s, 3H), 4.03-4.11 (m, 1H), 4.20-4.29 (m, 1H), 5.21-5.29 (m, 1H), 6.75 (d, J = 3.8 Hz, 1H), 6.76-6.87 (m, 4H), 6.92-7.12 (m, 3H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.01- 8.11 (m, 3 H).

< Example  126> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121, the target compound was obtained (yield: 94%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.71-1.85 (m, 1H), 1.97-2. 08 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.92 (m, 3H), 3.02-3.11 (m, 4H), 3.13-3.27 (m, 2H), 4.04-4.12 (m, 1H ), 4.22-4.31 (m, 1H), 5.20-5.30 (m, 1H), 6.70-6.82 (m, 4H), 6.92-7.14 (m, 4H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H).

< Example  127> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 121 to obtain the target compound (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70-1.85 (m, 1H), 1.97-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 3.00-3.04 (m, 4H), 3.09-3.24 (m, 2H), 4.02-4.10 (m, 1H ), 4.17-4.25 (m, 1H), 5.16-5.25 (m, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.78-6.85 (m, 2H), 6.88-7.01 (m, 5H), 7.03-7.11 (m, 4H), 7.16-7.21 (m, 1H), 7.35-7.42 (m, 2H), 7.95-8.07 (m, 3H).

< Example  128> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (2- Fluorophenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 121 to obtain the target compound (yield: 77%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.71-1.85 (m, 1H), 1.96-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 2.95-3.05 (m, 4H), 3.11-3.26 (m, 2H), 3.74 (s, 3H), 4.02-4.10 (m, 1H), 4.17-4.25 (m, 1H), 5.16-5.24 (m, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.78-6.86 (m, 4H), 6.92- 7.01 (m, 3H), 7.03-7.12 (m, 4H), 7.16-7.22 (m, 1H), 7.35-7.42 (m, 2H), 7.96-8.07 (m, 3H).

< Example  129> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 and 3-methoxyphenyl A target compound was obtained in the same manner as in Example 23, except that 20 mg (0.13 mmol) of isocyanate was reacted (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.70-2.78 (m, 2H), 2.85-2.91 (m, 3H), 2.92- 3.00 (m, 4H), 3.01-3.25 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.27 (m, 1H), 6.56-6.60 (m, 1H), 6.75-6.82 (m, 3H), 6.85-6.93 (m, 3H), 7.12-7.18 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.02-8.05 (m, 1H), 8.59 (s, 1H).

< Example  130> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

4- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 129 to obtain the target compound (yield: 81%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70-1.84 (m, 1H), 1.95-2.03 (m, 1H), 2.71-2.80 (m, 2H), 2.85-2.90 (m, 3H), 2.91- 3.01 (m, 4H), 3.05-3.26 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.26 (m, 1H), 6.55-6.60 (m, 1H), 6.75-6.89 (m, 5H), 7.12-7.18 (m, 2H), 7.51-7.62 (m, 3H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H).

< Example  131> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 129 to obtain the target compound (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.65-1.80 (m, 1H), 1.95-2.03 (m, 1H), 2.66-2.75 (m, 2H), 2.82-2.92 (m, 3H), 3.01- 3.11 (m, 5H), 3.15-3.24 (m, 1H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.18-5.25 (m, 1H), 6.56-6.60 (m, 1H), 6.66-6.80 (m, 4H), 6.86-6.91 (m, 1H), 7.05-7.18 (m, 3H), 7.51-7.62 (m, 2H), 7.85-7.88 (m , 2H), 7.90-7.93 (m, 1 H), 8.01-8.04 (m, 1 H), 8.58 (s, 1 H).

< Example  132> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129, the target compound was obtained (yield: 94% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.69-1.81 (m, 1H), 1.95-2.02 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.93 (m, 3H), 2.97 -3.05 (m, 5H), 3.06-3.20 (m, 1H), 3.78 (s, 3H), 4.06-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.56-6.61 (m, 1H) , 6.77-6.83 (m, 3H), 6.86-6.97 (m, 3H), 7.13-7.19 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 ( m, 2H).

< Example  133> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl Biphenyl -3- Carboxylate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129 to obtain the target compound (yield: 95% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.82 (m, 1H), 1.96-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.97- 3.00 (m, 4H), 3.01-3.21 (m, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.06-4.22 (m, 2H), 5.14-5.21 (m, 1H), 6.57- 6.61 (m, 1H), 6.77-6.89 (m, 6H), 7.13-7.19 (m, 2H), 7.39-7.49 (m, 3H), 7.59-7.66 (m, 4H), 8.06-8.10 (m, 2H ).

< Example  134> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129, the target compound was obtained (yield: 36%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.83 (m, 1H), 1.95-2.03 (m, 1H), 2.70-2.77 (m, 2H), 2.80-2.90 (m, 3H), 3.01 -3.20 (m, 6H), 3.79 (s, 3H), 4.10-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.57-6.62 (m, 1H), 6.70-6.82 (m, 4H) , 6.85-6.90 (m, 1H), 7.08-7.17 (m, 3H), 7.37-7.50 (m, 3H), 7.58-7.67 (m, 4H), 8.09 (d, J = 8.3 Hz, 2H).

< Example  135> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 129 to obtain the target compound (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70-1.81 (m, 1H), 1.93-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.79-2.89 (m, 3H), 2.98- 3.01 (m, 5H), 3.02-3.17 (m, 1H), 3.78 (s, 3H), 4.07-4.19 (m, 2H), 5.09-5.16 (m, 1H), 6.57-6.61 (m, 1H), 6.71 (s, 1H), 6.78-7.00 (m, 7H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.43 (m, 2H), 7.96-8.01 (m, 2H ).

< Example  136> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (3- Methoxyphenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 129 to obtain the target compound (yield: 92%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.71-1.81 (m, 1H), 1.93-2.02 (m, 1H), 2.71-2.79 (m, 2H), 2.80-2.89 (m, 3H), 2.97- 3.01 (m, 4H), 3.02-3.18 (m, 2H), 3.74 (s, 3H), 3.78 (s, 3H), 4.06-4.19 (m, 2H), 5.09-5.17 (m, 1H), 6.56- 6.62 (m, 1H), 6.72 (s, 1H), 6.78-7.88 (m, 5H), 6.94-7.01 (m, 2H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.42 (m, 2 H), 7.96-8.01 (m, 2 H).

< Example  137> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and 4-fluorophenyl of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23, except that 18 mg (0.13 mmol) of isocyanate was reacted (yield: 80%).

¹¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.82 (m, 1H), 1.95-2.04 (m, 1H), 2.70-2.78 (m, 2H), 2.84-2.94 (m, 3H), 2.96- 3.12 (m, 5H), 3.15-3.23 (m, 1H), 4.08-4.25 (m, 2H), 5.19-5.25 (m, 1H), 6.74-6.81 (m, 3H), 6.84-6.99 (m, 4H ), 7.28-7.35 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.05 (m, 1H), 8.58 (s , 1H).

< Example  138> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 137 to obtain the target compound (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.85 (m, 1H), 1.96-2.03 (m, 1H), 2.70-2.79 (m, 2H), 2.82-2.93 (m, 3H), 2.94- 3.00 (m, 4H), 3.02-3.13 (m, 1H), 3.16-3.24 (m, 1H), 3.72 (s, 3H), 4.06-4.23 (m, 2H), 5.18-5.25 (m, 1H), 6.74-6.83 (m, 5H), 6.90-6.97 (m, 2H), 7.29-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H).

< Example  139> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 137, the target compound was obtained (yield: 85%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.66-1.80 (m, 1H), 1.94-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.82-2.92 (m, 3H), 3.00- 3.10 (m, 5H), 3.14-3.23 (m, 1H), 4.09-4.24 (m, 2H), 5.16-5.24 (m, 1H), 6.66-6.78 (m, 4H), 6.91-6.99 (m, 2H ), 7.08 (t, J = 8.1 Hz, 1H), 7.28-7.36 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.89 (m, 2H), 7.90-7.94 (m, 1H), 8.01-8.04 (m, 1 H), 8.58 (s, 1 H).

< Example  140> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137 to obtain the target compound (yield: 86% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.81 (m, 1H), 1.94-2.02 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.96 -3.09 (m, 5H), 3.10-3.18 (m, 1H), 4.07-4.21 (m, 2H), 5.12-5.19 (m, 1H), 6.77-6.82 (m, 3H), 6.83-7.00 (m, 4H), 7.29-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06-8.11 (m, 2H).

< Example  141> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3- Carboxylate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137 to obtain the target compound (yield: 98% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.85 (m, 1H), 1.95-2.03 (m, 1H), 2.72-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94- 3.02 (m, 4H), 3.03-3.10 (m, 1H), 3.11-3.19 (m, 1H), 3.73 (s, 3H), 4.07-4.21 (m, 2H), 5.12-5.20 (m, 1H), 6.76-6.85 (m, 5H), 6.92-7.00 (m, 2H), 7.25-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.07-8.10 (m , 2H).

< Example  142> 3- (4- (3- Chlorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137, the target compound was obtained (yield: 88%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.65-1.80 (m, 1H), 1.93-2.00 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.97 -3.17 (m, 6H), 4.07-4.22 (m, 2H), 5.11-5.19 (m, 1H), 6.69-6.81 (m, 4H), 6.93-7.00 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 (m, 2H).

< Example  143> 3- (4- (4- Fluorophenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 137 to obtain the target compound (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.82 (m, 1H), 1.92-2.03 (m, 1H), 2.69-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.96- 3.06 (m, 5H), 3.07-3.15 (m, 1H), 4.06-4.18 (m, 2H), 5.08-5.15 (m, 1H), 6.73 (s, 1H), 6.78-6.85 (m, 2H), 6.88-7.00 (m, 6H), 7.03-7.08 (m, 2H), 7.17-7.23 (m, 1H), 7.29-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m , 2H).

< Example  144> 3- (4- (4- Methoxyphenyl Piperazin-1-yl) -1- (4- Fluorophenylcarbamoyl Piperidin-4-yl-4- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 137 to obtain the target compound (yield: 98%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.65-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.94- 3.05 (m, 5H), 3.06-3.15 (m, 1H), 3.74 (s, 3H), 4.05-4.17 (m, 2H), 5.07-5.15 (m, 1H), 6.77-6.86 (m, 5H), 6.91-7.01 (m, 4H), 7.03-7.09 (m, 2H), 7.16-7.22 (m, 1H), 7.27-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.95-8.00 (m , 2H).

< Example  145> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

48 mg (0.11 mmol) and 3,5-dichloro 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 Except for reacting 25 mg (0.13 mmol) of phenylisocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 85%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.80 (m, 1H), 1.97-2.06 (m, 1H), 2.67-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.92- 3.01 (m, 4H), 3.04-3.16 (m, 1H), 3.19-3.27 (m, 1H), 4.02-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.14-5.21 (m, 1H ), 6.73-6.80 (m, 2H), 6.86-6.92 (m, 2H), 6.94 (t, J = 1.8 Hz, 1H), 7.07 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H) , 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H).

< Example  146> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 145 to obtain the target compound (yield: 99%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.69-1.85 (m, 1H), 1.97-2.06 (m, 1H), 2.69-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.92 -3.00 (m, 4H), 3.08-3.20 (m, 1H), 3.21-3.28 (m, 1H), 3.72 (s, 3H), 4.02-4.08 (m, 1H), 4.13-4.22 (m, 1H) , 5.14-5.21 (m, 1H), 6.75-6.84 (m, 4H), 6.94 (t, J = 1.8 Hz, 1H), 7.02 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H).

< Example  147> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 145, the target compound was obtained (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.62-1.76 (m, 1H), 1.90-2.01 (m, 1H), 2.61-2.71 (m, 2H), 2.74-2.88 (m, 3H), 2.96 -3.06 (m, 4H), 3.07-3.16 (m, 1H), 3.17-3.25 (m, 1H), 3.97-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.12-5.19 (m, 1H), 6.64-6.68 (m, 1H), 6.72-6.76 (m, 2H), 6.93 (t, J = 1.8 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H ), 7.33 (d, J = 1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.84-7.87 (m, 2H), 7.89-7.92 (m, 1H), 7.98-8.02 (m, 1H), 8.55 (s, 1 H).

< Example  148> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 96% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ1.63-1.78 (m, 1H), 1.93-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.77-2.88 (m, 3H), 2.94 -3.03 (m, 4H), 3.04-3.13 (m, 1H), 3.14-3.22 (m, 1H), 4.00-4.10 (m, 1H), 4.13-4.22 (m, 1H), 5.09-5.17 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.94 (m, 2H), 6.95 (t, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H ), 7.35-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H).

< Example  149> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 100 %).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.65-1.80 (m, 1H), 1.95-2.04 (m, 1H), 2.68-2.76 (m, 2H), 2.77-2.89 (m, 3H), 2.92 -3.02 (m, 4H), 3.04-3.14 (m, 1H), 3.15-3.23 (m, 1H), 3.74 (s, 3H), 3.96-4.08 (m, 1H), 4.12-4.20 (m, 1H) , 5.10-5.17 (m, 1H), 6.75-6.83 (m, 4H), 6.96 (t, J = 1.8 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.34-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H).

< Example  150> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (3- Chlorophenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 93%) .

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.64-1.78 (m, 1H), 1.92-2.02 (m, 1H), 2.65-2.74 (m, 2H), 2.76-2.87 (m, 3H), 3.02 -3.10 (m, 4H), 3.11-3.21 (m, 2H), 4.00-4.10 (m, 1H), 4.12-4.20 (m, 1H), 5.08-5.15 (m, 1H), 6.67-6.68 (m, 1H), 6.70-6.80 (m, 2H), 6.96 (t, J = 1.8 Hz, 1H), 7.07 (s, 1H), 7.09 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.35-7.48 (m, 3H), 7.57-7.66 (m, 4H), 8.04-8.08 (m, 2H).

< Example  151> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Fluorophenyl ) Piperazin-1-yl) piperidin-4-yl-3- Of phenoxybenzoate  Produce

3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 145 to obtain the target compound (yield: 31%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.84 (m, 1H), 1.96-2.04 (m, 1H), 2.73-2.90 (m, 5H), 2.98-3.06 (m, 4H), 3.07 -3.22 (m, 2H), 4.00-4.16 (m, 2H), 5.04-5.12 (m, 1H), 6.79-6.85 (m, 3H), 6.88-7.01 (m, 5H), 7.03-7.08 (m, 2H), 7.17-7.25 (m, 2H), 7.33 (d, J = 1.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.95-8.00 (m, 2H).

< Example  152> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-3- Of phenoxybenzoate  Produce

3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 145 to obtain the target compound (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.67-1.80 (m, 1H), 1.92-2.03 (m, 1H), 2.70-2.88 (m, 5H), 2.94-3.02 (m, 4H), 3.04- 3.20 (m, 2H), 3.74 (s, 3H), 3.98-4.15 (m, 2H), 5.06-5.12 (m, 1H), 6.77-6.84 (m, 3H), 6.94-6.98 (m, 3H), 7.03-7.07 (m, 3H), 7.16-7.22 (m, 1H), 7.31-7.32 (m, 2H), 7.35-7.41 (m, 2H), 7.94-7.99 (m, 2H).

< Example  153> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

49 mg (0.11 mmol) and 3,5-dichloro 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 A target compound was obtained in the same manner as in Example 23, except that 25 mg (0.13 mmol) of phenylisocyanate was reacted (yield: 87%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.69-2.78 (m, 2H), 2.72-2.82 (m, 2H), 2.84- 3.04 (m, 7H), 3.12-3.22 (m, 1H), 3.24-3.34 (m, 1H), 3.80 (s, 3H), 3.98-4.08 (m, 1H), 4.12-4.23 (m, 1H), 5.15-5.22 (m, 1H), 6.79 (s, 1H), 6.82-6.89 (m, 2H), 6.92-6.98 (m, 3H), 7.33 (d, J = 1.8 Hz, 2H), 7.51-7.62 ( m, 2H), 7.85-7.94 (m, 3H), 8.01-8.04 (m, 1H), 8.58 (s, 1H).

< Example  154> 1- (3,5- Dimethoxyphenylcarbamoyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

49 mg (0.11 mmol) and 3,5-dimethic 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 Except for reacting 25 mg (0.13 mmol) of oxyphenylisocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.76-1.90 (m, 1H), 2.04-2.13 (m, 1H), 2.72-2.90 (m, 3H), 2.91-3.04 (m, 6H), 3.20- 3.40 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.98-4.09 (m, 1H), 4.20-4.28 (m, 1H), 5.28-5.36 ( m, 1H), 6.44-6.49 (m, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.80 (s, 1H), 6.82-6.88 (m, 2H), 6.92-6.98 (m, 1H) , 7.32 (s, 1H), 7.50-7.61 (m, 2H), 7.84-7.90 (m, 4H), 8.03-8.07 (m, 1H), 8.59 (s, 1H).

< Example  155> 1- (3- Chloro -4- Methoxyphenylcarbamoyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

49 mg (0.11 mmol) and 3-chloro-4 of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 A target compound was obtained in the same manner as in Example 23, except that 24 mg (0.13 mmol) of methoxyphenylisocyanate was reacted (yield: 94%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.73-2.82 (m, 2H), 2.83-3.04 (m, 7H), 3.08- 3.20 (m, 1H), 3.22-3.30 (m, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 4.03-4.10 (m, 1H), 4.15-4.25 (m, 1H), 5.18- 5.26 (m, 1H), 6.71 (s, 1H), 6.74-6.79 (m, 1H), 6.82-6.87 (m, 2H), 6.94-6.98 (m, 1H), 7.17-7.21 (m, 1H), 7.24-7.26 (m, 1H), 7.38-7.41 (m, 1H), 7.51-7.62 (m, 2H), 7.85-7.94 (m, 3H), 8.02-8.06 (m, 1H), 8.59 (s, 1H ).

< Example  156> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3- Carboxylate  Produce

3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 153 to obtain the target compound (yield: 80% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.70-1.80 (m, 1H), 1.98-2.08 (m, 1H), 2.73-2.82 (m, 2H), 2.83-2.94 (m, 3H), 2.96- 3.06 (m, 4H), 3.10-3.28 (m, 2H), 3.81 (s, 3H), 3.96-4.07 (m, 1H), 4.10-4.18 (m, 1H), 5.10-5.18 (m, 1H), 6.80 (s, 1H), 6.83-6.88 (m, 2H), 6.92-6.99 (m, 3H), 7.33 (d, J = 1.8 Hz, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 ( m, 4H), 8.06-8.10 (m, 2H).

< Example  157> 1- (3,5- Dimethoxyphenylcarbamoyl ) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 154 to obtain the target compound (yield: 84% ).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.74-1.88 (m, 1H), 2.02-2.12 (m, 1H), 2.72-2.86 (m, 3H), 2.90-3.06 (m, 6H), 3.16- 3.32 (m, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 3.98-4.08 (m, 1H), 4.18-4.27 (m, 1H), 5.23-5.30 ( m, 1H), 6.46-6.50 (m, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.80-6.88 (m, 3H), 6.92-6.99 (m, 1H), 7.30 (s, 1H) , 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J = 3.0 Hz, 1H), 8.08-8.11 (m, 2H).

< Example  158> 1- (3- Chloro -4-methoxyphenylcarbamoyl) -3- (4- (2- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Ray's  Produce

3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 155 to obtain the target compound (yield: 91 %).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72-1.86 (m, 1H), 1.98-2.10 (m, 1H), 2.74-2.83 (m, 2H), 2.84-2.96 (m, 3H), 2.97- 3.06 (m, 4H), 3.08-3.26 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.00-4.08 (m, 1H), 4.12-4.20 (m, 1H), 5.12- 5.22 (m, 1H), 6.63 (s, 1H), 6.78-6.84 (m, 2H), 6.85-6.88 (m, 2H), 6.94-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.26 (s, 1 H), 7.37-7.50 (m, 3 H), 7.59-7.68 (m, 4 H), 7.88 (d, J = 3.0 Hz, 1 H), 8.08-8.12 (m, 2H).

< Example  159> 1- (3,5- Dimethoxyphenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 154 except for using piperidin-4-yl-1-naphthoate (yield: 91%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.74-1.89 (m, 1H), 2.01-2.11 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94- 3.04 (m, 4H), 3.16-3.35 (m, 2H), 3.73 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 4.00-4.10 (m, 1H), 4.20-4.28 ( m, 1H), 5.28-5.35 (m, 1H), 6.45-6.50 (m, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.73-6.84 (m, 4H), 7.32 (s, 1H) , 7.49-7.61 (m, 2H), 7.84-7.91 (m, 4H), 8.02-8.05 (m, 1H), 8.56 (s, 1H).

< Example  160> 1- (3- Chloro -4-methoxyphenylcarbamoyl) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl-1- Naphthoate  Produce

3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 155 except for using piperidin-4-yl-1-naphthoate (yield: 99%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.83 (m, 1H), 1.96-2.04 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94- 3.00 (m, 4H), 3.04-3.16 (m, 1H), 3.18-3.26 (m, 1H), 3.72 (s, 3H), 3.82 (s, 3H), 4.04-4.12 (m, 1H), 4.15- 4.22 (m, 1H), 5.17-5.25 (m, 1H), 6.71-6.83 (m, 5H), 7.18-7.27 (m, 2H), 7.41 (d, J = 2.6 Hz, 1H), 7.50-7.62 ( m, 2H), 7.85-7.93 (m, 3H), 8.00-8.04 (m, 1H), 8.58 (s, 1H).

< Example  161> 1- (3,5- Dichlorophenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3-carboxyl Rate  Produce

3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- I) A target compound was obtained in the same manner as in Example 157 except for using piperidin-4-yl-1-naphthoate (yield: 84%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.72-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.70-2.79 (m, 2H), 2.80-2.96 (m, 3H), 2.98- 3.03 (m, 4H), 3.14-3.29 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.00-4.10 (m, 1H), 4.18-4.25 ( m, 1H), 5.23-5.30 (m, 1H), 6.46-6.51 (m, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.77-6.87 (m, 4H), 7.30 (s, 1H) , 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J = 3.0 Hz, 1H), 8.06-8.10 (m, 2H

< Example  162> 1- (3,5- Dimethoxyphenylcarbamoyl ) -3- (4- (4- Methoxyphenyl ) Piperazin-1-yl) piperidin-4-yl- Biphenyl -3- Carboxylate  Produce

3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 158 except for using piperidin-4-yl-1-naphthoate (yield: 86%).

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.68-1.83 (m, 1H), 1.94-2.03 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94- 3.04 (m, 4H), 3.06-3.22 (m, 2H), 3.74 (s, 3H), 3.82 (s, 3H), 4.00-4.19 (m, 2H), 5.12-5.21 (m, 1H), 6.71 ( s, 1H), 6.75-6.85 (m, 5H), 7.19-7.24 (m, 1H), 7.36-7.49 (m, 3H), 7.59-7.67 (m, 3H), 8.06-8.10 (m, 2H).

The yield, melting point and ¹ H NMR of the piperidine derivative represented by Chemical Formula 1 obtained according to the preparation method of the embodiment of the present invention are shown in Table 1 below.

Comparative Example Preparation of 4-phenylpiperidin-3-yl biphenyl-4-carboxylate

4-phenylpiperidin-3-yl biphenyl-4-carboxylate was prepared by the method described in International Publication No. 03/43987 (WO0343987).

< Experimental Example  1> beta- Secretase  Active inhibitory effect experiment 1

In order to determine the beta-secretase activity inhibitory effect by the piperidine derivative of the present invention, the following experiment was performed.

Compounds prepared in Examples 1 to 152 in a beta-secretase-1 substrate solution (Rh-EVNLDAEFK-Quencher, 750 nM in assay buffer) and blood having a conventional beta-secretase inhibitory activity as a comparative example 10 [mu] l of 4-phenylpiperidin-3-yl biphenyl-4-carboxylate, a ferridine compound, was added and mixed lightly, and then the baculovirus-expressed beta-secretase- 10 μl of a solution of 1 enzyme (1.0 unit / mL in assay buffer) was added to induce a reaction and then incubated at room temperature for 60 minutes. Immediately after completion of the culture, 10 µl of a stop solution was added to the reaction solution to stop the reaction, and the enzyme activity was measured by measuring its fluorescence at 545 nm (excitation) and 585 nm (emission) using FlexStation. Inhibitory activity against secretase was measured. The total volume of the above experiment was 40 μl and was performed on a 384-black microwell plate, and the inhibitory activity is shown as IC ₅₀ . Detailed compositions of enzymes, substrates, stop solutions, assay buffers, and the like used in the test are shown in Table 2.

division Furtherance Beta-secretase-1 enzyme  50 mM Tris solution (pH 7.5), 1 U / mL in 10% glycerol Beta-secretase-1 substrate  Rh-EVNLDAEFK-Quencher (750 nM) Beta-secretase-1 termination solution  2.5 M Sodium Acetate Beta-secretase-1 Assay Buffer  50 mM sodium acetate (pH 4.5)

The experimental results are shown in Table 3.

Example Beta-secretase inhibitory activity (IC ₅₀ , μM) Example Beta-secretase inhibitory activity (IC ₅₀ , μM) One 10 2 1.9 3 > 10 5 1.4 6 0.5 7 4.5 9 2.6 10 0.6 11 3.2 12 > 10 13 1.2 14 > 10 16 1.9 17 10 18 4.8 20 2.2 21 1.1 22 7.5 23 > 10 24 > 10 25 > 10 26 > 10 27 > 10 28 > 10 29 > 10 30 > 10 31 > 10 32 > 10 33 > 10 34 > 10 35 > 10 36 > 10 37 > 10 38 > 10 39 > 10 40 > 10 41 > 10 42 > 10 43 > 10 45 > 10 46 > 10 47 > 10 48 > 10 50 > 10 51 > 10 52 > 10 53 10 54 > 10 55 > 10 56 > 10 57 > 10 58 > 10 59 > 10 60 > 10 61 > 10 62 > 10 63 > 10 64 > 10 65 > 10 66 > 10 67 > 10 68 > 10 69 > 10 70 > 10 71 > 10 72 > 10 73 9 74 3.8 75 > 10 76 > 10 77 > 10 78 > 10 79 > 10 80 > 10 81 > 10 82 > 10 83 > 10 84 > 10 85 > 10 86 > 10 87 > 10 88 > 10 89 4.4 90 2.0 91 10 92 10 93 3.1 94 > 10 95 > 10 96 > 10 97 2.5 98 2.2 99 > 10 100 1.0 101 1.1 102 > 10 103 > 10 104 > 10 105 9 106 10 107 10 108 10 109 3.3 110 > 10 111 > 10 112 9 113 > 10 115 2.7 116 7.2 117 9.5 118 > 10 119 > 10 120 > 10 121 4.7 122 6.0 123 > 10 124 > 10 125 2.4 126 > 10 127 > 10 128 > 10 129 1.3 130 1.5 131 10 132 10 133 10 134 > 10 135 10 136 9 137 3.0 138 1.7 139 2.5 140 3.0 141 10 142 > 10 143 > 10 144 1.4 145 > 10 146 0.8 147 > 10 148 > 10 149 1.9 150 > 10 151 1.1 152 0.6 Comparative example 11

As shown in Table 3, the present invention avoid beta of piperidine derivatives of the - to sekeuri protease inhibitory activity IC ₅₀ uses a small amount than the conventional piperidine compound (11 μM) as a 0.6 ~ 10 μM beta- It can be seen that it can inhibit the activity of secretase.

< Experimental Example  2> beta- Secretase  Activity inhibitory effect experiment 2

In order to determine the inhibitory effect of beta-secretase activity by the piperidine derivative of the present invention, the following experiments based on cells were performed.

PC12tet-off pTRE2puro-APPsw stable cell lines were prepared in RPMI 1640 (10% FBS, 5% HS, 1% Penicillin / Streptomycin) at 100 μg / ml G418 (Clontech), 1 μg / ml Doxicyclin (Clontech), 3 ㎍ / ㎖ Puromycin (Clontech) was added and incubated at 5% CO ₂ , 37 ℃. Cultured cells were divided into 1.2 × 10 ⁶ cells / well in 0.05% PEI-coated 6-well plates and 24 hours later exchanged with 2 ml of condition media (5% HS, 1% FBS, 0.5% P / S) for 24 hours. Incubated. Next, 10 μM of the compounds of Examples 2, 6, 10, 13, 16, 17, 101, 129, 130, 138, 146, and 152, in which the inhibitory activity of beta-secretase was particularly excellent in Experimental Example 1, After reacting for 24 hours, the media was removed, 200 μl of cell extraction buffer (R & D, FP002) was added, and each microwell plate was transferred to an eppendorf tube and allowed to react on ice for 10-15 minutes. The reacted samples were centrifuged at 4 ° C. and 14,000 rpm for 10 minutes, and the supernatants were measured for fluorescence at 320 nm (excitation) and 405 nm (emission) by BACE FRET. It was. In this case, when the inhibition rate is 50 to 60%, A, when the inhibition rate is 40 to 50%, B, and when the inhibition rate is less than 40%, C is indicated.

Example Inhibition rate of beta-secretase enzyme activity Example Inhibition rate of beta-secretase enzyme activity 2 A 6 B 10 B 13 A 16 C 17 C 101 C 129 C 130 C 138 C 146 C 152 C

As shown in Table 4, the piperidine derivative according to the present invention has a beta-secretase enzyme inhibitory effect even in a cell test, and in Examples 2 and 13, it can be seen that the inhibitory effect is 50-60%. .

Therefore, the piperidine derivative according to the present invention can be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome caused by inhibiting the activity of beta-secretase enzyme.

Meanwhile, the piperidine derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> tablet (direct pressure)

After sifting 5.0 mg of piperidine derivative of Formula 1, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

< Formulation example  2> tablets (wet assembly)

5.0 mg of piperidine derivative of Formula 1 was sieved, followed by mixing 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.

< Formulation example  3> with powder Capsule

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

< Formulation example  4> Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

Claims (6)

A piperidine derivative substituted with an aryl piperazine represented by the following Formula 1 and a pharmaceutically acceptable salt thereof. <Formula 1>

(In Formula 1, R ¹ And R ² is independently —O—CO—R ⁴ or

Wherein R ⁴ is a C _6-12 aryl group substituted with a C _6-10 arylC _1-4 alkyl group, C _6-12 aryl, C _1-5 alkoxy or C _6-12 aryloxy, and Z is hydrogen , Halogen, C _1-4 straight or branched alkyl group or C _1-5 alkoxy group, R ³ is hydrogen, -CO-NH- (CH ₂ ) _m -R ⁵ or -CO-NH-C (R ⁶ ) (R ⁷ )-(CH ₂ ) _m -COO-R ^8, where R ⁵ is A C _6-12 aryl group substituted with 1 to 2 C _1-4 straight or branched alkyl or C _1-5 alkoxy or halogen, m represents an integer of 0 to 2, and R ⁶ and R ⁷ are independently hydrogen , C _1-4 group is straight or branched alkyl group or a benzyl, R ⁸ is a C _{1 -4} straight or branched alkyl group.) The compound of claim 1, wherein R ⁴ is a naphthyl group, a biphenyl group, or a phenoxybenzyl group; Z is hydrogen, halogen, methyl or methoxy, R ³ is

An aryl piperazine-substituted piperidine derivative and a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of. The method of claim 1, wherein the piperidine derivative is (1) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (2) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (3) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (4) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (5) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate; (6) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate; (7) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate; (8) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate; (9) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate; (10) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate; (11) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate; (12) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-2-naphthoate; (13) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (14) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (15) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (16) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate; (17) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate; (18) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate; (19) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate; (20) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate; (21) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate; (22) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate; (23) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (24) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (25) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate; (26) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (27) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (28) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate; (29) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (30) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (31) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate; (32) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (33) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (34) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate; (35) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (36) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (37) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate; (38) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (39) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (40) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate; (41) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (42) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate; (43) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate; (44) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (45) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate; (46) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate; (47) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (48) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate; (49) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate; (50) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate; (51) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-2 Naphthoate; (52) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate; (53) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate; (54) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-bi Phenyl-4-carboxylate; (55) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate; (56) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate; (57) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (58) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (59) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (60) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (61) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (62) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate; (63) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (64) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (65) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate; (66) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate; (67) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate; (68) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (69) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (70) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate; (71) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (72) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (73) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (74) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (75) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate; (76) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (77) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ; (78) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate; (79) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (80) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate; (81) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (82) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (83) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate; (84) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate; (85) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate; (86) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate ; (87) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate; (88) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate; (89) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (90) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (91) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate; (92) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate; (93) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate; (94) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate; (95) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (96) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (97) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (98) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (99) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate; (100) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate; (101) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine -4-yl-biphenyl-3-carboxylate; (102) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate; (103) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (104) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (105) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (106) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate; (107) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate; (108) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate; (109) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate; (110) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate; (111) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (112) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate; (113) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate; (114) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate; (115) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-1 Naphthoate; (116) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate; (117) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate; (118) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-bi Phenyl-3-carboxylate; (119) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate; (120) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate; (121) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (122) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (123) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (124) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (125) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (126) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (127) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (128) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (129) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate; (130) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate; (131) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate; (132) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (133) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (134) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate; (135) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (136) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (137) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (138) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (139) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate; (140) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (141) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ; (142) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate; (143) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (144) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate; (145) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (146) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (147) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (148) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; (149) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; (150) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate ; (151) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate; (152) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate; (153) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (154) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (155) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight; (156) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; (157) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car Carboxylates; (158) 1- (3-Chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3 Carboxylates; (159) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate; (160) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight; (161) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; And (162) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car An aryl piperazine-substituted piperidine derivative and a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of a cyclate. delete A composition for preventing and treating neurodegenerative diseases comprising an aryl piperazine-substituted piperidine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The composition of claim 5, wherein the neurodegenerative disease is Alzheimer's disease or Down syndrome.