WO2008018639A2 - Glycine transporter inhibitor - Google Patents

Abstract

The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt of the compound or a hydrate of the compound or the salt, which is useful for the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, and sleep disorders, based on glycine uptake inhibitory effect.

Description

DESCRIPTION GLYCINE TRANSPORTER INHIBITOR

TECHNICAL FIELD The present invention relates to a compound having a glycine transporter inhibitory effect . BACKGROUND ART

An NMDA receptor, one of glutamate receptors, exists in neural cell membranes in the brain and participates in various neurophysiological phenomena such as neural plasticity, cognition, attention, and memory. The NMDA receptor has several allosteriσ binding sites, one of which is a glycine- binding site (glycine-binding site of an NMDA receptor complex) . The glycine-binding site of an NMDA receptor complex has been reported to participate in the activation of the NMDA receptor (Molecular Psychiatry (2004) 9, 984-997).

An action potential reaches the presynaptic terminal of the glycinergic nerve, starting glycine release into synaptic clefts. The released glycine binds to postsynaptic receptors and so on and is then removed from the synaptic clefts by transporters . Thus , glycine transporters presumably regulate the amount of glycine in extracellular fluids and thereby regulate NMDA receptor function.

The glycine transporter (GIyT) is a protein that participates in reuptake of extracellular glycine into the cells . The presence of two subtypes , GIyTl and GlyT2 , has been elucidated so far. GIyTl is expressed mainly in the cerebral cortex, hippocampus, and thalamus, and has been reported to be associated with diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post- traumatic stress disorder, particular phobias, acute stress disorder, etc.)_* depression, drug abuse, convulsion, tremor, and sleep disorders (Current Medicinal Chemistry, 2006, 13, 1017-1044, Neuropsychopharmacology (2005), 1-23, Expert Opinion on Therapeutic Patents (2004) 14 (2) 201-214). Piperidine derivatives and pyrrolidine derivatives have been reported as compounds having a GIyTl inhibitory effect (WO 03/089411, WO 2004/013100, WO 2004/013101, WO 2005/037781, WO 2005/037782, WO 2005/037783, WO 2005/037785, WO 2005/037792) . DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel compound, a salt thereof or a hydrate of the compound or the salt, which is useful for the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders, based on glycine uptake inhibitory effect.

The present inventors have conducted diligent studies for a compound with a novel skeleton having an inhibitory effect on GIyTl and have consequently completed the present invention by finding out that compounds represented by the formulas described below are an excellent GIyTl inhibitor.

Hereinafter, the present invention will be described in detail.

Embodiments of the present invention (hereinafter referred to as "the compound of the present invention") are shown below.

An embodiment of the present invention relates to a compound of the following formula [I], or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt:

wherein ring A is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci.₆ alkyl, Ci-e haloalkyl, cyano, Ci_₆ alkoxy, halogen, Ci.₆ acyl and C₂-₇ alkoxycarbonyl; Ar¹ is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci_₆ alkyl, Ci_₆ haloalkyl, cyano, Ci-β alkoxy, Ci_₆ acyl, Ci.₆ haloacyl, Ci-₆ haloalkoxy, C₃_₈ cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy;

R¹ is hydrogen, Ci_₆ alkyl, C₃-₆ alkenyl, or C₃_₈ cycloalkyl, wherein the Ci_₆ alkyl is unsubstituted or substituted with cyano ;

R³ is hydrogen, Cχ.₆ alkyl, or halogen; and n is 1 or 2.

The present invention provide the following other embodiments :

2. A compound represented by formula [IA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein ring A is a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci_₆ alkyl, Ci-₆ alkoxy and halogen;

Ar¹ is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci.₆ alkyl, C_3.-₆ haloalkyl, σyano, Ci_₆ alkoxy, Ci-₆ acyl, C₃._₆ haloacyl, Ci_₆ haloalkoxy, C₃_₈ cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy (preferably, phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci.6 alkyl and Ci-6 haloalkyl) ;

R¹ is hydrogen, C₁.₆ alkyl, C₃.₆ alkenyl, or C₃-B cycloalkyl, wherein the Ci-β alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.

3. A compound represented by formula [ I ' ] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

R⁴ is hydrogen, Cχ-₆ haloalkyl, cyano or Ci_₆ acyl (preferably, cyano or Cχ-₆ acyl) ; Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, Cχ_₆ alkyl, Ci_₆ haloalkyl, cyano, Ci_₆ alkoxy, Ci_₆ acyl, Ci-₆ haloacyl and Ci_₆ haloalkoxy or with methylenedioxy; R¹ is hydrogen, Ci_₆ alkyl, C₃-6 alkenyl, or C₃_₈ cycloalkyl, wherein the Cχ.₆ alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.

4. The compound according to embodiment 3 , or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein R⁴ is hydrogen; and Ar¹ is phenyl or pyridyl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci.₆ alkyl, Ci_₆ haloalkyl, cyano, d_₆ alkoxy, Ci_₆ acyl, Ci-6 haloacyl and C₁.₆ haloalkoxy or with methylenedioxy.

5. The compound according to embodiment 2 , or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein ring A is pyrolyl, pyridyl, pyrimidinyl, pyrazinyl. pyrazolyl, imidazolyl, quinolyl, indolyl, thienyl or thiazolyl, wherein ring A is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci-₆ alkyl, C₁.₆ alkoxy and halogen.

6. The compound according to embodiment 2 represented by formula [II] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein ring A is a monocyclic or bicyclic aromatic ring (particularly, a five- or six-membered aromatic ring) having 1 or 2 nitrogen atoms as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with one substituent selected from the group consisting of C₁.₆ alkyl, halogen and Ci.₆ alkoxy (particularly, one Cχ.₆ alkyl);

Ar¹ is phenyl, pyridyl, or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci-β alkyl, Ci.β haloalkyl, Ci_₆ alkoxy and Ci_₆ haloalkoxy; and n is 1 or 2.

7. The compound according to embodiment 1 represented by formula [III] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-₆ alkyl and Ci-₆ haloalkyl;

R² is hydrogen or Ci.₆ alkyl; and n is 1 or 2, wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.

8. The compound according to embodiment 7 represented by formula [IIIA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_6 alkyl and Ci-6 haloalkyl; R² is hydrogen or Ci_β alkyl; and n is 1 or 2 , wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.

9. The compound according to embodiment 7 or 8 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of the pyrazolyl in the benzene ring is position 3.

10. The compound according to embodiment 1 represented by formula [IV] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

R⁵ is hydrogen, halogen or Ci-₆ alkoxy;

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-β alkyl and Ci-₆ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4. 11. The compound according to embodiment 10 represented by formula [IVA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

R⁵ is hydrogen, halogen or Ci_₆ alkoxy;

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_₆ alkyl and Ci_₆ haloalkyl; and n is 1 or 2, wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4.

12. The compound according to embodiment 11, or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein R⁵ is hydrogen; and Ar¹ is phenyl or pyridyl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_6 alkyl and C₁.₆ haloalkyl.

13. The compound according to embodiment 10, 11 or 12 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of pyridyl in the benzene ring is position 3. 14. The compound according to embodiment 1 represented by formula [V] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-γl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C₁.₆ alkyl and C₁-_S haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.

15. The compound according to embodiment 14 represented by formula [VA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-₆ alkyl and Ci-₆ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.

16. The compound according to embodiment 14 or 15 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of the pyrimidinyl in the benzene ring is position 3.

17. The compound according to embodiment 1 represented by formula [VI] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C_x.₆ alkyl and Ci-₆ haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrazinyl in the benzene ring is position 3 or 4.

18. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof or a hydrate thereof. wherein the substitution position of the pyrazinyl in the benzene ring is position 3.

19. The compound according to any one of embodiments 1, 2 and 5 to 18 or a pharmaceutically acceptable salt thereof or a hydrate thereof , wherein n is 2.

20. The compound according to embodiment 3 or 4 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein n is 2.

21. The compound according to any one of embodiments 1, 2 and 5 to 19 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein configuration of the asymmetric carbon atom at position 2 in the pyrrolidine or piperidine ring is S-configuration, and configuration of the asymmetric carbon atom bound with the nitrogen atom of the amide is also S-configuration .

22. The compound according to embodiment 3, 4 or 20 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein configuration of the asymmetric carbon atom at position 2 in the pyrrolidine or piperidine ring is S- configuration, and configuration of the asymmetric carbon atom bound with the nitrogen atom of the amide is also S- configuration .

23. The compound according to any one of embodiments 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is phenyl which has chloro , fluoro or methyl at position 2 and has trifluoromethyl at position 3, 5 or 6 and/or chloro at position 3 or 6.

24. The compound according to any one of embodiments 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is phenyl which has chloro or methyl at position 2, and trifluoromethyl at position 3 or 5, and may further have chloro at position 6.

25. The compound according to any one of embodiments 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.

26. The compound according to embodiment 3, 4, 20 or 22 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.

27. The compound according to any one of embodiments 1 to 3, 5 to 11 and 13 to 22 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is isoquinolin-1-yl. 28. 3-Chloro-N- ( (S) - ( 3- ( l-methyl-lH-pyrazol-4-yl) phenyl) ( (2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl) pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

29. 3-Chloro-N-( (S) - (3- ( 1-ethyl- lH-pyrazol-4-yl)phenyl)

( (2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

30. A hydrochloride salt of 3-chloro-N- ( (S) - (3- (1-ethyl-lH- pyrazol-4-yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4-

( trifluoromethyl)pyridine-2-carboxamide, or a hydrate thereof .

31. A maleate salt of 3-chloro-N- ( (S) - (3- ( 1-ethyl-lH- pyrazol-4-yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4-

(trifluoromethyl)pyridine-2-carboxamide, or a hydrate thereof,

32. 3-Chloro-N-( (S) - (2S) -piperidin-2-yl(3- ( lH-pyrazol-

4-yl)phenyl )methyl) -4- (trifluoromethyl)pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

33. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient . 34. The pharmaceutical composition according to embodiment 33, which is a glycine transporter inhibitor.

35. A pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, drug abuse, convulsion, tremor, and sleep disorders, comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The phrase "monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms" refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen, oxygen and sulfur. Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl, isoxazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl. The phrase "monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms" refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen and sulfur. Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl.

The phrase "monocyclic or bicycliσ aromatic ring having 1 or 2 nitrogen atoms as endocyclic atoms" refers to a monocyclic (e.g. 5- or 6-membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring 1 or 2 nitrogen atoms. Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, indolyl, quinolyl and isoquinolyl.

The term "Ci_₆ alkyl" used herein means a linear or branched alkyl group having 1 to 6 carbon atoms , and examples may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl.

The term "halogen (halo-)" used herein means fluorine, chlorine , bromine , and iodine atoms .

The term "Ci_6 haloalkyl" used herein means a halogen atom-substituted linear or branched alkyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C_3._₆ haloalkyl may include fluoromethyl, difluoromethyl, trifluoromethyl and trichloromethyl . The term "Ci_₆ alkoxy" used herein means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy and hexyloxy. The term "C₃-₈ cycloalkyl" used herein means a saturated carbocyclic group having 3 to 8 carbon atoms, and examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "Ci-₆ acyl" used herein means a carbonyl group bound with a hydrogen atom or linear or branched Ci_₅ alkyl or cyclic C₃-₅ alkyl, and examples may include formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropylcarbonyl and cyclobutylcarbonyl . The term "Ci_6 haloacyl" used herein means a halogen atom-substituted linear or branched acyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C₁-₆ haloacyl may include fluoroacetyl, difluoroacetyl, trifluoroacetyl and trichloroacetyl .

The term "Ci.₆ haloalkoxy" used herein means a halogen atom-substituted linear or branched alkoxy group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples may include fluoromethoxy, difluoromethoxy and trifluoromethoxy.

The term "C3-₆ alkenyl" used herein means a linear or branched C₃.₆ alkyl incorporating one double bond therein, and examples may include allyl and but-2-enyl.

The term "C2-7 alkoxycarbonyl" refers to a group composed of the above-defined Ci_₆ alkoxy and carbonyl attached to each other. Examples may include methoxycarbonyl and tert- butoxycarbonyl .

The term "pharmaceutically acceptable salt" used herein means an acid-addition salt that can be pharmaceutically accepted. Examples of the acid used may include: inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid; and organic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The conversion of the free form to the salt can be conducted in a conventional way.

Preferable embodiments of the compound of the present invention are shown below.

Specifically, ring A is preferably, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl, indolyl, imidazolyl, thienyl, thiazolyl (wherein the pyrazolyl and imidazolyl is unsubstituted or substituted with one Ci_₆ alkyl group, the thiazolyl is unsubstituted or substituted with one or two Ci_₆ alkyl groups , and the pyridyl is unsubstituted or substituted with halogen or Ci_₆alkoxy) , further preferably, unsubstituted or C₁.₆ alkyl-substituted pyrazolyl (e.g., lH-pyrazol-4-yl, 1- methyl-lH-pyrazol-4-yl, l-ethyl-lH-pyrazol-4-yl, 1-isopropyl- lH-pyrazol-4-yl, l-propyl-lH-pyrazol-4-yl) , pyridyl which is unsubstituted or substituted with halogen or d_₆alkoxy, pyrimidinyl (e.g., pyrimidin-5-yl) , pyrazinyl (e.g., pyrazin- 2-yl), or Ci_₆ alkyl-substituted imidazolyl (e.g., 3-methyl-3H- imidazol-4-yl) .

A substitution position of ring A in the benzene ring is preferably, position 3 or 4 , more preferably, position 3. R¹ is preferably, hydrogen or Ci_₆ alkyl, more preferably, hydrogen or methyl. Preferably, R¹ is hydrogen in light of the hepatic metabolic stability of the compound of the present invention. The hepatic metabolic stability was confirmed by a hepatic metabolic stability test , wherein a human liver microsome (obtained from XENOTECH LLC (Kansas City, KS, USA)) (1 mg of protein/mL) and the compound (5 μM) were added to 0.25 M phosphate buffer solution at pH 7.4 and preincubated at 37°C for 5 minutes, and reaction was then started by the addition of an NADPH production system and terminated 15 minutes later by the addition of a reaction stop solution, followed by measurement of the remaining compound by LC-MS. Ar¹ is preferably, (i) phenyl which has chloro, fluoro, or methyl at position 2 and has trifluoromethyl at position 3, 5 or 6 and/or chloro at position 3 or 6 (more preferably, phenyl which has chloro or methyl at position 2 and trifluoromethyl at position 3 or 5 , and may further have chloro at position 6); (ii) pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2 or (iii) isoquinolin-1-yl.

Specifically, preferable Ar¹ is 2-chloro-3- trifluoromethylphenyl , 3-chloro-2-methylphenyl, 2,3- dichlorophenyl , 2-methyl-3-trifluoromethylphenyl, 2-chloro-3- methylphenyl , 2-chloro-5-trifluoromethylphenyl, 2-methyl-5- trifluoromethylphenyl, 2 , 5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dichloro-3-trifluoromethylphenyl , 3-chloro-2-fluoro-6- trifluoromethylphenyl , 2 , 6-dimethylphenyl , 2,4,6- trichlorophenyl , 2-chloro-6-methylphenyl, 3-chloro-4- trifluoromethyl-pyridin-2-yl, 3-chloro-2-trifluoromethyl- pyridin-4-yl, and isoquinolin-1-yl, more preferably, 2-chloro- 3-trifluoromethylphenyl, 2 , 6-dichloro-3-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl , 2-methyl-3- trifluoromethylphenyl , 3-chloro-4-trifluoromethyl-pyridin-2-yl, 3-chloro-2-trifluoromethyl-pyridin-4-yl and isoquinolin-1-yl.

In formula [I'], Ar¹ is, in particular, preferably, pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2. Preferable compounds in the present invention are the compounds of formula [IA], [II], [III], [IIIA], [IV], [IVA], [V], [VA] and [VI] shown above.

Examples of preferable specific compounds may include: 2-chloro-N-( (S) -( ( 2S) -l-methylpiperidin-2-yl) ( 4-pyridin-3- ylphenyl)methyl) -3- (trifluoromethyl)benzamide,

3-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) (4-pyridin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N-( (S) -( (2S) -l-methylpiperidin-2-yl) ( 3-pyridin-3- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) -( (2S) -l-methylpiperidin-2-yl) ( 3-pyridin-4- ylphenyl)methyl) -3- (trifluoromethyl)benzamide , 2-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) (3-pyridin-2- ylphenyl)methyl) -3- (trifluoromethyl)benzamide. 2-chloro-N-((S)-( (2S) -l-methylpiperidin-2-yl) (4-pyridin-2- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) -( (2S) -l-methylpiperidin-2-yl) (3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S)-( ( 2S) -l-methylpiperidin-2-yl) (3- ( 1-methyl-lH- pyrazol-4-yl)phenyl)methyl) -3- (trifluoromethyl)benzamide , 2-chloro-N-( (S) - ( 3- ( 2-furyl)phenyl) ( ( 2S) -l-methylpiperidin-2- yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) -( (2S) -l-methylpiperidin-2-yl) ( 3-pyrazin-2- ylphenyl)methyl) -3- (trifluoromethyl)benzamide,

N- ( (S)-biphenyl-3-yl( ( 2S) -piperidin-2-yl)methyl) -3-chloro-4-

(trifluoromethyl)pyridine-2-carboxamide ,

3-chloro-N- ( ( S) - ( 2S) -piperidin-2-yl( 4-pyridin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N- ( ( S) - ( 2S) -piperidin-2-yl( 3-pyridin-3- ylphenyl)methyl) -3- (trifluoromethyl)benzamide, 3-chloro-N-( (S) - (2S) -piperidin-2-yl( 3-pyridin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide, 2-chloro-N- ( (S) -( 3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( ( S) - ( 2S) -piperidin-2-yl ( 3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) - ( 4- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2,6-dichloro-N-( (S) - (3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)' piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2,3-dichloro-N-( (S) - (3- ( 1-methyl- lH-pyrazol-4-yl)phenyl) ( (2S) piperidin-2-yl)methyl)benzamide , 2-chloro-N-( (S) - (2S) -piperidin-2-yl( 3- ( lH-pyrazol-4- yl)phenyl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N-( (S) - (3- ( l-isobutyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-((S)-(3-(l-ethyl-lH-pyrazol-4-yl)phenyl) ((2S)- piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide , 2-chloro-N- ( (S) - (2S) -piperidin-2-yl( 3- ( 1-propyl-lH-pyrazol-4- yl)phenyl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) - (3- ( 1-isopropyl-lH-pyrazol-4-yl)phenyl) ( (2S) - piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide,

2-methyl-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - (2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ((S) -(3- ( 1-methyl-lH-pyrazol-4-yl)phenyl)( (2S)- pyrrolidin-2-yl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) - (3-pyrimidin-5-ylphenyl) ( ( 2S) -pyrrolidin-2- yl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- (( S) - (3-pyridin-3-ylphenyl) ( (2S) -pyrrolidin-2- yl)methyl) -3- (trifluoromethyl)benzamide,

2 , 6-dichloro-N- ( ( S) - ( 3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) ^■ piperidin-2-yl)methyl)benzamide ,

2-chloro-N-( (S) - (3- ( 1-methyl- lH-pyrazol-4-γl)phenyl) ( (2S)- piperidin-2-yl)methyl) -5- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S)- (3- ( 1-isopropyl-lH-pyrazol-4-yl)phenyl) ( (2S)- pyrrolidin-2-yl)methyl) -3- (trifluoromethyl)benzamide, 3-chloro-N-( (S) - ( 3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide ,

2-methyl-N- ( (S) - (3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl) -5- ( trifluoromethyl)benzamide, 3-chloro-2-fluoro-N-((S)-(3-(l-methyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin- 2-yl)methyl) -6- (trifluoromethyl)benzamide ,

2,4, 6-trichloro-N- ( (S) - ( 3- ( 1-methyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl)benzamide, 2-chloro-6-methyl-N- ( (S) - ( 3- ( 1-methyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl)benzamide,

2 , 6-dichloro-N- ( (S) - ( 4- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide , 3-chloro-N-((S)-(3-(l-methyl-lH-pyrazol-4-yl)phenyl)((2S)- piperidin-2-yl)methyl) -2- (trifluoromethyl) isonicotinamide , 2-chloro-N-{(S)-[3-(l-methyl-lH-imidazol-5-yl)phenyl] [ (2S)- piperidin-2-yl]methyl}-3- (trifluoromethyl)benzamide , 3-chloro-N-[ (S) - ( 2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl)methyl] -4- (trifluoromethyl)pyridine-2-carboxamide , 3,6-dichloro-2-methoxy-N-{ (S) - [3- ( l-methyl-lH-pyrazol-4- yl)phenyl] [ (2S) -piperidin-2-yl]methyl}benzamide,

3-chloro-N-{ ( S) - ( 2S) -piperidin-2-yl[ 3- ( 1-propyl-lH-pyrazol-4- yl)phenyl]methyl}-4- (trifluoromethyl)pyridine-2-carboxamide, 3-chloro-N-{(S)-[3-(l-isopropyl-lH-pyrazol-4-yl)phenyl] [ (2S)- piperidin-2-yl]methyl}-4- ( trifluoromethyl)pyridine-2- carboxamide,

3-chloro-N- [ (S) - (2S) -piperidin-2-yl(3-pyrimidin-5- ylphenyl)methyl] -4- (trifluoromethyl)pyridine-2-carboxamide , 3-chloro-N-{(S)-[3-(l-ethyl-lH-pyrazol-4-yl)phenyl][(2S)- piperidin-2-yl]methyl}-4- ( trifluoromethyl)pyridine-2- carboxamide ,

3-chloro-N-( (S) -( ( 2S) -1- (cyanomethyl)piperidin-2-yl) (3- pyridin-3-ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide ,

2-chloro-N-( (S) -( (2S) -l-cyclopropylpiperidin-2-yl) (3-(l- methyl-lH-pyrazol-4-yl)phenyl)methyl) -3-

(trifluoromethyl)benzamide,

2-chloro-N-{ (S) -[ (2S) -l-isopropylpiperidin-2-yl] [3- (1-methyl- lH-pyrazol-4-yl)phenyl]methyl}-3- ( trifluoromethyl)benzamide ,

N-((S)-((2S)-1-allylpiperidin-2-yl) ( 3-pyrimidin-5- ylphenyl)methyl) -2-chloro-3- ( trifluoromethyl)benzamide ;

3-chloro-N- ( (S) - ( 2S) -piperidin-2-yl(3- ( lH-pyrazol-4- yl)phenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide ; N-( (S)-(3-(l-ethyl-lH-pyrazol-4-yl)phenyl) ( (2S) -piperidin-2- yl)methyl) isoquinoline-1-carboxamide;

3-chloro-N- ( (S) - (3- ( 6-methoxypyridin-3-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide; 3-chloro-N-( (S) - ( ( 2S) -piperidin-2-yl) ( 3-thiophen-2- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide;

3-chloro-N- ( (S) - ( (2S) -piperidin-2-yl) (3-quinolin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide;

3-chloro-N- ( ( S) - ( 3- ( 2 , 4-dimethyl-l , 3-thiazol-5- yljphenyl) ( (2S) -piperidin-2-yl)methyl) -4-

(trifluoromethyl)pyridine-2-carboxamide ;

N-( (S)-(4' -acetylbiphenyl-3-yl) ( ( 2S) -piperidin-2-yl)methyl) -3- chloro-4- (trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N- ( ( S) - ( 2S) -piperidin-2-yl( 4 ' - (trifluoromethyl)biphenyl-3-yl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide;

3-chloro-N- ( (S) - (4 ' -cyanobiphenyl-3-yl) ( ( 2S) -piperidin-2- γl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N-( (S) - ( 3- ( 6-fluoropyridin-3-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide; 3-chloro-N- ( ( S) - ( 3- ( IH-indol-5-yl)phenyl) ( ( 2S) -piperidin-2- yl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide;

6-chloro-N- ( ( S) - ( 3- ( 1-ethyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl) -2-fluoro-3-hydroxybenzamide; and a pharmaceutically acceptable salt thereof; and a hydrate thereof .

Examples of more preferable specific compounds may include :

3-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) ( 4-pyridin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide, 2-chloro-N-((S)-( (2S) -l-methylpiperidin-2-yl) (3-pyridin-3- ylphenyl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) (3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( ( S ) - ( ( 2S) - 1-methylpiperidin-2-yl) ( 3- ( 1-methyl-IH- pyrazol-4-yl)phenyl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) -( ( 2S) -l-methylpiperidin-2-yl) (3-pyrazin-2- ylphenyl)methyl) -3- (trifluoromethyl)benzamide, 3-chloro-N-( (S) - ( 2S) -piperidin-2-yl( 3-pyridin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N- ( ( S) - ( 3- ( 1-methyl- lH-pyrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide , 2-chloro-N- ( (S) - (2S) -piperidin-2-yl( 3-pγrimidin-5- ylphenyl)methyl) -3- (trifluoromethyl)benzamide,

2 , 6-dichloro-N- ( ( S) - ( 3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl ) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - (2S) -piperidin-2-yl(3- ( lH-pyrazol-4- yl)phenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) - (3- ( l-ethyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) - (2S) -piperidin-2-yl( 3- ( 1-propyl-lH-pyrazol-4- yl)phenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N-( (S) - ( 3- ( 1-isopropyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( (S) -(2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl)methyl) -3- (trifluoromethyl)benzamide, 2-chloro-N- ( ( S) - ( 3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) - pyrrolidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - ( 3-pyrimidin-5-ylphenyl) ( ( 2S) -pyrrolidin-2- yl)methyl) -3- ( trifluoromethyl)benzamide ,

2-chloro-N-( (S) - (3- ( l-methγl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -5- (trifluoromethyl)benzamide, 3-chloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide ,

3-chloro-2-fluoro-N- ( ( S) - ( 3- ( 1-methyl- lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -6- (trifluoromethyl)benzamide,

3-chloro-N-( (S) - (3- ( 1-methyl- lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -2- ( trifluoromethyl) isonicotinamide , 2-chloro-N-{ (S) - [3- ( l-methyl-lH-imidazol-5-yl)phenyl] [ (2S) - piperidin-2-yl ]methyl}-3- ( trifluoromethyl)benzamide , 3-chloro-N- [ (S) - (2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl)methyl] -4- (trifluoromethyl)pyridine-2-carboxamide, 3-chloro-N-{ ( S ) - ( 2S) -piperidin-2-yl[ 3- ( 1-propyl-lH-pyrazol-4- yl)phenyl]methyl} -4- ( trifluoromethyl)pyridine-2-carboxamide , 3-chloro-N-{ (S) - [3- ( l-isopropyl-lH-pyrazol-4-yl)phenyl] [ ( 2S) - piperidin-2-yl]methyl}-4- ( trifluoromethyl)pyridine-2- carboxamide ,

3-chloro-N- [ ( S ) - ( 2S ) -piperidin-2-γl( 3-pyrimidin-5- ylphenyl)methyl] -4- (trifluoromethyl)pyridine-2-carboxamide , 3-chloro-N-{ ( S) - [ 3- ( 1-ethyl- lH-pyrazol-4-yl)phenyl] [ ( 2S) - piperidin-2-yl]methyl}-4- (trifluoromethyl)pyridine-2- carboxamide,

3-chloro-N-( (S)-( (2S) -1- (cyanomethyl)piperidin-2-yl) (3- pyridin-3-ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide,

2-chloro-N-{ (S) -[ (2S) -l-isopropylpiperidin-2-yl] [3- ( 1-methyl- lH-pyrazol-4-yl)phenyl]methyl}-3- ( trifluoromethyl)benzamide , N- ( (S) - ( (2S) -l-allylpiperidin-2-yl) (3-pyrimidin-5- ylphenyl)methyl) -2-chloro-3- ( trifluoromethyl)benzamide ; 3-chloro-N- ( (S) - (2S) -piperidin-2-yl( 3- ( lH-pyrazol-4- yl)phenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; N-( (S)-(3-(l-ethyl-lH-pyrazol-4-yl)phenyl) ( ( 2S) -piperidin-2- yl)methyl) isoquinoline-1-carboxamide ; 3-chloro-N-( (S) - ( 3- ( 6-methoxypyridin-3-yl)phenyl) ( (2S)- piperid±n-2-y1)methyl) -4- (trifluoromethy1)pyridine-2- carboxamide;

3-chloro-N-( (S) -( ( 2S) -piperidin-2-yl) (3-thiophen-2- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide;

3-chloro-N-( (S) -( ( 2S) -piperidin-2-yl) (3-quinolin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine- 2-carboxamide;

3-chloro-N- (( S) -( 3- ( 2, 4-dimethyl-l,3-thiazol-5- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide;

N- ( (S)-(4'-acetylbiphenyl-3-yl) ( ( 2S) -piperidin-2-yl)methyl) -3- chloro-4- ( trifluoromethyl)pyridine-2-carboxamide;

3-chloro-N- ( (S) - ( 4 ' -cyanobiphenyl-3-yl) ( ( 2S) -piperidin-2- yl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N- ( (S) -( 3- ( 6-fluoropyridin-3-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide ;

3-chloro-N-( (S) - ( 3- ( lH-indol-5-yl)phenyl) ( ( 2S) -piperidin-2- yl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide; and a pharmaceutically acceptable salt thereof; and a hydrate thereof .

Examples of further preferable specific compounds may include : 3-chloro-N- ( (S) -( 2S) -piperidin-2-yl(3-pyridin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl ) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - ( 2S) -piperidin-2-yl( 3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide,

2,6-dichloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( ( S ) - ( 2S) -piperidin-2-yl( 3- ( lH-pyrazol-4- yl)phenyl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ((S)- (3- (l-ethyl-lH-pyrazol-4-γl)phenyl) ( (2S)- piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( ( S) - ( 2S ) -piperidin-2-yl( 3- ( 1-propyl-lH-pyrazol-4- yl)phenyl)methyl) -3- ( trifluoromethyl)benzamide ,

2-chloro-N- ( (S) - (3- ( l-isopropγl-lH-pγrazol-4-yl)phenyl) ( ( 2S) - piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S)- (3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -5- ( trifluoromethyl)benzamide , 3-chloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide,

3-chloro-N-( (S) - (3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -2- (trifluoromethyl) isonicotinamide, 2-chloro-N-{(S)-[3-(l-methyl-lH-imidazol-5-yl)phenyl] [ (2S)- piperidin-2-yl]methyl} -3- ( trifluoromethyl)benzamide , 3-chloro-N-[ (S) - (2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl)methyl] -4- (trifluoromethyl)pyridine-2-carboxamide, 3-chloro-N-{ (S) - (2S) -piperidin-2-yl[ 3- ( 1-propyl- lH-pyrazol-4- y1)phenyl]methyl}-4- ( trifluoromethyl)pyridine-2-carboxamide , 3-chloro-N-{(S)-[3-(l-isopropyl-lH-pyrazol-4-yl)phenyl] [ (2S)- piperidin-2-yl]methyl} -4- ( trifluoromethyl)pyridine-2- carboxamide , 3-chloro-N- [ (S) -(2S) -piperidin-2-yl( 3-pyrimidin-S- ylphenyl)methyl] -4- ( trifluoromethyl)pyridine-2-carboxamide , 3-chloro-N-{(S)-[3-(l-ethyl-lH-pyrazol-4-yl)phenyl] [(2S)- piperidin-2-yl]methyl}-4- ( trifluoromethyl)pyridine-2- carboxamide;

3-chloro-N-((S)-(2S)-piperidin-2-yl(3-(lH-pγrazol-4- yl)phenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide; N-( (S)-(3-(l-ethyl-lH-pyrazol-4-yl)phenyl) ( (2S) -piperidin-2- yl)methyl) isoquinoline-1-carboxamide ; 3-chloro-N-((S)-(3-(6-methoxypγridin-3-yl)phenyl)((2S)~ piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide;

3-chloro-N-( (S) -( ( 2S) -piperidin-2-yl) (3-thiophen-2- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N-( (S) -( (2S) -piperidin-2-yl) ( 3-quinolin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide ; 3-chloro-N-((S)-(3-(2,4-dimethyl-l,3-thiazol-5- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; N- ( (S) - (4 ' -acetγlbiphenyl-3-yl) ( (2S) -piperidin-2-yl)methyl) -3- chloro-4- ( trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N-( (S) - (4 ' -cyanobiphenyl-3-yl) ( (2S) -piperidin-2- yl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; 3-chloro-N-((S)-(3-(6-fluoropyridin-3-yl)phenyl)( (2S)- piperidin- 2-yl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide;

3-chloro-N-( (S) - (3- ( lH-indol-5-yl)phenyl) ( (2S) -piperidin-2- yl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; and a pharmaceutically acceptable salt thereof; and a hydrate thereof .

Examples of most preferable specific compounds may include :

3-Chloro-N-( (S) - ( 3- ( 1-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide;

3-Chloro-N-{ (S) - [3- ( l-ethyl-lH-pyrazol-4-yl)phenyl] [ (2S) - piperidin-2-yl]methyl}-4- (trifluoromethyl)pyridine-2- carboxamide;

3-Chloro-N- ( (S) - (2S) -piperidin-2-yl( 3- ( lH-pyrazol-4- yl)phenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide; and a pharmaceutically acceptable salt thereof; and a hydrate thereof.

The compound represented by formula [I] can be produced by a variety of synthesis methods . The methods described below are just a few examples of production processes for the compound of the present invention, and the present invention is not intended to be limited to them. In the following general production processes, each step is optionally interchangeable, and in each step, a nitrogen atom and a hydroxyl group can be protected with a protective group, if necessary and then, the protective group can be removed when the protection is unnecessary. In the general production processes, P¹ is a nitrogen protecting group by forming carbamate, such as a methoxycarbonyl , ethoxycarbonyl , tert- butoxycarbonyl or benzyloxycarbonyl group (see Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition", Wiley-Interscience); P² is a protecting group for a phenolic hydroxyl group, such as a methyl, benzyl or tert-butyldimethylsilyl group (supra.); P³ is an amino protecting group by forming an tertiary amino group, such as a methyl group or a benzyl or allyl group (supra.); P⁴ is a protecting group for a hydroxyl group, such as a pivaloyl group (supra.); X¹ is a chlorine, bromine or iodine atom; R^a is Ci_₆ alkyl (wherein the Ci.₆ alkyl is unsubstituted or substituted with a cyano group) ; and X² is a chlorine, bromine, or iodine atom or a methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group . All of other symbols are as already defined. Examples of an "inactive solvent" include: alcohols such as methanol, ethanol, isopropanol, n- butanol and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons such as pentane, hexane, toluene, benzene and xylene; esters such as ethyl acetate and ethyl formate; ketones such as acetone and methyl ethyl ketone; halogenated carbon solvents such as chloroform and dichloromethane; amides such as dimethylformamide and N-methylpyrrolidone; acetonitrile, dimethyl sulfoxide and water; and mixed solvents thereof. Examples of a "base" include: amines such as triethylamine , N,N-diisopropylethylamine, pyridine, 1,8- diazabicyclo[ 5.4.0]undec-7-ene, N,N-dimethylaniline, N,N- diethylaniline and 4-dimethylaminopyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide and sodium hydride; metal alcoholates such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal amides such as sodium amide, lithium diisopropylamide , lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide; alkyllithium such as n-butyllithium, sec-butyllithium, tert- butyllithium and methyllithium; and Grignard reagent such as methyl magnesium bromide. Examples of an "acid" include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid. [General production process 1]

(13) (14) Step 1: A compound (2) can be obtained by amidation reaction of a compound (1) with N,0-dimethylhydroxyamine in the presence or absence of a base in an inactive solvent . In this context, the amidation reaction can be practiced by many standard procedures generally known by those skilled in the art, and examples may include: amidation via a mixed anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate , or pivaloyl chloride; and amidation using a condensing agent such as l-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,3- dicyclohexylcarbodiimide , diphenylphosphorylazide, diethyl cyanophosphate , carbonyldiimidazole, or benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) . In this amidation, an additive such as 1- hydroxybenzotriazole (HOBt) can also be used, if necessary. Step 2: A compound (3) can be converted into a metal reagent with a metal or alkyllithium reagent and then reacted with the compound (2) in an inactive solvent to thereby obtain a compound ( 4 ) . In this context , examples of the metal may include magnesium and zinc, and examples of the alkyllithium reagent may include n-butyllithium, sec-butyllithium, tert- butyllithium and phenyllithium reagents .

Step 3 : The compound ( 4 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound ( 5 ) . In this context , the reducing agent is a reagent that can convert carbonyl groups into hydroxyl groups through reduction, and examples may include lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri- sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride , tetramethylammonium borohydride , lithium aluminum hydride, sodium aluminum hydride, sodium bis ( 2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and trichlorosilane.

Step 4: A compound (6) can be obtained by hydrolysis of the compound (5) with an acid or base or deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" in an inactive solvent.

Step 5 : The compound ( 6 ) can be reacted with an allylating agent such as allyl chloride or allyl bromide or a benzylating agent such as benzyl chloride or benzyl bromide in the presence or absence of a base in an inactive solvent to thereby obtain a compound (7).

Step 6 : When P³ is a methyl group , the compound ( 5 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound (7). In this context, the reducing agent is a reagent that can convert carbamate into methyl groups through reduction, and examples may include borane, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride . Step 7 : The compound ( 7 ) can be reacted with a sulfonylating agent in the presence or absence of a base in an inactive solvent and then reacted with ammonia to thereby obtain a compound (8). The sulfonylating agent is a reagent that can sulfonylate hydroxyl groups, and examples may include p- toluenesulfonyl chloride, methanesulfonyl chloride, p- toluenesulfonic acid anhydrides , methanesulfonic acid anhydrides , trifluoromethanesulfonic acid anhydrides and N- phenylbis ( trifluoromethanesulfonimide) . Step 8: The compound (10) can be obtained by amidation reaction of the compounds ( 8 ) with a compound ( 9 ) in the presence or absence of a base in an inactive solvent . In this context, the amidation can be practiced in the same way as in Step 1. Step 9: The compound (10) can be (1) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent (when P² is a methyl group); or (2) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent or hydrogenated with a palladium or platinum catalyst (when P² is a benzyl group) to thereby obtain a compound (11). In this context , examples of the palladium catalyst may include palladium black, palladium carbon and palladium hydroxide, and examples of the platinum catalyst may include platinum oxide. When P² is any group other than the protecting groups described above, the compound (11) can be obtained by removing P² through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition". Step 10: The compound (11) can be reacted with a triflating agent in the presence or absence of a base in an inactive solvent to thereby obtain a compound (12). In this context, examples of the triflating agent may include trifluoromethanesulfonic acid anhydrides and N- phenylbis (trifluoromethanesulfonimide) .

Step 11: The compound (12) can be reacted with a boric acid- or boric acid ester-substituted ring A by use of a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (13) of the present invention. In this context, examples of the palladium catalyst may include Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃J₄, PEPPSI-Ipr( trade mark) , and Pd(dppf)Cl₂, and examples of the ligand may include triphenylphosphine, 2 , 2-bis(diphenylphosphino) -1, 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl and 9 , 9-dimethyl- 4,5-bis(diphenylphosphino)xanthene (Xantphos) . Step 12: The compound (13) can be (1) subjected to deprotection reaction with N,N-dimethylbarbituric acid and a palladium catalyst (in this context, examples of the palladium catalyst may include Pd(OAc)₂, Pd₂(dba)₃, and Pd(PPh₃J₄) (when P³ is an allyl group); or (2) subjected to deprotection reaction through hydrogenation with a palladium or platinum catalyst (in this context, examples of the palladium catalyst may include palladium black, palladium carbon, and palladium hydroxide, and examples of the platinum catalyst may include platinum oxide) (when P³ is a benzyl group) to thereby obtain a compound (14) of the present invention. When P³ is any group other than the protecting groups described above, the compound (14) of the present invention can be obtained by removing P³ through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition"

[General production process 2]

(13)

(21)

Step 13: The compound (4) can be converted into a compound (15) by the same procedure as in Step 9 in the general production process 1.

Step 14: The compound (15) can be converted into a compound (16) by the same procedure as in Step 10 in the general production process 1. Step 15: The compound (16) can be converted into a compound

(17) by the same procedure as in Step 3 in the general production process 1. Step 16: The compound (17) can be converted into a compound

(18) by the same procedure as in Step 11 in the general production process 1.

Step 17: The compound (18) can be converted into a compound

(19) by the same procedure as in Step 4 in the general production process 1.

Step 18: The compound (19) can be converted into a compound

(20) by the same procedure as in Step 5 in the general production process 1.

Step 19: When P³ is a methyl group, the compound (18) can be converted into the compound (20) by the same procedure as in Step 6 in the general production process 1. Step 20: The compound (20) can be converted into a compound

(21) by the same procedure as in Step 7 in the general production process 1. Step 21: The compound (21) can be converted into the compound (13) of the present invention by the same procedure as in Step 8 in the general production process 1. Step 22: The compound (13) can be converted into the compound (14) of the present invention by the same procedure as in Step 12 in the general production process 1. [General production process 3]

Step 23: The compound (14) of the present invention can be reacted with a compound (22) in the presence or absence of a base in an inactive solvent to thereby obtain a compound (23)

The intermediate (18) can also be produced according to a general production process 4 below.

[General production process 4]

Step: 24: The compound (17) can be reacted with bispinacolborane using a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (24). In this context, examples of the palladium catalyst may include Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃) ₄, PEPPSI-Ipr( trade mark) and Pd(dppf)C1₂, and examples of the ligand may include triphenylphosphine, 2,2-bis (diphenylphosphino) - 1 , 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl, 9 , 9-dimethyl-4, 5- bis (diphenylphosphino)xanthene (Xantphos), and 1,1'- bisdiphenylphosphinoferrocene (dppf ) .

Step 25: The compound (24) can be reacted with a halogen- substituted ring A in the same way as in Step 11 in the general production process 1 to thereby obtain the compound (18).

Step 26: The compound (24) can be converted into a compound (30) through reaction with a halogenating reagent such as copper (II) bromide, bromine, iodine, N-bromosuccinimide, or N-iodosucσinimide, reaction with iodine or iodine monochloride in the presence of a base such as sodium hydroxide or sodium methoxide, reaction with chloramine-T and sodium iodide, or reaction with 1 , 3-dibromo-5 , 5-dimethylhydantoin, in an inactive solvent .

The intermediate (7) can also be produced according to a general production process 5 below. [General production process 5]

(27) (7)

Step 27: When P⁴ is a pivaloyl group, the compound (5) can be reacted with pivaloyl chloride in the presence or absence of a base in an inactive solvent to thereby obtain a compound (25). When P⁴ is any of other protecting groups, the compound (25) can be obtained by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" . Step 28: The compound (25) can be converted into a compound

(26) by the same procedure as in Step 4 in the general production process 1.

Step 29: The compound (26) can be converted into a compound

(27) by the same procedure as in Step 5 in the general production process 1.

Step 30: When P⁴ is a pivaloyl group, the compound (7) can be obtained by carrying out deprotection with a reducing agent such as lithium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, or diisobutylaluminum hydride in an inactive solvent or carrying out deprotection by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" . When P⁴ is any of other protecting groups, the compound (7) can be obtained by the deprotection procedure described in this literature .

The intermediate (18) can also be produced according to a general production process 6 below. [General production process 6]

Step 31: A compound (28) can be converted into a metal reagent by the procedure shown in Step 2 in the general production process 1 and then reacted with the compound (2) to thereby obtain a compound (29).

Step 32: The compound (18) can be obtained by the same procedure as in Step 3 in the general production process 1. [General production process 7]

(36) (14)

Step 33: The compound (2) can be reacted with a compound (31) by the same procedure as in Step 2 in the general production process 1 to thereby convert into a compound (32).

Step 34: The compound (32) can be reacted with hydroxylamine hydrochloride in an inactive solvent to thereby convert into a compound (33) .

Step 35: The compound (33) can be converted into a compound

(34) by the same procedure as in Step 11 in the general production process 1.

Step 36: The compound (34) can be converted into a compound

(35) by hydrogenation reaction with a metal catalyst in the presence or absence of a base or reaction with a reducing agent in the presence or absence of formic acid or an ammonium salt (e.g., ammonium formate, ammonium chloride, or ammonium acetate), in an inactive solvent. In this context, examples of the metal catalyst may include: palladium catalysts such as palladium hydroxide, palladium carbon and palladium black; nickel catalysts such as Raney nickel; and platinum catalysts such as platinum oxide. Examples of the reducing agent may include: boron reagents such as boron hydride (BH₃) , sodium borohydride (NaBH₄) and sodium cyanoborohydride (NaBH₃CN) ; aluminum reagents such as lithium aluminum hydride (LiAlH₄); metals such as zinc, magnesium and sodium; samarium iodide; and lithium naphthalenide . Step 37: The compound (35) can be converted into a compound (36) by the same procedure as in Step 8 in the general production process 1.

Step 38: The compound (36) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.

[General production process 8]

(14)

Step 39: The compound (30) can be converted into a compound

(37) by the same procedure as in Step 4 in the general production process 1.

Step 40: The compound (37) can be converted into a compound

(38) by the same procedure as in Step 5 in the general production process 1.

Step 41: The compound (38) can be converted into a compound

(39) by the same procedure as in Step 7 in the general production process 1.

Step 42: The compound (39) can be converted into a compound

(40) by the same procedure as in Step 8 in the general production process 1.

Step 43: The compound (40) can be converted into a compound (41) by the same procedure as in Step 12 in the general production process 1.

Step 44: The compound (41) can be converted into a compound

(42) through reaction with methyl chloroformate , ethyl chloroformate , tert-butyl dicarbonate, 2-[(tert- butoxycarbonyl)oxyimino] -2-phenylacetonitrile, or benzyl chloroformate in the presence or absence of a base in an inactive solvent or reaction with a reagent forming carbamate as a protecting group for a nitrogen atom described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" . Step 45: The compound (42) can be converted into a compound

(43) by the same procedure as in Step 11 in the general production process 1. Step 46: The compound (43) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.

The compound of the present invention may have plural asymmetric centers. Thus, the compound can exist in any of the forms of an optically active substance and a racemic body thereof and may further include plural diastereoisomers . All of these forms are encompassed within the scope of the present invention. Individual isomers may be obtained by a method known in the art, for example, the use of optically active starting materials or intermediates, optically selective or diasteroselective reaction in the production of intermediates or final products, or chromatographic separation in the production of intermediates or final products. When the compound of the present invention forms a hydrate or solvate, these compounds are also encompassed within the scope of the present invention. The compound of the present invention can be administered orally or parenterally . Examples of the dosage form thereof include tablets, capsules, granules, powdered medicines, powders, troches, ointments, creams, emulsions, suspensions, suppositories, and injections. Any of these preparations can be produced by a routine pharmaceutical technique (e.g., methods specified by Japanese Pharmacopoeia, 14th ed. ) . These dosage forms can be selected appropriately according to the conditions and age of a patient and the purpose of treatment . These preparations can be produced by incorporating pharmacologically acceptable carriers , that is , excipients (e.g., crystalline cellulose, starch, lactose, and mannitol), binders (e.g., hydroxypropylcellulose and polyvinyl pyrrolidone) , lubricants (e.g., magnesium stearate and talc), disintegrants (e.g., carboxymethylcellulose calcium), and various other pharmacologically acceptable additives, into a composition comprising the compound of the present invention.

The dosage of the compound of the present invention is 1 to 2000 mg/day in the treatment of an adult, which is administered at a single or divided daily dose. This dosage can be increased or decreased appropriately according to the age, body weight, and conditions of a patient.

Next , the present invention will be described more specifically with reference to Production Examples , Examples , and Test Example. However, the present invention is not intended to be limited to these Examples .

"Silica gel" and "NH-silica gel" used for purification using column chromatography were silica gel 6ON (Kanto Chemical Co., Inc.) and Chromatorex NH (Fuji Silysia) , respectively. TLC (silica gel) and TLC (NH-silica gel) used for purification using TLC were Silica gel 60F254 (Merck Ltd. ) and TLC Plate NH (Fuji Silysia) . Each instrumental data described in Production Examples and Examples was measured with measurement instruments below. MS spectrum: Shimadzu LCMS-20IOEV or micromass Platform LC

NMR spectrum: [¹H-NMR] 600 MHz: JNM-ECA600 (JEOL, Ltd.), 500 MHz: JNM-ECA500 (JEOL, Ltd.), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI2000/200 (Varian Inc.) Specific rotation: AUTOPOL V (Rudolph Research Analytical)

[Examples]

Compound names in Examples were designated by use of ACD/Name (ACD/Labs 8.00, Advanced Chemistry Development Inc.).

Abbreviations used in Production Examples, Examples, and Test Example are shown below.

ALX5407: N- [(3R) -3- ( [ 1 , 1 ' -biphenyl] -4-yloxy) -3- ( 4- fluorophenyl)propyl] -N-methylglycine HCl salt Boc: tert-butoxycarbonyl

BOP reagent: benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate

Bn: benzyl

DMAP : 4-dimethylaminopyridine DMF: N,N-dimethylformamide dppf : bisdiphenylphosphinoferrocene

EDC : 1-ethyl-3- ( 3-dimethylaminopropy1) carbodiimide

HEPES: N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid

HOBT: 1-hydroxybenzotriazole Me: methyl

MeOH : methanol

Piv: pivaloyl

TBAF: n-tetrabutylammonium fluoride

TBS: tert-butyldimethylsilyl Tf: trifluoromethanesulfonyl

THF : tetrahydrofuran

TLC: thin-layer chromatography

PEPPSI-Ipr(trade mark): [ 1 , 3-Bis( 2 , 6-Diisopropylphenyl) imidazol-2-ylidene] ( 3-chloropyridyl) palladium( II ) dichloride

Production Example 1 Synthesis of tert-butyl (2S) -2- ( (methoxy(methyl) amino) carbonyl)piperidine-1- carboxylate

Triethylamine (218 g) and N, O-dimethylhydroxyamine hydrochloride (84 g) were added to a chloroform solution (1200 ml) of (S) -l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (165 g) . After ice cooling, a BOP reagent (334 g) was gradually added thereto . The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate and sequentially washed with 0.5 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water, and saturated brine . The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=5: 1) to obtain the title compound (178 g) as a colorless oil. MS (ESI pos.) m/z : 273([M+H]+), (ESI pos.) m/z : 295([M+Na]+) IH NMR (200 MHz, CDC13) δ ppm 1.32 - 1.81 (m, 14 H), 1.93 - 2.06 (m, 1 H), 3.18 (s, 3 H), 3.30 - 3.61 (m, 1 H), 3.70 - 4 . 06 (m, 4 H) , 4 . 82 - 5 . 18 (m , 1 H)

A compound shown below was obtained in the same way.

tert-butyl (2S) -2- ( (methoxy(methyl) amino)carbonyl)pyrrolidine -1-carboxylate MS (ESI pos.) m/z : 259([M+H]+), (ESI pos . ) m/z : 281([M+Na]+)

IH NMR (600 MHz, CDC13) δ ppm 1.39 - 1.48 (m, 9 H), 1.79 -

2.03 (m, 3 H), 2.13 - 2.27 (m, 1 H), 3.20 (s, 3 H), 3.37 - 3.51 (m, 1 H), 3.53 - 3.63 (m, 1 H), 3.70 - 3.81 (m, 3 H), 4.57 - 4.74 (m, 1 H)

Production Example 2 Synthesis of tert-butyl (2S) -2- ((S)- hydroxy( 3-methoxyphenyl)methyl)piperidine-1- carboxylate

(1) Magnesium (7.1 g) was suspended in tetrahydrofuran (270 ml) under a nitrogen atmosphere. A small amount of iodine was added thereto, and 3-bromoanisole (35 ml) was then gradually added thereto. The mixture was stirred at room temperature for 1 hour, and this reaction solution was added dropwise to a tetrahydrofuran solution (300 ml) of tert-butyl (2S) -2- ( (methoxy(methyl)amino)carbonyl) piperidine-1-carboxylate (50 g) under ice cooling. The mixture was stirred at room temperature for 2 hours and 10% aqueous ammonium chloride solution was added to the mixture. followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine . The organic layer was dried over anhydrous sodium sulfate . The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=8:l) to obtain tert-butyl (2S) -2- (3-methoxybenzoyl)piperidine-l- carboxylate (33 g) as a pale yellow oil. MS (ESI pos.) m/z : 342([M+Na]+) IH NMR (600 MHz, CDC13) δ ppm 1.29 - 1.53 (m, 11 H), 1.53 - 1.88 (m, 3 H), 1.99 - 2.22 (m, 1 H), 3.07 - 3.29 (m, 1 H), 3.81 - 4.05 (m, 4 H), 5.41 - 5.69 (m, 1 H), 7.05 - 7.15 (m, 1 H) , 7.30 - 7.57 (m, 3 H) (2) A tetrahydrofuran solution (300 ml) of tert-butyl (2S) -2- (3-methoxybenzoyl)piperidine-l-carboxylate (33 g) was cooled to -78°C under a nitrogen atmosphere. L-Selectride (trade mark) (I M tetrahydrofuran solution, 200 ml) was added dropwise thereto over 40 minutes. The mixture was stirred at the same temperature for 3 hours. Then, 15% aqueous hydrogen peroxide solution (200 ml) was added dropwise thereto over 15 minutes , and the mixture was stirred at room temperature for 30 minutes . The organic solvent was evapolated under reduced pressure. Ethyl acetate and water were added to the resulting solution, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obatined solid was washed with hexane/ethyl acetate (=9:1) to obtain the title compound (22 g) as a colorless solid. MS (ESI pos.) m/z : 344([M+Na]+)

NMR IH NMR (600 MHz, CDC13) δ ppm 1.26 - 1.34 (m, 1 H) , 1.35 - 1.75 (m, 14 H), 2.84 - 3.15 (m, 1 H), 3.82 (s, 3 H), 3.95 - 4.46 (m, 2 H), 4.83 - 4.88 (m, 1 H), 6.81 - 6.87 (m, 1 H), 6.90 - 7.00 (m, 2 H), 7.22 - 7.31 (m, 1 H)

Compounds shown below were obtained in the same way.

tert-butyl (2S) -2- ( (S) - (3- (benzyloxy)phenyl) (hydroxy)methyl) piperidine-1-carboxylate

MS (ESI pos.) m/z : 398([M+H]+), (ESI pos.) m/z : 420([M+Na]+)

IH NMR (600 MHz, CDC13) δ ppm 1.24 - 1.32 (m, 1 H), 1.34 - 1.42 (m, 1 H), 1.42 - 1.62 (m, 12 H), 1.63 - 1.73 (m, 1 H),

2.86 - 3.11 (m, 1 H), 3.96 - 4.47 (m, 2 H), 4.82 - 4.87 (m, 1

H), 5.07 (s, 2 H), 6.90 - 6.93 (m, 1 H), 6.95 - 7.06 (m, 2 H),

7.26 - 7.30 (m, 1 H), 7.30 - 7.35 ^'(m, 1 H), 7.36 - 7.41 (m, 2

H) , 7.42 - 7.45 (m, 2 H) tert-butyl (2S) -2- ( (S) -hydroxy(3-methoxyphenyl)methyl) pyrrolidine-1-carboxylate

MS (ESI pos.) m/z : 308([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.19 - 4.98 (m, 20 H), 6.73

- 6.85 (m, 1 H), 6.84 - 7.01 (m, 2 H), 7.16 - 7.28 (m, 1 H) tert-butyl (2S) -2- ( (S) -biphenyl-3-yl(hydroxy)methyl) piperidine-1-carboxylate

MS (ESI pos.) m/z : 368([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.30 - 1.37 (m, 1 H), 1.37 - 1.65 (m, 13 H), 1.65 - 1.74 (m, 1 H), 2.87 - 3.18 (m, 1 H),

3.97 - 4.54 (m, 2 H), 4.95 (d, J=IO.1 Hz, 1 H), 7.31 - 7.40 (m, 2 H), 7.39 - 7.49 (m, 3 H), 7.50 - 7.65 (m, 4 H) tert-butyl ( 2S) -2- ( (S) -biphenyl-4-yl(hydroxy)methyl) piperidine-1-carboxylate

MS (ESI pos.) m/z : 390([M+Na]+)

IH NMR (600 MHz, CDC13) δ ppm 1.32 - 1.38 (m, 1 H) , 1.38 - 1.65 (m, 13 H), 1.66 - 1.74 (m, 1 H), 2.89 - 3.17 (m, 1 H),

3.98 - 4.55 (m, 2 H), 4.93 (d, J=IO.5 Hz, 1 H), 7.32 - 7.37 (m, 1 H), 7.40 - 7.49 (m, 4 H), 7.54 - 7.64 (m, 4 H) tert-butyl (2S)-2-( (S)-(4-( (tert-butyl(dimethyl) silyl)oxy) phenyl) (hydroxy)methyl)piperidine-1-carboxylate

MS (ESI pos.) m/z : 422([M+H]+), (ESI pos.) m/z : 444([M+Na]+)

IH NMR (600 MHz, DMSO-d6) δ ppm 0.17 (s, 6 H), 0.94 (s, 9 H), 1.11 - 1.19 (m, 1 H), 1.22 - 1.33 (m, 2 H), 1.35 - 1.47 (m, 10

H), 1.54 - 1.72 (m, 2 H), 2.79 - 3.01 (m, 1 H), 3.82 - 3.92 (m,

1 H), 4.02 - 4.20 (m, 1 H), 4.71 - 4.77 (m, 1 H), 6.77 - 6.86

(m, 2 H), 7.17 - 7.25 (m, 2 H) tert-butyl 2- [ (S) -hydroxy(3-methoxy-4-methylphenyl)methyl] piperidine-1-carboxylate

MS ; (ESI pos.) m/z : 336 ([M+H] +)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.34 (m, 1 H) , 1.34 -

1.63 (m, 13 H), 1.63 - 1.74 (m, 1 H), 2.20 (s, 3 H), 2.84 -

3.31 (m, 1 H), 3.84 (s, 3 H), 3.98 - 4.22 (m, 1 H), 4.23 - 4.47 (m, 1 H), 4.82 - 4.87 (m, 1 H), 6.82 (d, J=7.3 Hz, 1 H),

6.87 (br. s., 1 H), 7.09 (d, J=7.3 Hz, 1 H) tert-butyl 2-[ (S) - (4-chloro-3-methoxyphenyl) (hydroxy)methyl] piperidine-1-carboxylate S ; (ESI pos.) m/z : 356 ([M+H] +)

IH NMR (600 MHz, CDC13) δ ppm 1.20 - 1.72 (m, 15 H), 2.81 - 3.11 (m, 1 H), 3.47 (br. s., 1 H), 3.91 (s, 3 H), 3.95 - 4.09 (m, 1 H), 4.14 - 4.40 (m, 1 H), 4.83 - 4.87 (m, 1 H), 6.85 (dd, J=8.3, 1.8 Hz, 1 H), 6.99 (br. s., 1 H), 7.32 (d, J=8.3 Hz, 1 H)

Production Example 3 Synthesis of (S)-l-(( 2S)-I- allylpiperidin-2-yl) -1- ( 3-methoxyphenyl) methanamine

(1) An aqueous solution (350 ml) of potassium hydroxide (39 g) was added to a methanol solution (400 ml) of tert-butyl (2S)- 2-((S) -hydroxy( 3-methoxyphenyl)methyl)piperidine-1-carboxylate (22 g) and stirred at 100⁰C for 16 hours. After cooling to room temperature, the organic solvent was distilled off. Water was added to the resulting solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of hexane/ethyl acetate=19:l to obtain (S) - (3-methoxyphenyl) ( (2S) -piperidin-2- yl)methanol (19 g) as a coloress solid. MS (ESI pos.) m/z : 222([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.20 - 1.32 (m, 2 H), 1.34 - 1.44 (m, 2 H), 1.54 - 1.61 (m, 1 H), 1.73 - 1.79 (m, 1 H),

2.56 - 2.63 (m, 1 H), 2.63 - 2.68 (m, 1 H), 3.06 - 3.11 (m, 1 H), 3.82 (s, 3 H), 4.37 (d, J=6.9 Hz, 1 H), 6.79 - 6.85 (m, 1 H), 6.88 - 6.94 (m, 2 H), 7.23 - 7.28 (m, 1 H)

(2) Potassium carbonate (16 g) and allyl bromide (7.3 ml) were added to a DMF solution (200 ml) of (S) -(3- methoxyphenyl) ( ( 2S) -piperidin-2-yl)methanol (17 g) under a nitrogen atmosphere and stirred at 50°C for 2 hours. The reaction mixture was cooled on ice and water and ethyl acetate were added to the mixture. The organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The drying agent was filtered off , and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=19:l) to obtain (S) - ( (2S) -l-allylpiperidin-2-yl) (3- methoxyphenyl)methanol (17 g) as a colorless oil. MS (ESI pos.) m/z : 262([M+H]+) IH NMR (200 MHz, CDC13) δ ppm 1.12 - 1.77 (m, 6 H), 2.56 - 2.81 (m, 2 H), 2.93 - 3.11 (m, 1 H), 3.27 - 3.51 (m, 2 H), 3.81 (s, 3 H), 4.72 (d, J=9.7 Hz, 1 H), 5.11 - 5.26 (m, 2 H), 5.76 - 5.99 (m, 1 H), 6.76 - 6.85 (m, 1 H), 6.89 - 6.97 (m, 2 H) , 7 . 18 - 7 . 28 (m, 1 H)

(3) A chloroform solution (160 ml) of (S) -((2S)-I- allylpiperidin-2-yl) ( 3-methoxyphenyl)methanol (17 g) and triethylamine (15 ml) was cooled on ice under a nitrogen atmosphere. Methanesulfonyl chloride (6.9 ml) was added dropwise thereto. The mixture was stirred under ice cooling for 1.5 hours and at room temperature for additional 30 minutes . The reaction solution was concentrated under reduced pressure. 8 M Ammonia/methanol solution (150 ml) was added thereto, and the mixture was stirred at 40⁰C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol/28% ammonia water=50 : 1: 0.5) to obtain the title compound (13 g) as a yellow oil. MS (ESI pos.) m/z : 261([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.01 - 1.07 (m, 1 H) , 1.29 - 1.54 (m, 4 H), 1.59 - 1.69 (m, 1 H), 2.62 - 2.71 (m, 2 H), 3.01 - 3.08 (m, 1 H), 3.32 - 3.42 (m, 2 H), 3.81 (s, 3 H), 4.17 (d, J=9.6 Hz, 1 H), 5.10 - 5.15 (m, 1 H), 5.18 - 5.24 (m, 1 H), 5.84 - 5.93 (m, 1 H), 6.76 - 6.80 (m, 1 H), 6.91 - 6.96 (m, 2 H) , 7.19 - 7.25 (m, 1 H)

Compounds shown below were obtained in the same way.

(S)-1-((2S)-1-allylpiperidin-2-yl)-l-(3-(benzyloxy)phenyl) methanamine

MS (ESI pos.) m/z : 337([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 0.98 - 1.07 (m, 1 H) , 1.29 - 1.45 (m, 3 H), 1.45 - 1.54 (m, 1 H), 1.58 - 1.68 (m, 1 H), 2.62 - 2.73 (m, 2 H), 3.00 - 3.09 (m, 1 H), 3.32 - 3.45 (m, 2 H), 4.15 (d, J=9.6 Hz, 1 H), 5.07 (s, 2 H), 5.11 - 5.16 (m, 1 H), 5.19 - 5.24 (m, 1 H), 5.85 - 5.93 (m, 1 H), 6.85 - 6.88 (m, 1 H), 6.95 (d, J=7.8 Hz, 1 H), 7.00 - 7.04 (m, 1 H), 7.20 - 7.25 (m, 1 H), 7.29 - 7.35 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.41 - 7.46 (m, 2 H)

(S)-1-((2S)-1-allylpiperidin-2-yl) - 1-biphenyl-3-ylmethanamine MS (ESI pos.) m/z : 307([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.02 - 1.12 (m, 1 H) , 1.29 -

1.46 (m, 3 H), 1.46 - 1.56 (m, 1 H), 1.60 - 1.74 (m, 1 H), 2.66 - 2.75 (m, 2 H), 3.02 - 3.10 (m, 1 H), 3.33 - 3.45 (m, 2 H), 4.27 (d, J=9.6 Hz, 1 H), 5.09 - 5.27 (m, 2 H), 5.86 - 5.95 (m, 1 H), 7.28 - 7.52 (m, 6 H), 7.54 - 7.66 (m, 3 H) (S)-1-((2S)-1-allylpiperidin-2-yl) - 1-biphenyl-4-ylmethanamine

MS (ESI pos.) m/z : 307([M+H]+)

(S)-I- (3-methoxy-4-methylphenyl) -1- ( l-prop-2-ene-l-yl piperidine-2-yl)methanamine

MS ; (ESI pos.) m/z : 275 QM+H] +) IH NMR (600 MHz, CDC13) δ ppm 1.00 - 1.10 (m, 1 H), 1.28 -

1.75 (m, 5 H), 2.19 (s, 3 H), 2.61 - 2.71 (m, 2 H), 3.01 -

3.07 (m, 1 H), 3.32 - 3.41 (m, 2 H), 3.83 (s, 3 H), 4.16 (d,

J=9.6 Hz, 1 H), 5.09 - 5.13 (m, 1 H), 5.18 - 5.23 (m, 1 H),

5.85 - 5.93 (m, 1 H), 6.79 - 6.83 (m, 1 H), 6.88 - 6.90 (m, 1 H), 7.05 (d, J=7.8 Hz, 1 H)

( S) - 1- ( 4-chloro-3-methoxyphenyl) -1- ( 1-prop-2-ene- 1-yl piperidine-2-yl)methanamine S ; (ESI pos.) m/z : 295 ([M+H] + )

IH NMR (600 MHz, CDC13) δ ppm 0.98 - 1.74 (m, 6 H), 2.57 - 2.62 (m, 1 H). 2.63 - 2.70 (m, 1 H), 2.98 - 3.05 (m, 1 H), 3.30 - 3.39 (m, 2 H), 3.90 (s, 3 H), 4.18 (d, J=9.6 Hz, 1 H), 5.10 - 5.14 (m, 1 H), 5.17 - 5.23 (m, 1 H), 5.83 - 5.91 (m, 1 H), 6.82 - 6.87 (m, 1 H), 7.02 (d, J=I.8 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H)

Production Example 4 Synthesis of 3-((S)-(( 2S)-I- allylpiperidin-2-yl) ( (2-chloro-3-

( trifluoromethyl)benzoyl) amino)methyl)phenyl trifluoromethanesulfonate

(1) HOBt-H₂O (2.2 g) and EDC-HCl (2.5 g) were added to a DMF solution (15 ml) of 2-chloro-3-trifluoromethylbenzoic acid (2.6 g) and stirred at room temperature for 30 minutes. A DMF solution (15 ml) of (S) -1- ( ( 2S) -1-allylpiperidin-2-yl) -1- (3- methoxyphenyl) methanamine (3.0 g) was added thereto, and the mixture was stirred at room temperature for 3 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=50:l) to obtain N- ( (S) - ( (2S) -1- allylpiperidin-2-yl) ( 3-methoxyphenyl)methyl) -2-chloro-3- (trifluoromethyl)benzamide (3.4 g) as a colorless solid. MS (ESI pos.) m/z : 467 ( [M+H]+) , (ESI neg.) m/z : 465([M-H]-)

IH NMR (200 MHz, CDC13) δ ppm 1.25 - 1.88 (m, 6 H), 2.45 - 2.64 (m, 1 H), 2.75 - 3.03 (m, 2 H), 3.10 - 3.38 (m, 2 H), 3.81 (s, 3 H), 4.88 - 4.98 (m, 1 H), 5.02 - 5.17 (m, 2 H), 5.61 - 5.83 (m, 1 H), 6.75 - 6.84 (m, 1 H), 6.90 - 7.01 (m, 2 H), 7.19 - 7.32 (m, 1 H), 7.36 - 7.48 (m, 1 H), 7.64 - 7.81 (m, 3 H) (2) A chloroform solution (30 ml) of N- ( (S) - ( ( 2S) -1- allylpiperidin-2-yl) (3-methoxyphenyl)methyl) -2-chloro-3- ( trifluoromethyl)benzamide (3.3 g) was cooled on ice under a nitrogen atmosphere. BBr₃ (2.0 ml) was added thereto, and the mixture was stirred under ice cooling for 1.5 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=100:0 to 88:12) to obtain N- ( (S) - ( (2S) -1- allylpiperidin-2-yl) (3-hydroxyphenyl)methyl) -2-chloro-3- (trifluoromethyl)benzamide (3.2 g) in a colorless amorphous state. MS (ESI pos.) m/z : 453([M+H]+), (ESI neg.) m/z : 451([M-H]-)

IH NMR (300 MHz, CDC13) δ ppm 1.28 - 1.63 (m, 5 H), 1.70 - 1.86 (m, 1 H), 2.51 - 2.65 (m, 1 H), 2.74 - 3.03 (m, 2 H), 3.16 - 3.37 (m, 2 H), 4.90 (d, J=9.2 Hz, 1 H), 5.04 - 5.20 (m, 2 H), 5.62 - 5.82 (m, 1 H), 6.59 - 6.67 (m, 1 H), 6.78 - 6.93 (m, 2 H), 7.10 - 7.20 (m, 1 H), 7.37 - 7.45 (m, 1 H), 7.65 - 7.93 (m, 3 H) (3) Pyridine (2.6 ml) was added to a chloroform solution (20 ml) of N-( (S)-((2S)-l-allylpiperidin-2-yl) (3-hydroxyphenγl) methyl) -2-chloro-3- (trifluoromethyl)benzamide (3.0 g) under a nitrogen atmosphere. After ice cooling, a trifluoromethanesulfonic acid anhydride (1.3 ml) was added dropwise thereto over 2 minutes . The mixture was stirred under ice cooling for 30 minutes and at room temperature for additional 1.5 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with water and a brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=100:0 to 97:3) to obtain the title compound (3.4 g) as a reddish brown oil.

MS (ESI pos.) m/z : 585([M+H]+), (ESI neg.) m/z : 583([M-H]-) IH NMR (200 MHz, CDC13) δ ppm 1.22 - 1.91 (m, 6 H), 2.49 - 2.70 (m, 1 H), 2.71 - 3.03 (m, 2 H), 3.12 - 3.38 (m, 2 H), 4.92 - 5.03 (m, 1 H), 5.05 - 5.20 (m, 2 H), 5.61 - 5.84 (m, 1 H), 7.12 - 7.34 (m, 2 H), 7.37 - 7.50 (m, 3 H), 7.65 - 7.85 (m, 3 H)

Compounds shown below were synthesized in the same way.

3-((S)-((2S)-l-allylpyrrolidin-2-yl) ( (2-chloro-3-

(trifluoromethyl)benzoyl) amino)methyl)phenyl trifluoromethanesulfonate

MS (ESI pos.) m/z : 571([M+H]+) IH NMR (600 MHz, CDC13) δ (ppm) ; 1.64 - 1.78 (m, 2 H), 1.80 -

1.90 (m, 1 H), 2.15 - 2.24 (m, 1 H), 2.32 - 2.39 (m, 1 H),

2.55 (dd, J=14.0, 7.6 Hz, 1 H), 2.70 (dd, J=13.8, 5.0 Hz, 1 H),

3.02 - 3.08 (m, 1 H), 3.14 - 3.19 (m, 1 H), 4.84 (d, J=16.0 Hz,

1 H), 4.95 (d, J=IO.1 Hz, 1 H), 5.19 (d, J=7.3 Hz, 1 H), 5.56 - 5.66 (m, 1 H), 7.15 - 7.19 (m, 1 H), 7.30 (s, 1 H), 7.37 -

7.41 (m, 1 H), 7.41 - 7.51 (m, 3 H), 7.75 (d, J=7.8 Hz, 1 H),

7.79 - 7.83 (m, 1 H)

3-( (S)-( (2S)-l-allylpiperidin-2-yl) ( ( 2 , 6-dichloro-3-

( trifluoromethyl)benzoyl) amino)methyl)phenyl trifluoromethanesulfonate

(ESI pos.) m/z : 619([M+H]+), (ESI neg.) m/z : 617([M-H]-)

IH NMR (600 MHz, CDC13) δ ppm 1.29 - 1.86 (m, 6 H), 2.55 -

2.63 (m, 1 H), 2.74 - 2.81 (m. 1 H), 2.92 - 2.99 (m, 1 H), 3.20 - 3.31 (m, 2 H) , 4.94 - 5.02 (m, 1 H), 5.05 - 5.15 (m, 2 H), 5.65 - 5.75 (m, 1 H), 7.17 - 7.69 (m, 7 H) 3-( (S)-( (2S)-l-allylpiperidin-2-yl) ( (2,3- dichlorobenzoyl)amino)methyl)phenyl trifluoromethanesulfonate (ESI pos.) m/z : 551([M+H]+), (ESI neg.) m/z : 549([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.27 - 1.42 (m, 2 H), 1.49 - 1.64 (m, 3 H), 1.74 - 1.85 (m, 1 H), 2.53 - 2.60 (m, 1 H), 2.75 - 2.82 (m, 1 H), 2.89 - 2.95 (m, 1 H), 3.17 (dd, J=13.8, 6.0 Hz, 1 H), 3.28 (dd, J=14.0, 6.6 Hz, 1 H), 4.96 (dd, J=8.9, 3.4 Hz, 1 H), 5.06 - 5.15 (m, 2 H), 5.67 - 5.78 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7.27 - 7.31 (m, 2 H), 7.39 - 7.48 (m, 3 H), 7.55 (dd, J=8.0, 1.6 Hz, 1 H), 7.82 (br. s., 1 H) 3-((S)-((2S)-l-allylpiperidin-2-yl) ( (3-chloro-2- methylbenzoyl)amino)methyl)phenyl trifluoromethanesulfonate MS (ESI pos.) m/z : 531([M+H]+), (ESI neg.) m/z : 529([M-H]-)

IH NMR (600 MHz, CDC13) δ ppm 1.23 - 1.33 (m, 1 H), 1.36 -

1.45 (m, 1 H), 1.48 - 1.60 (m, 3 H), 1.74 - 1.84 (m, 1 H),

2.41 (s, 3 H), 2.55 - 2.64 (m, 1 H), 2.73 - 2.82 (m, 1 H),

2.87 - 2.96 (m, 1 H), 3.14 - 3.22 (m, 1 H), 3.27 (dd, J=13.8, 6.4 Hz, 1 H), 4.95 (dd, J=8.9, 3.4 Hz, 1 H), 5.04 - 5.19 (m, 2

H), 5.65 - 5.75 (m, 1 H), 7.15 - 7.21 (m, 2 H), 7.21 - 7.31 (m,

2 H) , 7.33 - 7.50 (m, 4 H)

5- [(S)-({ [2-chloro-3-

(trifluoromethy1)phenyl]carbony1}amino) ( 1-prop-2-ene-1- ylpiperidine-2-yl)methyl] -2-methylphenyl trifluoromethanesulphonate

MS ; (ESI pos.) m/z : 599 ([M+H] +)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.33 (m, 1 H), 1.35 - 1.42 (m_» 1 H) , 1.50 - 1.61 (m, 3 H) , 1.74 - 1.82 (m, 1 H), 2.36 (s, 3 H), 2.55 - 2.61 (m, 1 H) , 2.74 - 2.79 (m, 1 H), 2.89 - 2.95 (m, 1 H), 3.18 - 3.23 (m, 1 H), 3.26 - 3.31 (m, 1 H), 4.92 (dd, J=9.2, 3.2 Hz, 1 H) , 5.09 - 5.14 (m, 2 H) , 5.68 - 5.76 (m, 1 H), 7.24 - 7.26 (m, 1 H), 7.27 - 7.32 (m, 2 H) , 7.44 (t, J=7.8 Hz, 1 H), 7.68 (dd, J=7.8, 1.4 Hz, 1 H), 7.75 - 7.80 (m, 2 H)

2-chloro-5- [ (S) - ( { [2-chloro-3- (trifluoromethyl)phenyl]carbonyl}amino) ] (l-prop-2-ene-l- ylpiperidine-2-yl)methyl]phenyl trifluoromethanesulphonate MS; (ESI pos.) m/z : 619 ([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.21 - 1.81 (m, 6 H), 2.57 - 2.62 (m, 1 H), 2.72 - 2.77 (m, 1 H), 2.87 - 2.94 (m, 1 H), 3.18 - 3.23 (m, 1 H), 3.25 - 3.30 (m, 1 H), 4.92 (dd, J=9.2, 2.8 Hz, 1 H), 5.09 - 5.14 (m, 2 H), 5.67 - 5.75 (m, 1 H), 7.34 - 7.37 (m, 2 H), 7.42 - 7.46 (m, 1 H), 7.47 - 7.50 (m, 1 H), 7.66 - 7.69 (m, 1 H), 7.77 - 7.79 (m, 1 H), 7.80 - 7.83 (m, 1 H)

Production Example 5 Synthesis of 3- ( (S) - ( (2-chloro-3- ( trifluoromethyl)benzoyl) amino) ( (2S) -1- methylpiperidin-2-yl)methyl)phenyl trifluoromethanesulfonate

(1) A tetrahydrofuran solution (120 ml) of tert-butyl (2S) -2- ( (S) - (3- (benzyloxy)phenyl) (hydroxy)methyl)piperidine-1- carboxylate (8.7 g) was cooled on ice under a nitrogen atmosphere. Lithium aluminum hydride (4.2 g) was gradually added thereto. The mixture was stirred at 80⁰C for 1 hour. The reaction mixture was cooled on ice. A saturated aqueous sodium potassium tartrate solution and 10% aqueous sodium hydroxide solution were added thereto, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off with a funnel firmly covered with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain (S) -(3- (benzyloxy)phenyl) ( (2S) -1- methylpiperidin-2-yl)methanol (6.8 g) as a colorless oil. MS (ESI pos.) m/z : 312([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.24 - 1.29 (m, 1 H), 1.37 - 1.49 (m, 3 H), 1.53 - 1.60 (m, 1 H), 1.63 - 1.72 (m, 1 H), 2.47 - 2.53 (m, 4 H), 2.61 - 2.67 (m, 1 H), 2.99 - 3.05 (m, 1 H), 4.60 (d, J=9.2 Hz, 1 H), 5.07 (s, 2 H), 6.87 - 6.89 (m, 1 H), 6.94 - 6.98 (m, 1 H), 7.02 - 7.04 (m, 1 H), 7.24 (t, J=8.0 Hz, 1 H), 7.30 - 7.34 (m, 1 H), 7.36 - 7.40 (m, 2 H), 7.42 - 7 . 45 (m, 2 H)

(2) A chloroform solution (50 ml) of (S) -( 3-

(benzyloxy)phenyl) ( (2S) -l-methγlpiperidin-2-yl)methanol (6.8 g) and triethylamine (4.2 ml) was cooled on ice. Methanesulfonyl chloride (1.9 ml) was added dropwise thereto. The mixture was stirred under ice cooling for 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 8 M ammonia/methanol solution (40 ml) and stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol/28% ammonia water=50 : 1: 0.5 to 30:1:0.3) to obtain (S) -1- (3- (benzyloxy)phenyl) -l-( (2S) -1-methylpiperidin- 2-yl)methanamine (4.8 g) as a yellow oil. MS (ESI pos.) m/z : 311([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.10 - 1.19 (m, 1 H), 1.22 -

1.35 (m, 2 H), 1.37 - 1.52 (m, 2 H), 1.61 - 1.69 (m, 1 H), 2.44 (s, 3 H), 2.49 - 2.54 (m, 1 H), 2.59 - 2.66 (m, 1 H), 2.97 - 3.02 (m, 1 H), 3.99 (d, J=8.3 Hz, 1 H), 5.07 (s, 2 H), 6.86 (dd, J=8.0, 2.5 Hz, 1 H), 6.94 - 6.97 (m, 1 H), 7.02 -

7.04 (m, 1 H), 7.23 (t, J=7.8 Hz, 1 H), 7.30 - 7.34 (m, 1 H),

7.36 - 7.40 (m, 2 H), 7.42 - 7.46 (m, 2 H)

(3) N- ( ( S) - ( 3- (Benzyloxy)phenyl) ( ( 2S) - 1-methylpiperidin-2-yl) methyl) -2-chloro-3- (trifluoromethyl)benzamide (4.7 g) was obtained as a colorless solid from (S)-I- (3-

(benzyloxy)phenyl) -1- ( ( 2S) -1-methylpiperidin-2-yl) methanamine (4.0 g) and 2-chloro-3-trifluorobenzoic acid (2.9 g) in the same way as in Production Example 4(1). MS (ESI pos.) m/z : 517([M+H]+), (ESI neg.) m/z : 515([M-H]-) (4) A chloroform solution (20 ml) of N- ((S)- ( 3- (benzyloxy)phenyl) ( (2S) -l-methylpiperidin-2-yl) methyl) -2-chloro-3- (trifluoromethyl)benzamide (4.6 g) was cooled to -50 to -40⁰C under a nitrogen atmosphere. A chloroform solution (20 ml) of BBr₃ (2.0 ml) was added thereto over 5 minutes. The mixture was left standing at -40⁰C for 15 minutes . A saturated aqueous solution of sodium bicarbonate was added dropwise thereto, and the mixture was stirred at room temperature for 10 minutes, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off , and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=9 : 1) to obtain 2-chloro-N- ( (S) - (3-hydroxyphenyl) ( (2S) -1- methylpiperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide (3.8 g) as a colorless solid. MS (ESI pos.) m/z : 427 ( [M+H] + ) , (ESI neg.) m/z : 425([M-H]-) (5) The title compound (0.86 g) was obtained in a brown amorphous state from 2-chloro-N- ( (S) - (3-hydroxyphenyl) ( (2S) -1- methylpiperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide (1.0 g) in the same way as in Production Example 4(3). MS (ESI pos.) m/z : 559([M+H]+), (ESI neg.) m/z : 557([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.34 - 1.43 (m, 1 H) , 1.44 - 1.57 (m, 3 H), 1.57 - 1.66 (m, 1 H), 1.75 - 1.84 (m, 1 H), 2.15 (br. s., 3 H). 2.37 - 2.46 (m, 1 H), 2.61 - 2.69 (m, 1 H), 2.82 - 2.91 (m, 1 H), 4.92 - 4.96 (m, 1 H), 7.15 - 7.20 (m, 1 H) , 7.30 - 7.34 (m, 1 H) , 7.41 - 7.50 (m, 3 H), 7.59 - 7.75 (m, 2 H) , 7.78 - 7.82 (m, 1 H)

Production Example 6 Synthesis of tert-butyl (2S) -2- (4- ( ( ( trifluoromethyl)sulfonyl)oxy)benzoyl)piperidine-l- carboxylate

(1) 5% Palladium carbon (1.0 g) was added to a mixture of tert-butyl ( 2S) -2- ( 4- (benzyloxy)benzoyl)piperidine-l- carboxylate (9.9 g) synthesized in the same way as in Production Example 2(1) and methanol (120 ml) and stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off through a Celite (trade mark) pad, and the filtrate was concentrated under reduced pressure. The residue was solidified with a mixed solvent of hexane/ethyl acetate(=2: 1) . The solid was collected by filtration to obtain tert-butyl (2S) -2- (4- hydroxybenzoyl)piperidine-l-carboxylate (4.9 g) .

MS (ESI pos.) m/z : 306([M+H]+), (ESI neg.) m/z : 304([M-H]-)

IH NMR (600 MHz, DMSO-d6) δ ppm 1.08 - 2.04 (m, 15 H), 3.10 - 3.21 (m, 1 H), 3.76 - 3.84 (m, 1 H), 5.42 - 5.54 (m, 1 H), 6.82 - 6.86 (m, 2 H), 7.80 - 7.85 (m, 2 H) (2) The title compound (6.8 g) was obtained as a pale yellow solid from tert-butyl (2S) -2- (4-hydroxybenzoyl)piperidine-l- carboxylate (4.9 g) in the same way as in Production Example 4(3).

MS (ESI pos.) m/z : 438([M+H]+), (ESI pos . ) m/z : 460([M+Na]+) IH NMR (600 MHz, CDC13) δ ppm 1.30 - 2.16 (m, 15 H), 2.96 - 3.26 (m, 1 H), 3.83 - 4.05 (m, 1 H), 5.35 - 5.65 (m, 1 H), 7.32 - 7.43 (m, 2 H), 7.99 - 8.11 (m, 2 H)

A compound shown below was synthesized in the same way.

tert-butyl (2S)-2-(3-( ( (trifluoromethyl)sulfonyl)oxy)benzoyl) piperidine-1-carboxylate

MS (ESI pos.) m/z : 438([M+H]+), (ESI pos.) m/z : 460([M+Na]+) IH NMR (600 MHz, CDC13) δ (ppm) ; 1.29 - 2.16 (m, 15 H), 2.96 - 3.25 (m, 1 H), 3.80 - 4.00 (m, 1 H), 5.29 - 5.61 (m, 1 H), 7.40 - 7.62 (m, 2 H), 7.75 - 8.02 (m, 2 H)

Production Example 7 Synthesis of (S)-l-(( 2S)-I- allylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine

(1) tert-Butyl ( 2S) -2- ( (S) -hydroxγ( 4- ( ( (trifluoromethyl) sulfonyl)oxγ)phenyl)methyl)piperidine-l-carboxylate (6.3 g) was obtained from tert-butyl (2S) -2- (4- (( (trifluoromethyl)sulfonyl) oxy)benzoyl)piperidine-1-carboxylate (6.7 g) in the same way as in Production Example 2(2). MS (ESI pos.) m/z : 440([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.21 - 1.32 (m, 1 H) , 1.37 - 1.76 (m, 14 H), 2.85 - 3.17 (m, 1 H), 3.96 - 4.50 (m, 2 H),

4.87 - 5.00 (m, 1 H), 7.26 - 7.37 (m, 2 H), 7.44 - 7.55 (m, 2 H)

(2) tert-Butyl (2S) -2- ( (S) -hydroxy(4- ( ( (trifluoromethyl) sulfonyl) oxy)phenyl)methyl)piperidine-l-carboxylate (6.0 g) was dissolved in a mixed solvent of DMF (90 ml) and ethanol (45 ml). Potassium carbonate (2.8 g) and 3-pyridineboronic acid (2.5 g) were added thereto. After the reaction vessel was purged with nitrogen gas, Pd(PPh₃J₄ (0.47 g) was added thereto, and the mixture was stirred at 90⁰C for 1.5 hours. Ethanol was distilled off under reduced pressure. Ethyl acetate and water was added to the resulting solution, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=3:l to 1:2) to obtain tert-butyl (2S) -2- ((S)- hydroxy( 4-pyridin-3-ylphenyl)methyl)piperidine-1-carboxylate (4.4 g) as a pale yellow solid. MS (ESI pos.) m/z : 369([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.31 - 1.38 (m, 1 H) , 1.40 -• 1.55 (m, 11 H), 1.56 - 1.84 (m, 3 H), 2.97 - 3.16 (m, 1 H), 3.99 - 4.50 (m, 2 H), 4.89 - 5.01 (m, 1 H), 7.35 - 7.39 (m, 1 H), 7.45 - 7.62 (m, 4 H), 7.85 - 7.90 (m, 1 H), 8.56 - 8.61 (m, 1 H) , 8.82 - 8.86 (m, 1 H) (3) An aqueous solution (40 ml) of potassium hydroxide (3.2 g) was added to a methanol solution (50 ml) of tert-butyl (2S) -2- ((S) -hydroxy( 4-pyridin-3-ylphenyl)methyl)piperidine-1- carboxylate (4.2 g) and stirred at 100⁰C for 2 hours. The reaction mixture was concentrated under reduced pressure . Water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=l:l and subsequently, ethyl acetate/methanol=19 : 1) to obtain ( S) - ( 2S) -piperidin-2-yl( 4-pyridin-3-ylphenyl)methanol (1.5 g) as a colorless solid. MS (ESI pos.) m/z : 269([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.24 - 1.36 (m, 2 H), 1.37 - 1.47 (m, 2 H), 1.57 - 1.64 (m, 1 H), 1.76 - 1.82 (m, 1 H),

2.60 - 2.67 (m, 1 H), 2.68 - 2.73 (m, 1 H), 3.11 - 3.16 (m, 1 H), 4.46 (d, J=6.9 Hz, 1 H), 7.35 - 7.38 (m, 1 H), 7.45 - 7.48 (m, 2 H), 7.56 - 7.59 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.58 - 8 . 60 (m, 1 H ) , 8 . 83 - 8 . 85 (m , 1 H )

(4) Potassium carbonate (1.5 g) and allyl bromide (0.52 ml) were added to a DMF solution (15 ml) of (S) - (2S) -piperidin-2- yl(4-pγridin-3-γlphenyl)methanol (1.4 g) and stirred at 80⁰C for 1.5 hours . Water and chloroform were added thereto . The aqueous layer was extracted with chloroform, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=4:l to 3:1) to obtain (S) - ( ( 2S) -l-allylpiperidin-2-yl) (4-pyridin-3- ylphenyl)methanol (0.68 g) as a yellow solid. MS (ESI pos.) m/z : 309([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.20 - 1.28 (m, 1 H) , 1.31 - 1.40 (m, 1 H), 1.51 - 1.67 (m, 3 H), 1.69 - 1.78 (m, 1 H), 2.63 - 2.70 (m, 1 H), 2.74 - 2.80 (m, 1 H), 3.01 - 3.09 (m, 1 H), 3.32 - 3.41 (m, 1 H), 3.42 - 3.49 (m, 1 H), 4.81 (d, J=IO.1 Hz, 1 H), 5.16 - 5.25 (m, 2 H), 5.85 - 5.93 (m, 1 H), 7.34 - 7.37 (m, 1 H), 7.47 - 7.49 (m, 2 H), 7.54 - 7.57 (m, 2 H), 7.85 - 7.88 (m, 1 H), 8.58 (dd, J=4.8, 1.6 Hz, 1 H), 8.85 (d, J=2.3 Hz, 1 H)

(5) Triethylamine (0.7 ml) was added to a chloroform solution (15 ml) of (S) -((2S) -l-allylpiperidin-2-yl) ( 4-pyridin-3-yl phenyl)methanol (1.1 g) . After ice cooling, methanesulfonyl chloride (0.31 ml) was added dropwise thereto. The mixture was stirred under ice cooling for 30 minutes . The reaction solution was concentrated under reduced pressure. The residue was dissolved in 8 M ammonia/methanol solution (8 ml).

Reaction was carried out in a microwave reactor at 120⁰C for 20 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol/28% ammonia water=19:l:0.2 and subsequently, NH-silica gel, hexane/ethyl acetate=4:l to 1:1) to obtain the title compound (0.92 g) as a yellow oil. MS (ESI pos.) m/z : 308([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.04 - 1.12 (m, 1 H), 1.23 - 1.56 (m, 4 H), 1.62 - 1.72 (m, 1 H), 2.67 - 2.74 (m, 2 H), 3.03 - 3.11 (m, 1 H), 3.36 - 3.42 (m, 2 H), 4.28 (d, J=IO.1 Hz, 1 H), 5.12 - 5.16 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.87 - 5.95 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.52 - 7.56 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.57 - 8.59 (m, 1 H), 8.85 (d, J=2.3 Hz, 1 H)

Compounds shown below were synthesized in the same way.

(S)-l-((2S)-l-allylpiperidin-2-yl)-l-(4-(l-methyl-lH-pyrazol-

4-yl)phenyl)methanamine

MS (ESI pos.) m/z : 311([M+H]+)

IH NMR (600.MHz, CDC13) δ (ppm) ; 1.11 - 4.00 (m, 14 H), 4.09

(d, J=IO.5 Hz, 1 H), 5.22 - 5.35 (m, 2 H), 5.90 - 6.03 (m, 1 H), 7.35 - 7.39 (m, 2 H), 7.39 - 7.46 (m, 2 H), 7.57 - 7.58 (m,

1 H) , 7.71 - 7.73 (m, 1 H)

(S)-1-((2S)-1-allylpiperidin-2-yl) - 1- ( 4-pyrimidin- 5-ylphenyl) methanamine MS (ESI pos.) m/z : 309([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.31 - 4.44 (m, 12 H), 5.46 (d, J=Il.0 Hz, 2 H), 6.05 - 6.19 (m, 1 H), 7.49 - 7.72 (m, 4 H), 8.89 - 8.92 (m, 2 H), 9.20 (s, 1 H) (S) -1- ( (2S) -1-allylpiperidin-2-yl) -1- (3- ( 1-methyl-lH-pyrazol- 4-yl)phenyl)methanamine MS (ESI pos.) m/z : 311([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.01 - 1.09 (m, 1 H) , 1.29 - 1.55 (m, 4 H), 1.60 - 1.89 (m, 1 H), 2.65 - 2.72 (m, 2 H), 3.02 - 3.08 (m, 1 H), 3.33 - 3.43 (m, 2 H), 3.94 (s, 3 H),

4.22 (d, J=IO.1 Hz, 1 H), 5.13 (dd, J=IO.1, 1.8 Hz, 1 H), 5.19 - 5.24 (m, 1 H), 5.86 - 5.94 (m, 1 H), 7.18 - 7.21 (m, 1 H), 7.30 (t, J=7.8 Hz, 1 H), 7.34 - 7.37 (m, 1 H), 7.46 - 7.50 (m, 1 H), 7.64 (s, 1 H), 7.77 (s, 1 H) (S) -1- ( (2S) -l-allylpiperidin-2-yl) -1- (3-pyridin-3-ylphenyl) methanamine MS (ESI pos.) m/z : 308([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.03 - 1.11 (m, 1 H) , 1.31 - 1.57 (m, 4 H), 1.63 - 1.71 (m, 1 H), 2.66 - 2.76 (m, 2 H), 3.03 - 3.11 (m, 1 H), 3.35 - 3.44 (m, 2 H), 4.29 (d, J=IO.1 Hz, 1 H), 5.12 - 5.17 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.86 - 5.95 (m, 1 H), 7.34 - 7.38 (m, 1 H), 7.39 - 7.52 (m, 3 H), 7.58 - 7.61 (m, 1 H), 7.87 - 7.91 (m, 1 H), 8.57 - 8.60 (m, 1 H), 8.85 - 8.86 (m, 1 H) (S) -l-( (2S)-l-allylpiperidin-2-yl)-l-(3-pyrimidin-5-ylphenyl) methanamine

MS (ESI pos.) m/z : 309([M+H]+) IH NMR (600 MHz, CDC13) δ (ppm) ; 1.15 - 1.78 (m, 6 H), 2.59 - 2.68 (m, 1 H), 2.76 (d, J=14.2 Hz, 1 H), 2.97 - 3.08 (m, 1 H), 3.30 - 3.47 (m, 2 H), 4.83 (d, J=IO.1 Hz, 1 H), 5.14 - 5.26 (m, 2 H), 5.81 - 5.95 (m, 1 H), 7.38 - 7.71 (m, 4 H), 8.95 (s, 2 H) , 9.20 (s, 1 H) (S) -1- ( (2S) -l-allylpiperidin-2-yl) -1- (3- ( 1-isopropyl-lH- pyrazol-4-yl)phenyl)methanamine MS (ESI pos.) m/z : 339([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.02 - 1.09 (m, 1 H), 1.30 - 1.59 (m, 4 H), 1.55 (d, J=6.9 Hz, 6 H), 1.61 - 1.85 (m, 1 H), 2.67 - 2.73 (m, 2 H), 3.03 - 3.09 (m, 1 H), 3.34 - 3.43 (m, 2 H), 4.23 (d, J=9.6 Hz, 1 H), 4.50 - 4.56 (m, 1 H), 5.11 - 5.15 (m, 1 H), 5.19 - 5.25 (m, 1 H), 5.86 - 5.95 (m, 1 H), 7.16 - 7.19 (m, 1 H), 7.29 (t, J=7.6 Hz, 1 H), 7.36 - 7.39 (m, 1 H), 7.50 - 7.52 (m, 1 H), 7.71 (s, 1 H), 7.79 (s, 1 H) (S) -1-((2S) -l-allylpiperidin-2-yl) -l-( 3- ( 1-propyl-lH-pyrazol- 4-yl)phenyl)methanamine MS (ESI pos.) m/z : 339([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 0.95 (t, J=7.3 Hz, 3 H), 1.03 - 1.11 (m, 1 H), 1.29 - 1.73 (m, 5 H), 1.89 - 1.96 (m, 2 H), 2.67 - 2.73 (m, 2 H), 3.02 - 3.10 (m, 1 H), 3.33 - 3.44 (m, 2 H), 4.11 (t, J=7.1 Hz, 2 H), 4.22 (d, J=9.6 Hz, 1 H), 5.10 -

5.16 (m, 1 H), 5.19 - 5.25 (m, 1 H), 5.85 - 5.96 (m, 1 H),

7.17 - 7.20 (m, 1 H), 7.30 (t, J=7.6 Hz, 1 H), 7.35 - 7.39 (m, 1 H), 7.49 - 7.52 (m, 1 H), 7.66 (s, 1 H), 7.79 (s, 1 H) (S) -1-((2S) -l-allylpiperidin-2-yl) -l-( 3- ( l-ethyl-lH-pγrazol-4- yl)phenyl)methanamine MS (ESI pos.) m/z : 325([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.02 - 1.10 (m, 1 H), 1.30 - 1.57 (m, 4 H), 1.53 (t, J=7.3 Hz, 3 H), 1.58 - 1.84 (m, 1 H), 2.67 - 2.73 (m, 2 H), 3.03 - 3.09 (m,l H), 3.34 - 3.44 (m, 2 H), 4.18 - 4.24 (m, 3 H), 5.11 - 5.16 (m, 1 H), 5.18 - 5.26 (m, 1 H), 5.85 - 5.95 (m, 1 H), 7.19 (d, J=7.8 Hz, 1 H), 7.30 (t, J=7.8 Hz, 1 H), 7.35 - 7.38 (m, 1 H), 7.50 (br. s., 1 H), 7.68 (s, 1 H) , 7.78 (s, 1 H)

Production Example 8 Synthesis of (S) -l-biphenyl-4-yl-l- ( ( 2S) - 1-methylpiperidin-2-yl)methanamine

(1) tert-Butyl (2S) -2- ( (S) -biphenyl-4-yl(hydroxy)methyl) piperidine-1-carboxylate (3.5 g) was dissolved in THF (60 ml) under a nitrogen atmosphere. After ice cooling, lithium aluminum hydride (1.4 g) was gradually added thereto, and the mixture was stirred at 80⁰C for 2 hours. The reaction mixture was cooled on ice. A saturated aqueous sodium potassium tartrate solution and 10% aqueous sodium hydroxide solution were added thereto, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off with a funnel covered with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain (S)-biphenyl-4-yl( (2S) -1-methylpiperidin-2-yl)methanol (2.6 g) as a colorless solid. MS (ESI pos.) m/z : 282([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.35 (m, 1 H), 1.39 - 1.54 (m, 2 H), 1.54 - 1.62 (m, 1 H), 1.66 - 1.76 (m, 1 H), 1.82 - 1.88 (m, 1 H) , 2.52 (s, 3 H) , 2.54 - 2.59 (m, 1 H), 2.63 - 2.69 (m, 1 H), 3.02 - 3.08 (m, 1 H) , 4.69 (d, J=9.2 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.41 - 7.46 (m, 4 H), 7.54 - 7.61 (m, 4 H)

(2) The title compound (1.2 g) was obtained as a brownish red oil from (S) -biphenyl-4-yl( (2S) -l-methylpiperidin-2- yl)methanol (1.7 g) in the same way as in Production Example

7(5). MS (ESI pos.) m/z : 281([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.15 - 1.23 (m, 1 H), 1.29 - 1.38 (m, 2 H), 1.40 - 1.53 (m, 2 H), 1.65 - 1.72 (m, 1 H), 2.47 (s, 3 H), 2.51 - 2.56 (m, 1 H), 2.57 - 2.64 (m, 1 H), 2.98 - 3.04 (m, 1 H), 4.11 (d, J=8.3 Hz, 1 H), 7.31 - 7.35 (m, 1 H), 7.40 - 7.46 (m, 4 H), 7.53 - 7.62 (m, 4 H)

A compound shown below was synthesized in the same way.

(S) -l-biphenyl-3-yl-l- ( (2S) -l-methylpiperidin-2-yl)methanamine MS (ESI pos.) m/z : 281([M+H]+)

Production Example 9 Synthesis of (S)-l-(( 2S)-I- allylpyrrolidin-2-yl) - 1- ( 3-methoxyphenyl) methanamine

(1) tert-Butyl (2S) -2- ( (S) -hydroxy( 3-methoxyphenyl)methyl) pyrrolidine- 1-carboxylate (50 g) and triethylamine (50 g) were dissolved in chloroform (600 ml). After ice cooling, pivaloyl chloride (40 g) and N,N-dimethylaminopyridine (2.0 g) were added thereto, and the mixture was stirred at room temperature for 9 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=20 : 1) to obtain tert-butyl (2S) -2- ((S)- ( (2,2-dimethylpropanoyl)oxy) (3-methoxyphenyl) methyl)pyrrolidine- 1-carboxylate (54 g) as a yellow oil.

MS (ESI pos.) m/z : 392([M+H]+)

IH NMR (600 MHz, DMSO-d6) δ (ppm) ; 0.90 - 3.47 (m, 24 H),

3.66 - 3.73 (m, 3 H), 3.89 - 4.08 (m, 1 H), 5.72 - 6.24 (m, 1 H), 6.64 - 6.91 (m, 3 H), 7.21 - 7.32 (m, 1 H)

(2) 4 M HCl/ethyl acetate solution (250 ml) was added to a diethyl ether solution (200 ml) of tert-butyl (2S) -2- ((S)- ((2,2-dimethylpropanoyl ) oxy) ( 3-methoxyphenyl) methyl)pyrrolidine-1-carboxylate (54 g) and stirred at room temperature for 7 hours . The precipitate was collected by filtration, then washed with diethyl ether, and dried under reduced pressure to obtain (S) - (3-methoxyphenyl) ( (2S) - pyrrolidin-2-yl)methyl pivalate monohydrochloride (19 g) . The filtrate was concentrated. Diethyl ether was added thereto, and the mixture was stirred overnight . The precipitate was collected by filtration, then washed with diethyl ether, and dried under reduced pressure to further obtain (S) -(3- methoxyphenyl) ( (2S) -pyrrolidin-2-yl)methyl pivalate monohydrochloride (12 g) . MS (ESI pos.) m/z : 292([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.28 (s, 9 H), 1.73 - 1.86 (m, 2 H), 1.86 - 1.97 (m, 1 H), 1.97 - 2.05 (m, 1 H), 3.31 - 3.45 (m, 2 H), 3.77 (s, 3 H), 3.92 - 4.01 (m, 1 H), 5.88 (d, J=8.3 Hz, 1 H), 6.82 - 6.87 (m, 1 H), 6.96 - 7.00 (m, 2 H), 7.21 - 7.30 (m, 1 H), 9.22 - 9.31 (m, 1 H), 10.29 - 10.37 (m, 1 H) (3) (S)-(3-Methoxyphenyl) ( (2S) -pyrrolidin-2-yl)methyl pivalate monohydrochloride (30 g) was dissolved in DMF (200 ml).

Potassium carbonate (38 g) and allyl bromide (13 g) were added thereto, and the mixture was stirred at 90⁰C for 6 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and purified by column chromatography (silica gel, hexane/ethyl acetate=4:l) to obtain (S)-(( 2S)-I- allylpyrrolidin-2-yl)( 3-methoxyphenyl)methyl pivalate (26 g) as a colorless oil. S (ESI pos.) m/z : 332([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.20 (s, 9 H), 1.38 - 1.68 (m, 4 H), 2.23 - 2.32 (m, 1 H), 2.92 - 3.09 (ra, 3 H), 3.63 (dd, J=13.8, 5.0 Hz, 1 H), 3.78 (s, 3 H), 5.08 (d, J=IO.1 Hz, 1 H), 5.18 (d, J=16.0 Hz, 1 H), 5.56 (d, J=6.9 Hz, 1 H), 5.85 - 5.97 (m, 1 H), 6.79 (dd, J=8.3, 2.8 Hz, 1 H), 6.87 - 6.91 (m, 1 H), 6.93 (d, J=7.8 Hz, 1 H), 7.20 (t, J=7.8 Hz, 1 H)

(4) Lithium aluminum hydride (3.3 g) was suspended in dry tetrahydrofuran (100 ml). A tetrahydrofuran solution (30 ml) of (S)-( (2S) -l-allylpyrrolidin-2-yl) ( 3-methoxyphenyl)methyl pivalate (26 g) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off with a funnel firmly covered with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain crude (S)-((2S)- 1-allylpyrrolidin-2-yl) ( 3-methoxyphenyl)methanol (22 g) as a colorless oil. MS (ESI pos.) m/z : 248([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.66 - 1.95 (m, 4 H), 2.40 - 2.53 (m, 1 H), 2.85 - 3.00 (m, 2 H), 3.05 - 3.17 (m, 2 H), 3.80 (s, 3 H), 4.25 (d, J=5.5 Hz, 1 H), 4.27 - 4.37 (m, 1 H), 5.02 - 5.14 (m, 2 H), 5.74 - 5.90 (m, 1 H), 6.78 (dd, J=8.5, 2.5 Hz, 1 H), 6.89 - 6.95 (m, 2 H), 7.18 - 7.26 (m, 1 H)

(5) ( S) -l-(( 2S)-I-AlIylpyrrolidin-2-yl) -1- (3-methoxyphenyl) methanamine (12 g) was obtained from crude (S) -((2S)-I- allylpyrrolidin-2-yl) (3-methoxyphenyl)methanol (22 g) in the same way as in Production Example 3(3). MS (ESI pos.) m/z : 247([M+H]+)

IH NMR (600 MHz, CDC13) δ (ppm) ; 1.45 - 1.83 (m, 4 H), 2.32 - 2.43 (m, 1 H), 2.79 - 2.89 (m, 1 H), 2.93 - 3.01 (m, 1 H), 3.01 - 3.08 (m, 1 H), 3.36 (dd, J=13.8, 5.0 Hz, 1 H), 3.70 (d, J=6.9 Hz, 1 H), 3.80 (s, 3 H), 5.06 (d, J=10.1 Hz, 1 H), 5.14 (d, J=17.0 Hz, 1 H), 5.82 - 5.95 (m, 1 H), 6.73 - 6.79 (m, 1 H), 6.88 - 6.95 (m, 2 H), 7.21 (t, J=7.8 Hz, 1 H)

Production Example 10 Synthesis of (S)-l-(( 2S)-I- allylpiperidin-2-yl) -1- ( 3-pyrazin-2-ylphenyl) methanamine

(1) tert-Butyl ( 2S) -2- ( (S) -hydroxy( 3- ( ( ( trifluoromethyl) sulfonyl)oxy)phenyl)methyl)piperidine-l-carboxylate (7.9 g) synthesized in the same way as in Production Example 7(1) was dissolved in dioxane (150 ml). After the reaction vessel was purged with nitrogen gas, potassium acetate (5.3 g) , Pd(dppf)Cl₂ (1.46 g), bispinacolborane (5.0 g) , and dppf (1.2 g) were added thereto, and the mixture was stirred at 80⁰C for 3 hours. After cooling to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed, with water and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off , and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=3:l to 2:1) to obtain tert- butyl ( 2S) -2- ( ( S) -hydroxy(3-(4,4,5,5-1etramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl)methyl)piperidine-l-carboxylate (6.8 g) in a pale yellow amorphous state. MS (ESI pos.) m/z : 418([M+H]+)

(2) tert-Butyl (2S) -2- ( (S) -hydroxy(3- (4,4, 5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl)methyl)piperidine-l-carboxγlate (1.2 g) and potassium carbonate (0.77 g) were suspended in a mixed solvent (18 ml) of DMF/ethanol (=2:1). After the reaction vessel was purged with nitrogen gas, 2-chloropyrazine (0.64 g) and Pd(PPh₃J₄ (96 mg) were added thereto, and the mixture was stirred at 9O⁰C for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate . The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=2:l to 1:2) to obtain tert-butyl (2S) -2- ( (S) -hydroxy(3-pyrazin~2- ylphenyl) methyl)piperidine-l-carboxylate (0.79 g) in a colorless amorphous state.

MS (ESI pos.) m/z : 370([M+H]+) IH NMR (200 MHz, CDC13) δ ppm 1.32 - 1.86 (m, 15 H), 2.91 - 3.18 (m, 1 H), 3.99 - 4.25 (m, 1 H), 4.35 - 4.54 (m, 1 H), 5.00 (d, J=IO.5 Hz, 1 H), 7.48 - 7.57 (m, 2 H), 7.92 - 7.99 (m, 1 H), 8.03 - 8.08 (m, 1 H), 8.52 (d, J=2.6 Hz, 1 H), 8.62 - 8.66 (m, 1 H), 9.04 (d, J=I.3 Hz, 1 H)

(3) (S) -(2S) -Piperidin-2-yl(3-pyrazin-2~ylphenyl)methanol (0.52 g) was obtained from tert-butyl (2S) -2- ( (S) -hydroxy(3- pyrazin-2-yl phenyl)methyl)piperidine-l-carboxylate (0.75 g) in the same way as in Production Example 3(1). MS (ESI pos.) m/z : 270([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.21 - 1.32 (m, 2 H), 1.35 - 1.44 (m, 2 H), 1.55 - 1.61 (m, 1 H), 1.72 - 1.78 (m, 1 H), 2.57 - 2.64 (m, 1 H), 2.69 - 2.74 (m, 1 H), 3.07 - 3.12 (m, 1 H), 4.47 (d, J=6.9 Hz, 1 H), 7.45 - 7.52 (m, 2 H), 7.90 - 7.93 (m, 1 H), 8.00 - 8.02 (m, 1 H), 8.51 (d, J=2.8 Hz, 1 H), 8.62 - 8.63 (m, 1 H), 9.03 (d, J=I.4 Hz, 1 H)

(4) (S)-((2S)~l-Allylpiperidin-2-yl)(3-pyrazin-2- ylphenyl)methanol (0.31 g) was obtained from (S) -(2S)- piperidin-2-yl(3-pyrazin-2-ylphenyl)methanol (0.47 g) in the same way as in Production Example 3(2). (ESI pos.) m/z : 310([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.21 - 1.79 (m, 6 H), 2.65 - 2.73 (m, 1 H), 2.74 - 2.81 (m, 1 H), 3.00 - 3.09 (m, 1 H), 3.33 - 3.40 (m, 1 H), 3.42 - 3.51 (m, 1 H), 4.86 (d, J=IO.1 Hz, 1 H), 5.15 - 5.25 (m, 2 H), 5.85 - 5.94 (m, 1 H), 7.46 - 7.51 (m, 2 H), 7.91 - 7.95 (m, 1 H), 8.01 - 8.03 (m, 1 H), 8.51 (d, J=2.8 Hz, 1 H), 8.62 - 8.65 (m, 1 H), 9.04 (d, J=I.8 Hz, 1 H) (5) The title compound (0.24 g) was obtained from (S)-(( 2S)-I- allylpiperidin-2-yl) (3-pyrazin-2-ylphenγl)methanol (0.28 g) in the same way as in Production Example 3(3). MS (ESI pos.) m/z : 309([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.04 - 1.11 (m, 1 H), 1.31 - 1.77 (m, 5 H), 2.67 - 2.77 (m, 2 H), 3.04 - 3.11 (m, 1 H), 3.34 - 3.46 (m, 2 H), 4.32 (d, J=IO.1 Hz, 1 H), 5.13 - 5.16 (m, 1 H), 5.20 - 5.25 (m, 1 H), 5.87 - 5.96 (m, 1 H), 7.45 - 7.52 (m, 2 H), 7.88 - 7.91 (m, 1 H), 8.02 - 8.04 (m, 1 H), 8.50 - 8.52 (m, 1 H), 8.63 - 8.65 (m, 1 H), 9.04 - 9.06 (m, 1 H)

A compound shown below was synthesized in the same way.

( S) -1- ( ( 2S) -1-allylpiperidin-2-yl) -1- ( 3- ( 1-methyl-lH-imidazol- 5-yl)phenyl)methanamine

MS (ESI pos.) m/z : 311([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.02 - 1.09 (m, 1 H), 1.31 -

1.68 (m, 5 H), 2.65 - 2.72 (m, 2 H), 3.02 - 3.09 (m, 1 H),

3.36 - 3.41 (m, 2 H), 3.67 (s, 3 H), 4.25 (d, J=IO.1 Hz, 1 H), 5.11 - 5.16 (m, 1 H), 5.19 - 5.26 (m, 1 H), 5.85 - 5.95 (m, 1

H), 7.10 - 7.11 (m, 1 H), 7.27 - 7.29 (m, 1 H), 7.36 - 7.41 (m,

3 H) , 7.51 (s, 1 H)

Production Example 11 Synthesis of (S)-l-(( 2S)-I- methylpiperidin-2-yl) -1- (4-pyridin-3-ylphenyl) methanamine

( 1 ) 4-((S) -Hydroxy((2S)-I-methylpiperidin-2-yl)methyl)phenol (6.3 g) was obtained as a colorless solid from tert-butyl (2S)-2-((S)-(4-((tert- butyl( dimethyl) silyl) oxy)phenyl) (hydroxy)methyl)piperidine- 1- carboxylate (14 g) in the same way as in Production Example

8(1).

MS (ESI pos.) m/z : 222([M+H]+), (ESI neg. ) m/z : 220([M-H]-) IH NMR (600 MHz, DMSO-d6) δ ppm 0.79 - 0.88 (m, 1 H) , 1.10 - 1.20 (m, 1 H), 1.21 - 1.31 (m, 1 H), 1.35 - 1.46 (m, 2 H), 1.52 - 1.61 (m, 1 H), 2.15 - 2.22 (m, 2 H), 2.39 (s, 3 H), 2.78 - 2.84 (m, 1 H), 4.69 (d, J=6.0 Hz, 1 H), 6.65 - 6.69 (m, 2 H), 7.09 - 7.13 (m, 2 H), 9.18 (br. s., 1 H) (2) 4-( (S)-hydroxy((2S)-l-methylpiperidin-2-yl)methyl)phenol (1.0 g) was dissolved in DMF (20 ml). Imidazole (1.3 g) , tert-butyldimethylsilyl chloride (2.2 g) , and DMAP (catalytic amount) were added thereto, and the mixture was stirred at room temperature for 3 days . Ethyl acetate and water were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=9 : 1) to obtain (2S) -2- ( (S) -( ( tert-butyl(dimethyl)silyl)oxy) (4- ((tert-butyl (dimethyl) silyl)oxy)phenyl)methyl) -1-methylpiperidine (1.6 g) as a colorless oil.

MS (ESI pos.) m/z : 450([M+H]+)

(3) An ethanol solution (5 ml) of (2S) -2- ( (S) - ( (tert- butyl(dimethyl) silyl)oxy) (4- ( (tert-butyl

(dimethyl) silyl)oxy)phenyl)methyl)-1-methylpiperidine (1.5 g) was added to an ethanol solution (5 ml) of potassium hydroxide (0.27 g) and stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure. Water was added thereto, and the mixture was neutralized with a saturated aqueous solution of ammonium chloride. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate . The drying agent was filtered off , and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=4:l to 3:1) to obtain 4- ( (S) -( (tert- butyl( dimethyl) silyl) oxy) ( ( 2S) -1-methylpiperidin-2- yl)methyl)phenol (0.73 g) as a colorless solid. MS (ESI pos.) m/z : 336([M+H]+) IH NMR (600 MHz, DMSO-dβ) δ ppm -0.12 (s, 3 H), 0.04 (s, 3 H), 0.64 - 0.72 (m, 1 H), 0.86 (s, 9 H), 1.01 - 1.12 (m, 1 H), 1.11 - 1.21 (m, 1 H), 1.36 - 1.43 (m, 1 H), 1.52 - 1.65 (m, 2 H), 1.93 - 2.03 (m, 2 H), 2.39 (s, 3 H), 2.72 - 2.78 (m, 1 H), 5.03 (d, J=4.1 Hz, 1 H), 6.63 - 6.69 (m, 2 H), 7.07 - 7.11 (m, 2 H) , 9.17 (s, 1 H)

(4) 4-( (S)-( (tert-Butyl(dimethyl)silyl)oxγ) ( (2S)-I- methylpiperidin-2-yl)methyl)phenyl trifluoromethanesulfonate (0.89 g) was obtained from 4- ( (S) - ( (tert- butyl( dimethyl)silyl)oxy) ( (2S) -l-methylpiperidin-2- yl)methyl)phenol (0.69 g) in the same way as in Production

Example 4(3).

MS (ESI pos.) m/z : 468([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm -0.07 (s, 3 H), 0.08 (s, 3 H), 0.55 - 0.64 (m, 1 H), 0.91 (s, 9 H), 1.09 - 1.18 (m, 1 H),

1.23 - 1.33 (m, 1 H), 1.45 - 1.52 (m, 1 H), 1.58 - 1.64 (m, 1 H), 1.64 - 1.72 (m, 1 H), 2.01 - 2.12 (m, 2 H), 2.49 (s, 3 H), 2.84 - 2.91 (m, 1 H), 5.12 - 5.19 (m, 1 H), 7.17 - 7.22 (m, 2 H) , 7.45 - 7.49 (m. 2 H) (5) 3-(4-((S)-((tert-Butyl(dimethyl)silyl)oxy)( (2S)-I- methylpiperidin-2-yl)methyl)phenyl)pyridine (0.71 g) was obtained as a pale yellow oil from 4- ( (S) - ( (tert- butyl( dimethyl) silyl) oxy) ((2S)-I-methylpiperidin-2- yl)methyl)phenyl trifluoromethanesulfonate (0.84 g) in the same way as in Production Example 7(2). MS (ESI pos.) m/z : 397([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm -0.06 (s, 3 H), 0.10 (s, 3 H), 0.73 - 0.82 (m, 1 H), 0.93 (s, 9 H), 1.12 - 1.22 (m, 1 H), 1.28 - 1.38 (m, 1 H) , 1.46 - 1.53 (m, 1 H) , 1.59 - 1.67 (m, 1 H), 1.74 - 1.80 (m, 1 H) , 2.04 - 2.16 (m, 2 H) , 2.54 (s, 3 H) , 2.86 - 2.93 (m, 1 H) , 5.18 (d, J=3.7 Hz, 1 H) , 7.33 - 7.36 (m, 1 H) , 7.45 - 7.49 (m, 2 H), 7.51 - 7.54 (m, 2 H) , 7.87 - 7.90 (m, 1 H) , 8.55 - 8.58 (m, 1 H), 8.86 - 8.88 (m, 1 H)

(6) I M TBAF/THF solution (3.4 ml) was added to a tetrahydrofuran solution (5 ml) of 3- (4- ( (S) - ( ( tert- butyl(dimethyl) silyl) oxy)

( (2S) -l-methylpiperidin-2-yl)methyl)phenyl)pyridine (0.67 g) and stirred at room temperature for 8 hours. 1 M TBAF/THF solution (3.4 ml) was further added thereto, and the mixture was stirred at room temperature for 16 hours . A saturated aqueous solution of sodium bicarbonate (30 ml) was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=4:l to 2:1) to obtain (S) - ( ( 2S) -l-methylpiperidin-2- yl) (4-pyridin~3-ylphenyl) methanol (0.44 g) as a colorless oil.

MS (ESI pos.) m/z : 283([M+H]+)

IH NMR (200 MHz, CDC13) δ ppm 1.30 - 1.84 (m, 6 H), 2.52 (s, 3

H), 2.53 - 2.75 (m, 2 H), 2.97 - 3.14 (m, 1 H), 4.70 (d, J=8.8 Hz, 1 H), 7.31 - 7.40 (m, 1 H), 7.44 - 7.60 (m, 4 H), 7.83 - 7.91 (m, 1 H), 8.55 - 8.61 (m, 1 H), 8.83 - 8.87 (m, 1 H)

(7) (S)-l-((2S)-l-methylpiperidin-2-yl)-l-(4-pyridin-3- ylphenyl) methanamine (0.27 g) was obtained, from (S) -((2S)-I- methylpiperidin-2-yl) ( 4-pyridin-3-ylphenyl) methanol (0.40 g) in the same way as in Production Example 3(3). MS (ESI pos.) m/z : 282([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.13 - 1.21 (m, 1 H), 1.29 - 1.38 (m, 2 H), 1.40 - 1.53 (m, 2 H), 1.65 - 1.73 (m, 1 H), 2.47 (s, 3 H), 2.50 - 2.55 (m, 1 H), 2.57 - 2.63 (m, 1 H), 2.98 - 3.04 (m, 1 H), 4.14 (d, J=7.8 Hz, 1 H), 7.34 - 7.37 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.53 - 7.56 (m, 2 H), 7.85 - 7.89 (m, 1 H), 8.56 - 8.59 (m, 1 H), 8.84 - 8.86 (m, 1 H)

A compound shown below was synthesized in the same way.

(S) -l-( (2S)-l-methylpiperidin-2-yl)-l-(4-pyridin-4-ylphenyl) methanamine

MS (ESI pos.) m/z : 282([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.12 - 1.73 (m, 6 H), 2.47 (s, 3

H), 2.49 - 2.54 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.98 - 3.03 (m, 1 H), 4.15 (d, J=7.8 Hz, 1 H), 7.47 - 7.64 (m, 6 H), 8.62 -

8.67 (m, 2 H)

Production Example 12 Synthesis of (S)-l-(( 2S)-I- methylpiperidin-2-yl) -1- (3-pyridin-4-ylphenyl) methanamine

(1) tert-Butyl (2S) -2- (3-hydroxybenzoyl)piperidine-l- carboxylate (6.6 g) was obtained in a pale brownish red solid in the same way as in Production Example 11(6) from tert-butyl (2S)-2-(3-((tert-butyl(dimethyl) silyl)oxy)benzoyl)piperidine- 1-carboxylate (9.3 g) obtained in the same way as in Production Example 2(1).

MS (ESI pos.) m/z : 328( [M+Na] +) , (ESI neg.) m/z : 304([M-H]-) IH NMR (200 MHz, DMSO-d6) δ ppm 1.01 - 2.04 (m, 15 H), 3.00 - 3.25 (m, 1 H), 3.71 - 3.89 (m, 1 H), 5.41 - 5.53 (m, 1 H),

6.98 - 7.09 (m, 1 H), 7.22 - 7.43 (m, 3 H), 9.82 (s, 1 H)

(2) tert-Butyl (2S)-2-(3-

( ( (trifluoromethyl)sulfonyl)oxy)benzoyl)piperidine-l- carboxylate (6.4 g) was obtained as a yellow oil from tert- butyl (2S)-2-(3-hydroxybenzoyl)piperidine-l-carboxγlate (5.0 g) in the same way as in Production Example 4(3). MS (ESI pos.) m/z : 460( [M+Na] +) , (ESI neg.) m/z : 436([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.31 - 1.53 (m, 11 H) , 1.57 - 1.75 (m, 2 H), 1.76 - 1.90 (m, 1 H), 1.97 - 2.15 (m, 1 H),

2.99 - 3.22 (m, 1 H), 3.82 - 4.00 (m, 1 H), 5.33 - 5.61 (m, 1 H) , 7 . 43 - 7 . 50 (m , 1 H ) , 7 . 51 - 7 . 64 (m, 1 H) , 7 . 75 - 7 . 88 (m , 1 H) , 7 . 88 - 8 . 03 (m, 1 H )

(3) tert-Butyl (2S) -2- ( (S) -hydroxy(3- ( ( ( trifluoromethyl) sulfonyl)oxy)phenyl)methyl)piperidine-l-carboxylate (5.6 g) was obtained as a pale yellow oil from tert-butyl (2S) -2- (3- ( ( (trifluoromethyl) sulfonyl)oxy)benzoyl)piperidine-1- carboxylate (5.8 g) in the same way as in Production Example 2(2).

MS (ESI pos.) m/z : 440 ( [M+H] + ) , (ESI pos.) m/z : 462([M+Na]+) IH NMR (600 MHz, CDC13) δ ppm 1.22 - 1.28 (m, 1 H) , 1.38 - 1.63 (m, 13 H), 1.66 - 1.73 (m, 1 H), 2.82 - 3.15 (m, 1 H), 3.94 - 4.39 (m, 2 H), 4.88 - 4.96 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.27 - 7.31 (m, 1 H), 7.39 - 7.48 (m, 2 H)

(4) tert-Butyl (2S) -2- ( (S) -hydroxy( 3-pγridin-4- ylphenyl)methyl) piperidine-1-carboxylate (1.0 g) was obtained in a colorless amorphous state from tert-butyl (2S) -2- ( (S) -hydroxy(3-

( ( ( trifluoromethyl) sulfonyl) oxy)phenyl) methyl)piperidine-1-carboxylate (1.25 g) in the same way as in Production Example 7(2).

MS (ESI pos.) m/z : 369([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.29 - 1.37 (m, 1 H) , 1.39 - 1.54 (m, 11 H), 1.54 - 1.65 (m, 2 H), 1.66 - 1.75 (m, 1 H), 2.96 - 3.15 (m, 1 H), 3.98 - 4.52 (m, 2 H), 4.97 (d, J=IO.1 Hz, 1 H), 7.43 - 7.55 (m, 4 H), 7.55 - 7.59 (m, 1 H), 7.64 - 7.69 (m, 1 H) , 8.64 - 8.67 (m, 2 H)

(5) (S) - ( ( 2S) -1-Methylpiperidin-2-yl) ( 3-pyridin-4-ylphenyl) methanol (0.35 g) was obtained as a pale yellow oil from tert- butyl (2S) -2- ((S) -hydroxy(3-pyridin-4- ylphenyl)methyl)piperidine- 1- carboxylate (0.98 g) in the same way as in Production Example 8(1). MS (ESI pos.) m/z : 283([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.35 (m, 1 H), 1.40 - 1.54 (m, 3 H), 1.54 - 1.63 (m, 1 H), 1.68 - 1.76 (m, 1 H), 2.52 (s, 3 H), 2.54 - 2.59 (m, 1 H), 2.64 - 2.71 (m, 1 H), 3.02 - 3.08 (m, 1 H), 4.72 (d, J=9.2 Hz, 1 H), 7.41 - 7.49 (m, 2 H), 7.51 - 7.57 (m, 3 H), 7.65 - 7.69 (m, 1 H), 8.64 - 8.67 (m, 2 H)

(6) The title compound (0.12 g) was obtained as a pale yellow oil from (S) - ( (2S) -l-methylpiperidin-2-yl) (3-pyridin-4-yl phenyl)methanol (0.30 g) in the same way as in Production Example 3(3) .

MS (ESI pos.) m/z : 282([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.15 - 1.23 (m, 1 H) , 1.29 - 1.39 (m, 2 H), 1.40 - 1.73 (m, 3 H), 2.48 (s, 3 H), 2.54 - 2.60 (m, 1 H), 2.60 - 2.67 (m, 1 H), 2.99 - 3.04 (m, 1 H), 4.14 (d, J=7.8 Hz, 1 H), 7.42 - 7.46 (m, 2 H), 7.51 - 7.55 (m, 3 H), 7.67 - 7.69 (m, 1 H), 8.64 - 8.67 (m, 2 H)

A compound shown below was synthesized in the same way.

(S) -l-( (2S) -l-methylpiperidin-2-yl) -1- ( 3-pyridin-3-ylphenyl) methanamine

MS (ESI pos.) m/z : 282([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.15 - 1.71 (m, 6 H), 2.48 (s, 3 H), 2.54 - 2.60 (m, 1 H) , 2.60 - 2.66 (m, 1 H), 2.99 - 3.04 (m, 1 H), 4.14 (d, J=8.3 Hz, 1 H), 7.34 - 7.38 (m, 1 H), 7.40 - 7.49 (m, 3 H) , 7.60 - 7.62 (m, 1 H) , 7.88 - 7.91 (m, 1 H) , 8.59 (dd, J=4.6, 1.4 Hz, 1 H), 8.86 (d, J=2.3 Hz, 1 H)

Production Example 13 Synthesis of (S)-l-(( 2S)-I- methylpiperidin-2-yl) - 1- ( 3-pyridin-2-ylphenyl) methanamine

(1) tert-Butyl (2S) -2- ( (S) -hydroxy(3- (4 , 4 , 5 , 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl)methyl)piperidine-1-carboxylate (1.3 g) was obtained as a colorless oil from tert-butyl (2S)- 2- ( (S) -hydroxy( 3- ( ( (trifluoromethyl) sulfonyl)oxy)phenyl) methyl)piperidine-1-carboxylate (1.5 g) in the same way as in Production Example 10(1).

MS (ESI pos.) m/z : 418([M+H]+)

(2) tert-Butyl ( 2S) -2- ( (S) -hydroxy(3-pyridin-2- ylphenyl)methyl) piperidine- 1-carboxylate (0.50 g) was obtained as a colorless oil from tert-butyl (2S) -2- ( (S) -hydroxy(3- (4,4, 5, 5- tetramethyl-

1,3, 2-dioxaborolan-2-yl)phenyl)methyl)piperidine-1-carboxylate (1.2 g) and 2-bromopyridine (0.68 g) in the same way as in Production Example 10(2). MS (ESI pos.) m/z : 369([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.31 - 1.37 (m, 1 H) , 1.37 - 1.66 (m, 13 H), 1.66 - 1.74 (m, 1 H), 2.90 - 3.17 (m, 1 H), 3.98 - 4.53 (m, 2 H), 4.96 - 5.01 (m, 1 H), 7.22 - 7.26 (m, 1 H), 7.42 - 7.51 (m, 2 H), 7.74 - 7.78 (m, 2 H), 7.92 - 7.97 (m, 1 H), 7.99 - 8.01 (m, 1 H), 8.68 - 8.71 (m, 1 H)

(3) ( S) - ( ( 2S) -1-Methylpiperidin- 2-yl) ( 3-pyridin-2-ylphenyl) methanol (0.36 g) was obtained as a pale yellow oil from tert- butyl (2S)-2-( (S) -hydroxy(3-pyridin-2- ylphenyl)methyl)piperidine-1- carboxylate (0.47 g) in the same way as in Production Example 5(1). MS (ESI pos.) m/z : 283([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.30 - 1.77 (m, 6 H), 2.53 (s, 3 H), 2.62 - 2.72 (m, 2 H), 3.02 - 3.09 (m, 1 H), 4.72 (d, J=8.7 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.72 - 7.77 (m, 2 H), 7.88 - 7.92 (m, 1 H), 7.99 - 8.03 (m, 1 H), 8.68 - 8.71 (m, 1 H)

(4) The title compound (0.13 g) was obtained as a yellow oil from (S) - ( (2S)-l-methylpiperidin-2-yl) ( 3-pyridin-2-ylphenyl) methanol (0.32 g) in the same way as in Production Example 5(2). MS (ESI pos.) m/z : 282([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.17 - 1.24 (m, 1 H) , 1.28 -

1.37 (m, 2 H), 1.38 - 1.53 (m, 2 H), 1.64 - 1.71 (m, 1 H),

2.48 (s, 3 H), 2.58 - 2.70 (m, 2 H), 2.99 - 3.05 (m, 1 H), 4.12 - 4.15 (m, 1 H), 7.20 - 7.25 (m, 1 H), 7.41 - 7.46 (m, 2 H), 7.73 - 7.77 (m, 2 H), 7.84 - 7.88 (m, 1 H), 7.98 - 8.00 (m, 1 H) , 8.68 - 8.71 (m, 1 H)

Production Example 14 Synthesis of (S)-l-(( 2S)-I- methylpiperidin-2-yl) - 1- ( 4-pyridin-2-ylphenyl) methanamine

(1) ( 2S) -2- ( (S) -((tert-Butyl(dimethyl) silyl)oxy) (4-(4,4,5,5- tetramethyl- 1 , 3 , 2-dioxaborolan-2-yl)phenyl)methyl) -1- methylpiperidine (1.2 g) was obtained as a brownish red oil from 4-( (S)-((tert-butyl(dimethyl)silyl)oxy) ((2S)-I- methylpiperidin-2-yl)methyl)phenyl trifluoromethanesulfonate (1.2 g) in the same way as in Production Example 10(1). MS (ESI pos.) m/z : 446([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm -0.15 (s, 3 H), 0.05 (s, 3 H), 0.68 - 0.78 (m, 1 H), 0.89 (s, 9 H), 1.07 - 1.17 (m, 1 H), 1.26 - 1.38 (m, 13 H), 1.42 - 1.67 (m, 3 H), 2.02 - 2.14 (m, 2 H), 2.50 (s, 3 H), 2.81 - 2.87 (m, 1 H), 5.08 - 5.11 (m, 1 H), 7.33 - 7.37 (m, 2 H), 7.70 - 7.75 (m, 2 H) (2) 2-(4-( (S)-( (tert-butyl(dimethyl) silyl)oxy) ( (2S)-I- methylpiperidin-2-yl)methyl)phenyl)pyridine (0.91 g) was obtain as a colorless oil from (2S) -2- ( (S) - ( (tert- butyl(dimethyl) silyl)oxy)(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methyl) -1- methylpiperidine (1.1 g) in the same way as in Production Example 10(2) .

MS (ESI pos.) m/z : 397([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm -0.10 (s, 3 H), 0.08 (s, 3 H), 0.75 - 0.84 (m, 1 H), 0.92 (s, 9 H), 1.10 - 1.21 (m, 1 H), 1.27 - 1.37 (m, 1 H), 1.44 - 1.51 (m, 1 H), 1.57 - 1.64 (m, 1 H), 1.69 - 1.76 (m, 1 H), 2.03 - 2.19 (m, 2 H), 2.54 (s, 3 H), 2.81 - 2.93 (m, 1 H), 5.13 - 5.20 (m, 1 H), 7.18 - 7.23 (m, 1 H), 7.44 - 7.48 (m, 2 H), 7.70 - 7.75 (m, 2 H), 7.90 - 7.94 (m, 2 H) , 8.67 - 8.69 (m, 1 H) (3) (S) -( (2S)-I-Methylpiperidin-2-yl) (4-pyridin-2-ylphenyl) methanol (0.38 g) was obtained as a colorless oil from 2-(4- ( (S) - ( (tert-butyl(dimethyl)silyl)oxy) ( (2S) -1- methylpiperidin-2-yl)methyl)phenyl)pyridine (0.85 g) in the same way as in Production Example 11(6). MS (ESI pos.) m/z : 283([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.29 - 1.35 (m, 1 H), 1.40 - 1.63 (m, 4 H), 1.68 - 1.76 (m, 1 H), 2.51 (s, 3 H), 2.55 - 2.60 (m, 1 H), 2.64 - 2.70 (m, 1 H), 3.02 - 3.08 (m, 1 H), 4.70 (d, J=8.7 Hz, 1 H), 7.19 - 7.24 (m, 1 H), 7.47 - 7.50 (m, 2 H), 7.71 - 7.77 (m, 2 H), 7.94 - 7.99 (m, 2 H), 8.67 - 8.70 (m, 1 H)

(4) (S)-l-((2S)-l-Methylpiperidin-2-yl)-l-(4-pyridin-2-yl phenyl)methanamine (0.12 g) was obtained as a pale yellow solid from (S) - ( (2S) -l-methylpiperidin-2-yl) ( 4-pyridin-2-yl phenyl)methanol (0.29 g) in the same way as in Production Example 3(3).

MS (ESI pos.) m/z : 282( [M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.16 - 1.72 (m, 6 H), 2.49 (s, 3 H), 2.57 - 2.72 (m, 2 H), 3.00 - 3.06 (m, 1 H), 4.09 (d, J=8.3 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.45 - 7.50 (m, 2 H), 7.70 - 7.77 (m, 2 H), 7.93 - 7.98 (m, 2 H), 8.67 - 8.71 (m, 1 H)

Production Example 15 Synthesis of N- ( (S) - ( (2S) -1- allylpiperidin-2-yl) ( 3-bromophenyl)methyl) -2- chloro-3- (trifluoromethyl)benzamide

(1) An aqueous solution (25 ml) of CuBr₂ (3.1 g) was added to a methanol solution (25 ml) of tert-butyl (2S) -2- ((S)- hydroxy( 3- ( 4 , 4 , 5 , 5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)methyl)piperidine-l-carboxylate (1.9 g) and stirred at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure. Chloroform and a saturated aqueous solution of sodium bicarbonate were poured thereto, and the mixture was stirred. Insoluble matter was filtered off through a Celite (trade mark) pad. The organic layer of the filtrate was separated with a separating funnel. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, chloroform/methanol=100 : 0 to 9:1) to obtain (S)-(3-bromophenyl) ( ( 2S) ~piperidin-2-yl)methanol (0.99 g) as a blue solid.

MS (ESI pos.) m/z : 270([M+H] + ), (ESI pos.) m/z : 272([M+3] + ) IH NMR (600 MHz, CDC13) δ ppm 1.20 - 1.64 (m, 5 H), 1.74 - 1.81 (m, 1 H), 2.56 - 2.66 (m, 2 H), 3.05 - 3.11 (m, 1 H), 4.33 - 4.39 (m, 1 H), 7.18 - 7.24 (m, 1 H), 7.25 - 7.29 (m, 1 H), 7.39 - 7.43 (m, 1 H), 7.51 - 7.54 (m, 1 H)

(2) (S) - ( (2S) -l-Allylpiperidin-2-yl) ( 3-bromophenyl)methanol (0.68 g) was obtained as a colorless oil from (S) -(3- bromophenyl) ( (2S) -piperidin-2-yl)methanol (0.95 g) in the same way as in Production Example 3(2).

MS (ESI pos.) m/z : 310 ( [M+H] + ) , (ESI pos.) m/z : 312([M+3]+)

IH NMR (600 MHz, CDC13) δ ppm 1.15 - 1.22 (m, 1 H), 1.30 - 1.37 (m, 1 H), 1.47 - 1.73 (m, 4 H), 2.55 - 2.60 (m, 1 H), 2.71 - 2.77 (m, 1 H), 2.96 - 3.03 (m, 1 H), 3.30 - 3.36 (m, 1 H), 3.39 - 3.45 (m, 1 H), 4.70 (d, J=9.6 Hz, 1 H), 5.15 - 5.23 (m, 2 H), 5.81 - 5.90 (m, 1 H), 7.19 (t, J=7.8 Hz, 1 H), 7.25 - 7.28 (m, 1 H), 7.37 - 7.41 (m, 1 H), 7.51 - 7.54 (m, 1 H)

(3) (S)-1-((2S)-1-Allylpiperidin-2-yl) - 1- ( 3-bromophenyl) methanamine (0.42 g) was obtained as a yellow oil from (S)- ( (2S)-l-allylpiperidin-2-yl) ( 3-bromophenyl)methanol (0.64 g) in the same way as in Production Example 3(3).

MS (ESI pos.) m/z : 309([M+H]+), (ESI pos . ) m/z : 311([M+3]+) IH NMR (600 MHz, CDC13) δ ppm 0.97 - 1.04 (m, 1 H), 1.29 - 1.66 (m, 5 H), 2.59 - 2.69 (m, 2 H), 2.99 - 3.05 (m, 1 H), 3.33 - 3.37 (m, 2 H), 4.17 (d, J=9.6 Hz, 1 H), 5.11 - 5.15 (m, 1 H), 5.18 - 5.23 (m, 1 H), 5.84 - 5.92 (m, 1 H), 7.17 (t, J=7.8 Hz, 1 H), 7.27 - 7.29 (m, 1 H), 7.35 - 7.38 (m, 1 H), 7.52 - 7.54 (m, 1 H)

( 4 ) N- ( ( S ) - ( ( 2S) - 1-Allylpiperidin-2-yl) ( 3-bromophenyl) methyl) -2-chloro-3- ( trifluoromethyl)benzamide (0.52 g) was obtained as a colorless solid from (S)-l-(( 2S)-I- allylpiperidin-2-yl) -1- (3-bromophenyl) methanamine (0.39 g) in the same way as in Production Example 4(1).

MS (ESI pos.) m/z : 515([M+H]+), (ESI pos.) m/z : 517([M+3]+) IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.35 (m, 1 H) , 1.35 - 1.43 (m, 1 H), 1.48 - 1.60 (m, 3 H), 1.74 - 1.82 (m, 1 H), 2.54 - 2.62 (m, 1 H), 2.77 - 2.82 (m, 1 H), 2.88 - 2.96 (m, 1

H), 3.17 - 3.24 (m, 1 H), 3.25 - 3.32 (m, 1 H), 4.87 - 4.93 (m, 1 H), 5.07 - 5.16 (m, 2 H), 5.68 - 5.77 (m, 1 H), 7.22 (t, J=7.8 Hz, 1 H), 7.30 - 7.34 (m, 1 H), 7.37 - 7.46 (m, 2 H), 7.49 - 7.52 (m, 1 H), 7.69 - 7.79 (m, 3 H)

Production Example 16 Synthesis of tert-butyl (2S)-2-((S)-(3- bromophenyl) ( ( (3-chloro-4- ( trifluoromethyl) pyridin-2-yl) carbonyl) amino)methyl)piperidine-1-carboxylate

(1) N-((S)-(3-Bromophenyl) ( ( 2S) -1-prop-2-en-1-ylpiperidin-2- yi) methyl) -3-chloro-4- ( trifluoromethyl)pyridine-2-σarboxamide (2.78 g) was obtained as a yellow oil from (S) -1- ( (2S) -1-prop- 2-en-1-ylpiperidin-2-yl) -1- ( 3-bromophenyl) methanamine (1.86 g) in the same way as in Production Example

4(1).

MS; (ESI pos.) m/z : 516 ([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.34 (m, 1 H), 1.37 - 1.45 (m, 1 H), 1.47 - 1.56 (m, 3 H), 1.74 - 1.80 (m, 1 H),

2.56 - 2.61 (m, 1 H), 2.83 - 2.88 (m, 1 H), 2.92 - 2.98 (m, 1 H), 3.18 - 3.23 (m, 1 H), 3.31 (dd, J=14.2, 6.4 Hz, 1 H), 4.90 (dd, J=9.2, 4.1 Hz, 1 H), 5.10-5.13 (m,l H), 5.15-5.22 (m, 1 H), 5.76 - 5.84 (m, 1 H), 7.20 (t, J=7.8 Hz, 1 H), 7.32 (d, J=7.8 Hz, 1 H), 7.36 - 7.39 (m, 1 H), 7.49 - 7.51 (m, 1 H), 7.71 (d, J=5.0 Hz, 1 H), 8.68 (d, J=5.0 Hz, 1 H), 8.79 (d, J=3.2 Hz, 1 H)

(2) 1,3-Dimethylbarbituric acid (1.01 g) and tetrakis(triphenylphosphine)palladium (15 mg) were added to a chloroform solution (10 ml) of N- ( (S) - (3-bromophenyl) ( ( 2S) -1- prop-2-en-1-ylpiperidin-2-yl) methyl) -3-chloro-4- ( trifluoromethyl)pyridine-2-carboxamide (1.35 g) under a nitrogen atmosphere and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and passed through an NH-silica gel for removing the drying agent and preliminary purification. The filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (8 ml). tert-Butyl Dicarbonate (1.2 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours . The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=3:l) to obtain the title compound (1.39 g) in a colorless amorphous state. MS; (ESI pos.) m/z : 576 ([M+H]+), (ESI neg.) m/z : 574([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.76 (m, 15 H), 2.77 - 2.85 (m, 0.2 H), 2.93 - 3.03 (m, 0.8 H), 3.94 - 4.04 (m, 0.8 H), 4.12 - 4.18 (m, 0.2 H), 4.42 - 4.52 (m, 0.2 H), 4.60 - 4.70 (m, 0.8 H), 5.34 - 5.46 (m, 1 H), 7.23 (t, J=7.8 Hz, 1 H), 7.31 - 7.44 (m, 2 H), 7.50 - 7.55 (m, 0.2 H), 7.59 - 7.64 (m, 0.8 H), 7.64 - 7.68 (m, 0.8 H), 7.68 - 7.72 (m, 0.2 H), 8.43 - 8.56 (m, 1 H), 8.58 (d, J=5.0 Hz, 1 H)

Production Example 17 Synthesis of tert-butyl (2S) -2- ((S)- amino( 3-( 1-ethyl-lH-pyrazol-4-yl)phenyl)methyl) piperidine-1-carboxylate

(1) 1,3-Dibromobenzene (148.3 g) was dissolved in tetrahydrofuran (680 ml) under a nitrogen atmosphere. 2.64 M Hexane solution (175 ml) of n-butyllithium was added dropwise to this solution at -70⁰C or lower. The mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (230 ml) of tert-butyl (2S) -2- ( (methoxy(methyl) amino) carbony1)piperidine- 1- carboxylate (114 g) was added dropwise thereto at -70⁰C or lower. The mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added thereto, and the mixture was heated to room temperature. The mixture was stirred at room temperature for 1 hour. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=8:l) to obtain tert-butyl (2S)-2-( (3-bromophenyl)carbonyl)piperidine-l- carboxylate (71.2g) as a pale yellow solid. MS; (ESI pos . ) m/z : 368 ([M+H]+), (ESI pos . ) m/z : 268 ([M-99] + )

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.88 (m, 14 H), 1.96 - 2.20 (m, 1 H), 2.98 - 3.17 (m, 1 H), 3.82 - 4.06 (m, 1 H), 5.33 - 5.64 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7.63 - 7.72 (m, 1 H), 7.76 - 7.89 (m, 1 H), 8.00 - 8.09 (m, 1 H)

(2) Hydroxylamine hydrochloride (1.92 g) was added to an ethanol solution (50 mL) of tert-butyl (2S)-2-((3- bromophenyl)carbonyl)piperidine-l-carboxylate (5.10 g) and the ethanol solution was refluxed for 5 hours . 4 N Hydrochloric acid/ethyl acetate (12 ml) was added to the reaction solution under ice cooling, and the mixture was stirred overnight at room temperature . The mixture was concentrated under reduced pressure. Hexane and ethyl acetate were added thereto, and the mixture was stirred. The solid was collected by filtration. This solid was suspended in methanol (50 mL). Triethylamine (5.8 ml) was added thereto, and di-tert-butyl dicarbonate (9.5 ml) was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue. This ethyl acetate layer was washed with 5% aqueous potassium bisulfate solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=10:l to 2:1) to obtain tert- butyl (2S)-2-((3-bromopheny1) (hydroxyimino)methyl) piperidine-1-carboxylate (4.18 g) as a pale yellow oil.

MS; (ESI pos.) m/z : 383 ([MH-H] + ), (ESI pos . ) m/z : 283 ([M- 99] + )

(3) An aqueous solution (100 ml) of 10.8% potassium carbonate and an ethanol solution (100 ml) of l-ethyl-4- (4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (15 g) were added to a toluene solution (100 ml) of tert-butyl (2S)-2-((3- bromophenyl) (hydroxyimino)methyl)piperidine-1- carboxylate (19.9 g) . PEPPSI-Ipr (TM) (705 mg) was added thereto under a nitrogen atmosphere, and the mixture was stirred at 70⁰C for 2 hours. After cooling to room temperature, saturated brine was added thereto, followed by two extractions with ethyl acetate . The combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=2:l to 1:1). The obtained oil was dissolved in diethyl ether and washed with water. The ethereal layer was dried over anhydrous sodium sulfate . The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (2S)-

2-( (3-(l-ethyl-lH-pyrazol-4- yl)phenyl) (hydroxyimino)methyl)piperidine-l-carboxylate (13.0 g) in a pale yellow amorphous state. The obtained amorphous compound, which contained impurities, was utilized in the following reaction without further purification. MS; (ESI pos.) m/z : 399 ([M+H]+), (ESI pos.) m/z : 299 ([M-99] +)

(4) tert-Butyl (2S) -2- ( (3- ( l-ethyl-lH-pyrazol-4-yl)phenyl) (hydroxyimino)methyl)piperidine-1-carboxylate (92 mg) was dissolved in 8 N ammonia/methanol (1 ml) under a nitrogen atmosphere. 10% palladium carbon (18 mg) was added thereto. The mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. 8 N Ammonia/methanol (1 ml) was further added thereto, and the mixture was stirred at 50⁰C for 7.5 hours. After filtration through a Celite (trade mark) pad, the filtrate was concentrated under reduced pressure to obtain the title compound (88 mg) as a colorless oil. MS; (ESI pos.) m/z : 385 ([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.28 - 1.32 (m, 1 H) , 1.34 - 1.73 (m, 14 H), 1.54 (t, J=7.3 Hz, 3 H), 2.80 - 3.04 (m, 1 H), 4.01 - 4.51 (m, 3 H), 4.21 (q, J=7.3 Hz, 2 H), 7.14 - 7.21 (m, 1 H), 7.28 - 7.35 (m, 1 H), 7.37 - 7.41 (m, 1 H), 7.42 - 7.50 (m, 1 H), 7.62 - 7.71 (m, 1 H), 7.77 (s, 1 H)

Raw material compounds used in the production of the compound of the present invention were synthesized as shown below. (A) Synthesis of 3-chloro-4-trifluoromethylpyridine-2- carboxylic acid

(1) 3-Chloro-4-iodopyridine was obtained from 3-chloropγridine by the method described in Tetrahedron (1993.) 49 (1), 49. (2) 3-Chloro-4-trifluoromethylpyridine was obtained from 3- chloro-4-iodopγridine by the method described in Eur. J. Org. Chem., (2004), 3793.

(3) The title compound was obtained from 3-chloro-4- trifluoromethylpyridine by the method described in Eur . J . Org . Chem., (2004), 3793.

(B) Synthesis of 3-chloro-2-trifluoromethylisonicotinic acid

(1) 3-Chloro-2-iodopyridine was obtained from 2,3- dichloropyridine by the method described in Eur. J. Org. Chem., (2002), 4181.

(2) 3-Chloro-2-trifluoropyridine was obtained from 3-chloro-2- iodopyridine by the method described in Synthesis, (2004) 1619. (3) The title compound was obtained from 3-chloro-2- trifluoropyridine by the method described in Synthesis, (2004)

1619.

(C) Synthesis of pyrazoleboronic acid pinacol ester

1-methyl-5- ( 4,4,5 , 5-tetramethyl- [1,3, 2 ]dioχ_aborolan-2-yl) -IH- 007/065988

110 pyrazole, 1-ethyl-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl) -lH-pyrazole, 1-ethyl-4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl) -lH-pyrazole , 1-isopropyl-4-(4,4,5,5- tetramethyl- [1, 3, 2]dioxaborolan-2-yl) -lH-pyrazole, and 1-n- propyl-4- ( 4,4,5 , 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -IH- pyrazole were synthesized according to the procedure described in Journal of Heterocyclic Chemistry 41, 931 (2004) or a similar method thereof.

Example 1

Synthesis of 2-chloro-N- ( (S) - (3- ( 1-methyl-lH-pyrazol-4- yl)phenyl)((2S)- piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide monohydrochloride (Compound 21)

(1) 3- ( (S)- ( (2S)-I-AlIylpiperidin-2-yl) ( ( 2-chloro-3- (trifluoromethyl)benzoyl)amino)methyl)phenyl trifluoromethanesulfonate (3.3 g) , 1-methyl-lH-pyrazole-4- boronic acid pinacol ester (1.8 g) , and potassium carbonate (1.8 g) were suspended in a mixed solvent (40 ml) of DMF/ethanol (=2:1). After the reaction vessel was purged with nitrogen gas, Pd(PPh₃J₄ (0.33 g) was added thereto, and the mixture was stirred at 90⁰C for 3 hours. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, chloroform/methanol=9 : 1) to obtain N- ((S)- ((2S)-1-allylpiperidin-2-yl) ( 3- ( 1-methyl-lH-pyrazol-4- yl)phenyl)methyl) -2-chloro-3- ( trifluoromethyl)benzamide (2.1 g) in a pale yellow amorphous state. MS (ESI pos.) m/z : 517([M+H]+), (ESI neg.) m/z : 515([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.32 - 1.44 (m, 2 H), 1.47 - 1.64 (m, 3 H), 1.76 - 1.86 (m, 1 H), 2.55 - 2.60 (m, 1 H), 2.84 - 2.88 (m, 1 H), 2.93 - 2.99 (m, 1 H), 3.20 - 3.25 (m, 1 H), 3.28 - 3.34 (m, 1 H), 3.95 (s, 3 H), 4.92 - 5.00 (m, 1 H), 5.07 - 5.16 (m, 2 H), 5.69 - 5.78 (m, 1 H), 7.21 - 7.79 (m, 10 H)

(2) 1,3-Dimethylbarbituric acid (1.9 g) and Pd(PPh₃J₄ (46 mg) were added to a chloroform solution (20 ml) of N- ( (S) - ( ( 2S) -1- allylpiperidin-2-yl) (3- ( 1-methyl-lH-pyrazol-4- yl)phenyl)methyl) -2-chloro-3- (trifluoromethyl)benzamide (2.1 g) under a nitrogen atmosphere and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=9: 1 and NH-silica gel. chloroform/methanol=9: 1) to obtain 2-chloro-N- ( (S) - (3- (1- methyl-lH-pyrazol-4-yl)phenyl) ( (2S) - piperidin-2-yl)methyl) -3- ( trifluoromethyl)benzamide (1.3 g) .

This compound was dissolved in ethanol (13 ml) and 4 M HCl/ethyl acetate solution (1.1 ml) was added to the ethanol solution under ice cooling. The resulting solution was concentrated under reduced pressure and solidified by the addition of ethyl acetate. The precipitate was collected by filtration to obtain the title compound (1.2 g) .

Example 2

Synthesis of 3-chloro-N- ( (S) - (2S) -piperidin-2-yl(4-pyridin-3- ylphenyl) methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide dihydrochloride (Compound 18)

(1) HOBt-H₂O (0.21 g) and EDC-HCl (0.25 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpyridine-2- carboxylic acid (0.24 g) and stirred at room temperature for

15 minutes. (S) -1- ( ( 2S) -l-Allylpiperidin-2-yl) -1- ( 4-pyridin-

3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred at room temperature for 4 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=6:l to 1:1) to obtain N- ( (S) - ( (2S) -l-allylpiperidin-2- yl) ( 4-pyridin-3-ylphenyl) methyl) -3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide (0.24 g) in a pale yellow amorphous state.

MS (ESI pos.) m/z : 515([M+H]+), (ESI neg.) m/z : 513([M-H]-) IH NMR (600 MHz, CDC13 ) δ ppm 1.33 - 1.47 (m, 2 H), 1.48 - 1.64 (m, 3 H), 1.78 - 1.85 (m, 1 H), 2.57 - 2.63 (m, 1 H), 2.90 - 2.96 (m, 1 H), 2.96 - 3.03 (m, 1 H), 3.20 - 3.28 (m, 1 H), 3.32 - 3.39 (m, 1 H), 4.98 - 5.03 (m, 1 H), 5.09 - 5.14 (m, 1 H), 5.18 - 5.23 (m, 1 H), 5.77 - 5.88 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.47 - 7.51 (m, 2 H), 7.53 - 7.57 (m, 2 H), 7.71 (d, J=5.0 Hz, 1 H), 7.84 - 7.87 (m, 1 H), 8.56 - 8.59 (m, 1 H), 8.69 (d, J=4.6 Hz, 1 H), 8.80 - 8.85 (m, 2 H)

(2) 1,3-Dimethylbarbituric acid (0.18 g) and Pd(PPh₃J₄ (4.4 mg) were added to a chloroform solution (3 ml) of N- ( (S) - ( (2S) -1- allylpiperidin-2-yl) (4-pyridin-3-ylphenyl) methyl) -3-chloro-4- ( trifluoromethyl)pyridine-2-carboxamide (0.20 g) under a nitrogen atmosphere and stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol/28% aqueous NH₃ (ammonia) solution=49: 1:0.5) to obtain 3-chloro-N- ( (S) - (2S) -piperidin-2- yl( 4-pyridin-3-ylphenyl) methyl) -4- (trifluoromethyl)pyridine-2-carboxamide (0.17 g) in a pale red amorphous state. The obtained purified product was dissolved in ethyl acetate (8 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the ethyl acetate solution under ice cooling. The resulting solution was stirred at room temperature for 1 hour. The precipitate was collected by filtration to obtain the title compound (0.17 g) .

Synthesis of N- ( (S) -biphenyl-3-yl( (2S) -piperidin-2-yl)methyl) - 3-chloro-4-

( trifluoromethyl)pyridine-2-carboxamide monohydrochloride (Compound 16)

(1) HOBt-H₂O (0.30 g) and EDC-HCl (0.34 g) were added to a DMF solution (5 ml) of 3-chloro-4-trifluoromethylpyridine-2- carboxylic acid (0.34 g) and stirred at room temperature for 15 minutes. (S) -1- ( ( 2S) -l-Allylpiperidin-2-yl) -l-biphenyl-3- ylmethanamine (0.40 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=99:l to 49:1) to obtain N- [ (S) - [ ( 2S) -1- allylpiperidin-2-yl] (biphenyl-3-yl)methyl] -3- chloro-4- (trifluoromethyl)pyridine-2-carboxamide (0.53 g) in a pale yellow amorphous state.

(ESI pos.) m/z : 514([M+H]+), (ESI neg. ) m/z : 512([M-H]-) (2) 1,3-Dimethylbarbituric acid (0.42 g) and Pd(PPh₃J₄ (10 mg) were added to a chloroform solution (5 ml) of N- [ (S) - [ (2S) -1- allylpiperidin-2-yl] (biphenyl-3-yl)methyl] -3- chloro-4- ( trifluoromethyl)pyridine-2-carboxamide (0.46 g) under a nitrogen atmosphere and stirred at room temperature for 2 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel. chloroform/methanol/28% aqueous NH₃ (ammonia) solution=49: 1:0.5 and subsequently, NH-silica gel, hexane/ethyl acetate=3:l to 2:1) to obtain N- { (S) -biphenyl-3- yl[ (2S)-piperidin-2-yl]methyl}-3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide (0.30 g) in a colorless amorphous state. The obtained purified product was dissolved in ethyl acetate (3 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the ethyl acetate solution. The resulting solution was concentrated under reduced pressure to obtain the title compound (0.25 g) in a colorless amorphous state.

Synthesis of 3-chloro-N- [ (S) - (2S) -piperidin-2-yl(3-pyridin-3- ylphenyl) methyl] -4- ( trifluoromethyl)pyridine-2-carboxamide dihydrochloride (Compound 20)

(1) HOBt-H₂O (0.22 g) and EDC-HCl (0.25 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpγridine-2- carboxylic acid (0.24 g) and stirred at room temperature for

15 minutes. (S) -1- ( (2S) -l-Allylpiperidin-2-yl) -1- ( 3-pyridin-

3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate . The drying agent was filtered off , and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=99:l to 30:1) to obtain N- [ (S) - [ ( 2S) -1- allylpiperidin-2-yl] ( 3-pyridin-3-ylphenyl) methyl] -3-chloro-4- ( trifluoromethyl)pyridine-2-carboxamide (0.38 g) as a yellow solid. MS (ESI pos.) m/z : 515([M+H]+), (ESI neg.) m/z : 513([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.34 - 1.46 (m, 2 H), 1.48 - 1.64 (m, 3 H), 1.77 - 1.86 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.90 - 3.02 (m, 2 H), 3.20 - 3.26 (m, 1 H), 3.29 - 3.37 (m, 1 H), 5.03 (dd, J=8.9, 4.4 Hz, 1 H), 5.08 - 5.13 (m, 1 H), 5.16 - 5.22 (m, 1 H), 5.76 - 5.86 (m, 1 H), 7.33 - 7.37 (m, 1 H), 7.42 - 7.48 (m, 3 H), 7.56 - 7.59 (m, 1 H), 7.71 (d, J=5.0 Hz, 1 H), 7.85 - 7.89 (m, 1 H), 8.58 (dd, J=4.6, 1.4 Hz, 1 H), 8.69 (d, J=4.6 Hz, 1 H), 8.79 - 8.85 (m, 2 H) (2) 1,3-Dimethylbarbituric acid (0.24 g) and Pd(PPh₃J₄ (6 mg) were added to a chloroform solution (5 ml) of N- [(S)-[( 2S)-I- allylpiperidin-2-yl] ( 3-pyridin-3-ylphenyl) methyl ] -3-chloro-4- (trifluoromethyl)pyridine-2-carboxamide (0.27 g) under a nitrogen atmosphere and stirred at room temperature for 4 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol/28% aqueous NH₃ solution=50 : 1 : 0.5) to obtain 3-chloro-N- [ (S) - (2S) -piperidin-2-yl(3-pyridin-3- ylphenyl)methyl] -4- ( trifluoromethyl)pyridine-2-carboxamide (0.24 g) in a pale yellow amorphous state. The obtained purified product was dissolved in ethyl acetate (8 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the acetate solution under ice cooling. The resulting solution was stirred at room temperature for 1 hour. The precipitate was collected by filtration to obtain the title compound (0.24 g) as a colorless solid.

Synthesis of 2-chloro-N- ( (S) - ( 2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl) methyl) -3- ( trifluoromethyl)benzamide monohydrochloride (Compound 39)

(1) HOBt-H₂O (0.14 g) and EDC-HCl (0.17 g) were added to a DMF solution (4 ml) of 2-chloro-3-trifluoromethylbenzoic acid (0.18 g) and stirred at room temperature for 15 minutes. (S)- l-( (2S)-I-Allylpiperidin-2-yl) -1- (3-pγrazin-2-γlphenyl) methanamine (0.22 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=100:0 to 97:3) to obtain N- [ (S) - [ ( 2S) -1- allylpiperidin-2-yl] ( 3-pyrazin-2-ylphenyl) methyl] -2-chloro-3- (trifluoromethyl)benzamide (0.25 g) as a pale yellow solid.

MS (ESI pos.) m/z : 515 ( [M+H]+) , (ESI neg.) m/z : 513([M-H]-) IH NMR (600 MHz, CDC13) δ ppm 1.34 - 1.87 (m, 6 H), 2.56 - 2.63 (m, 1 H), 2.87- 3.01 (m, 2 H), 3.20 - 3.27 (m, 1 H), 3.28 - 3.34 (m, 1 H), 5.02 - 5.16 (m, 3 H), 5.70 - 5.79 (m, 1 H), 7.41 - 7.45 (m, 1 H), 7.49 - 7.53 (m, 2 H), 7.70 - 7.74 (m, 1 H), 7.76 - 7.79 (m, 1 H), 7.80 - 7.86 (m, 1 H), 7.90 - 7.94 (m, 1 H), 8.05 - 8.08 (m, 1 H), 8.50 - 8.52 (m, 1 H), 8.63 - 8.66 (m, 1 H), 9.03 - 9.05 (m, 1 H) (2) 1,3-Dimethylbarbituric acid (0.18 g) and Pd(PPh₃J₄ (4.5 mg) were added to a chloroform solution (2 ml) of N- [ (S) - [ (2S) -1- allylpiperidin-2-yl] ( 3-pyrazin-2-ylphenyl) methyl] -2-chloro-3- (trifluoromethyl)benzamide (0.20 g) under a nitrogen atmosphere and stirred at room temperature for 4 hours . A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=75:25) and TLC (silica gel, chloroform/methanol=9 : 1) to obtain 2-chloro-N- [ (S) - (2S) -piperidin-2-yl(3-pyrazin-2- ylphenyl) methyl] -3- (trifluoromethyl)benzamide (0.14 g) . The obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.15 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the colorless, amorphous title compound (0.11 g) .

Synthesis of 2-chloro-N-{ (S) - [3- ( l-methyl-lH-imidazol-5- yl)phenyl][(2S)- piperidin-2-yl]methyl} -3- ( trifluoromethyl)benzamide dihydrochloride (Compound 70)

(1) HOBt-H₂O (0.11 g) and EDC-HCl (0.14 g) were added to a DMF solution (4 ml) of 2-chloro-3-trifluoromethylbenzoic acid (0.15 g) and stirred at room temperature for 15 minutes. (S)- 1-((2S)-I-Allylpiperidin-2-yl) - 1- ( 3- ( 1-methyl- IH-imidazol-5- yl)phenyl)methanamine (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto , and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate , and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=67 : 33 to 0:100 and subsequently, silica gel, chloroform/methanol=100 : 0 to 97:3) to obtain N-{(S)- t(2S)-l-allylpiperidin-2-yl] [3- ( l-methyl-lH-imidazol-5- yl)phenyl]methyl}-2-chloro-3- (trifluoromethyl)benzamide (0.21 g) in a colorless amorphous state. MS(ESI pos.) m/z : 517([M+H]+) IH NMR (600 MHz, CDC13) δ ppm 1.30 - 1.93 (m, 6 H), 2.54 - 2.62 (m, 1 H), 2.83 - 2.91 (m, 1 H), 2.91 - 2.99 (m, 1 H), 3.18 - 3.25 (m, 1 H), 3.28 - 3.36 (m, 1 H), 3.67 (s, 3 H), 4.94 - 5.02 (m, 1 H), 5.05 - 5.15 (m, 2 H), 5.68 - 5.79 (m, 1 H), 7.10 (s, 1 H), 7.28 - 7.32 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.52 (s, 1 H), 7.67 - 7.73 (m, 1 H), 7.76 - 7.84 (m, 2 H)

(2) 1,3-Dimethylbarbituric acid (0.17 g) and Pd(PPh₃J₄ (4.2 mg) were added to a chloroform solution (2 ml) of N-{ (S) - [ (2S) -1- allylpiperidin-2-yl] [3- ( 1-methyl- lH-imidazol-5- yl)phenyl]methγl}-2-chloro-3- (trifluoromethyl)benzamide (0.19 g) under a nitrogen atmosphere and stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=67 : 33 to 0:100) and TLC (silica gel, chloroform/methanol=9:l) to obtain 2-chloro-N-{ (S) - [3- ( 1- methyl-lH-imidazol-5-yl)phenyl] [ (2S) - piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (0.12 g) . The obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution under ice cooling. The resulting solution was stirred at room temperature for 30 minutes . The precipitate was collected by filtration to obtain the title compound (0.12 g) .

Synthesis of 3-chloro-N- [ (S) - ( 2S) -piperidin-2-yl( 3-pyrimidin- 5-ylphenyl) methyl] -4- ( trifluoromethyl)pyridine-2-carboxamide monohydrochloride (Compound 75)

(1) HOBt-H₂O (0.35 g) and EDC-HCl (0.40 g) were added to a DMF solution (7 ml) of 3-chloro-4-trifluoromethylpyridine-2- carboxylic acid (0.38 g) and stirred at room temperature for 30 minutes. A DMF solution (3 ml) of (S) -1- ( (2S) -1- allylpiperidin-2-yl) -1- (3-pyrimidin-5-ylphenyl) methanamine (0.47 g) was added thereto, and the mixture was stirred at room temperature for 2 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=l:2) to obtain N- [ (S) - [ (2S) -l-allylpiperidin-2-yl] ( 3- pyrimidin-5-ylphenyl) methyl] -3-σhloro-4- (trifluoromethyl)pyridine-2-carboxamide (0.29 g) in a pale yellow amorphous state. MS (ESI pos.) m/z : 516([M+H]+)

IH NMR (600 MHz, CDC13) δ ppm 1.33 - 1.83 (m, 6 H), 2.47 - 2.55 (m, 1 H), 2.85 - 2.92 (m, 1 H), 2.97 - 3.05 (m, 1 H), 3.07 - 3.14 (m, 1 H), 3.34 - 3.41 (m, 1 H), 4.99 - 5.05 (m, 1 H), 5.06 - 5.16 (m, 2 H), 5.73 - 5.84 (m, 1 H), 6.94 (d, J=8.7 Hz, 1 H), 7.18 - 7.21 (m, 1 H), 7.26 - 7.33 (m, 2 H), 7.36 - 7.42 (m, 2 H), 7.58 - 7.59 (m, 1 H), 7.72 - 7.73 (m, 1 H), 8.09 - 8.10 (m, 1 H), 9.17 - 9.21 (m, 1 H) (2) 1,3-Dimethylbarbituric acid (0.25 g) and Pd(PPh₃)₄ (6.0 mg) were added to a chloroform solution (10 ml) of N- [ (S) - 1 (2S) -1- allylpiperidin-2-yl] ( 3-pyrimidin-5-ylphenyl) methyl] -3-chlόro-4- (trifluoromethyl)pyridine-2-carboxamide (0.28 g) under a nitrogen atmosphere and stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=95 : 5 and subsequently, NH-silica gel, hexane/ethyl acetate=l:l) to obtain 3-chloro-N- [ (S) -(2S) - piperidin-2-yl( 3-pyrimidin-5-ylphenyl) methyl] -4- (trifluoromethyl)pyridine-2-carboxamide (0.13 g) . The obtained purified product was dissolved in ethyl acetate (2 ml) and methanol (1 ml) and 4 M HCl/ethyl acetate solution (2 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the title compound (0.14 g) .

Example 3

Synthesis of 2-chloro-N- ( (S) -( (2S) -l-methylpiperidin-2-yl) (3- pyridin-3-yl phenyl)methyl) -3- (trifluoromethyl)benzamide dihydrochloride (Compound 7)

HOBt-H₂O (87 mg) and EDC-HCl (98 mg) were added to a DMF solution (3 ml) of 2-chloro-3-trifluoromethylbenzoic acid (96 mg) and stirred at room temperature for 15 minutes. (S)-I- ((2S)-I-Methylpiperidin-2-yl) -1- ( 3-pyridin-3-ylphenyl) methanamine (100 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours . Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=3:l to 1:1) to obtain 2-chloro-N- ( (S) - ( ( 2S) -1- methylpiperidin-2-yl) (3-pyridin-3-yl phenyl)methyl) -3- (trifluoromethyl)benzamide (0.14 g) in a colorless amorphous state. The obtained purified product was dissolved in ethyl acetate (4 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the mixture. The resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was solidified with a mixed solvent of chloroform (1 ml) and diisopropyl ether (3 ml). The obtained solid was collected by filtration to obtain the title compound (0.14 g) .

Example 4

Synthesis of 2-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) (3- (1-methyl-IH- pyrazol-4-yl)phenyl)methyl) -3- (trifluoromethyl)benzamide monohydrochloride (Compound 12)

The title compound (88 mg) was obtained in a colorless amorphous state from 3- ( (S) - ( (2-chloro-3- (trifluoromethyl)benzoyl)amino) ((2S)-I-methylpiperidin-2-yl)methyl)phenyl trifluoromethanesulfonate (0.20 g) and l-methyl-lH-pyrazole-4- boronic acid pinacol ester (0.15 g) in the same way as in Example 1(1). Example 5

Synthesis of 2-chloro~N-{ (S) - [3- (3, 5-dimethylisoxazol-4- yl)phenyl][(2S)- piperidin-2-yl]methyl} -3- ( trifluoromethyl)benzamide monohydrochloride (Compound 69)

N- ( (S) - ( ( 2S) -l-Allylpiperidin-2-yl) (3- bromophenyl)methyl) -2-chloro-3- (trifluoromethyl)benzamide (53 mg) was dissolved in a mixed solvent (1 ml) of DMF/water (2:1) After the reaction vessel was purged with nitrogen gas, sodium bicarbonate (52 mg) , 3 , 5-dimethylisoxazoleboronic acid pinacol ester (91 mg) , and Pd(PPh₃J₄ (4 mg) were added thereto, and the mixture was heated overnight at 100⁰C. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (NH-silica gel, hexane/ethyl acetate=l:2 and subsequently, silica gel, chloroform/methanol=9 : 1) to obtain 2-chloro-N- ( ( S) - ( 3- ( 3 , 5-dimethylisoxazol-4- yl)phenyl) ( ( 2S) -piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide (12 mg) in a colorless amorphous state. This purified product was dissolved in ethyl acetate (1 ml) and 4 M HCl/ethyl acetate (0.1 ml) was added to the mixture. The resulting solution was concentrated under reduced pressure to obtain the title compound (12 mg) .

Example 6

Synthesis of 2-chloro-N- ( (S) - ( (2S) -l-methylpiperidin-2-yl) (3- pyrazin-2-yl phenyl)methyl) -3- ( trifluoromethyl)benzamide monohydrochloride (Compound 14)

(1) 3-( (S) -( ( 2-Chloro-3- ( trifluoromethyl)benzoyl) amino) ( (2S)- l-methylpiperidin-2-yl)methyl)phenyl trifluoromethanesulfonate (0.30 g) was dissolved in 1,4-dioxane (6.0 ml). After the reaction vessel was purged with nitrogen gas, bispinacolborane (274 mg) , Pd(dppf) Cl₂-CH₂Cl₂ (44 mg) , dppf (60 mg) , and potassium acetate (317 mg) were added thereto, and the mixture was stirred at 8O⁰C for 4 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=30:l) to obtain 2-chloro-N- ( (S) - ( (2S) -1- methylpiperidin-2-yl)(3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl) -3- (trifluoromethyl)benzamide (0.23 g) in a black amorphous state. ( 2 ) 2-Chloro-N- ((S)-((2S)-1-methylpiperidin-2-yl)(3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methyl) -3- (trifluoromethyl)benzamide (0.23 g) obtained in the preceding paragraph (1), 2-chloropyrazine (0.12 g) , and potassium carbonate (0.21 g) were suspended in a mixed solvent (3 ml) of DMF/ethanol (=2:1). After the reaction vessel was purged with nitrogen gas, Pd(PPh₃J₄ (29 mg) was added thereto, and the mixture was stirred at 90⁰C for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added thereto , followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol=19 : 1 to 9:1 and subsequently, NH-silica gel, hexane/ethyl acetate=3:l to 2:1) to obtain 2-chloro-N- ((S)- ((2S)-I-methylpiperidin-2-yl) (3- pyrazin-2-ylphenyl)methyl) -3- ( trifluoromethyl)benzamide ( 58 mg) as a colorless solid. The obtained solid was dissolved in ethyl acetate (8 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the ethyl acetate solution. The resulting solution was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (58 nag) in a colorless amorphous state.

Example 7

Synthesis of 3-chloro-N- ( (S) - ( (2S) -1- (cyanomethyl)piperidin-2- yl) ( 3-pyridin-3-ylphenyl)methyl) -4- (trifluoromethyl)pyridine- 2-carboxamide (Compound 82)

3-Chloro-N- ( (S) - ( 2S) -piperidin-2-yl( 3-pyridin-3- ylphenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide (30 mg) was added to a DMF solution (1 ml) of bromoacetonitrile (16 mg) and N,N-diisopropylethylamine (16 mg) and stirred at

90⁰C for 2 hours. The reaction mixture was diluted with a mixed solvent of ethyl acetate/hexane (=2:1) and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (silica gel, hexane/ethyl acetate=l:4) to obtain the title compound (18 mg) .

Example 8

Synthesis of 2-chloro-N- ( (S) - ( (2S) -l-cyclopropylpiperidin-2- yl ) ( 3 - ( 1 -methyl- lH-pyrazol- 4 -γl ) phenyl ) methyl ) - 3 - ( trif luoromethyl ) benzamide monohydrochloride ( Compound 83 )

2-Chloro-N- ( (S) - ( 3- ( 1-methyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -3- (trifluoromethyl)benzamide (0.12 g), [(1- ethoxycyclopropyl)oxy]trimethylsilane (0.30 ml), and acetic acid (0.14 ml) were dissolved in methanol (2 ml) under a nitrogen atmosphere. A Molecular Sieve 3A in a powder form (50 mg) and sodium cyanotrihydroborate (51 mg) were added thereto, and the mixture was refluxed for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate . The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=4:l to 1:1 and subsequently, silica gel, chloroform/methanol=100:0 to 97:3) to obtain 2-chloro-N- ( (S) - ( (2S) -l-cyclopropylpiperidin-2-yl) (3- ( 1-methyl-lH-pyrazol-4- yl)phenyl)methyl) -3- (trifluoromethyl)benzamide (81 mg) in a colorless amorphous state. The obtained compound was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution. The solvent was distilled off under reduced pressure. The obtained solid was washed with a mixed solvent of hexane/ethyl acetate (=1:1) to obtain the title compound (70 mg) .

Example 9

Synthesis of 3-chloro-N- ( (S) - (3- ( l-ethyl-lH-pyrazol-4- yl)phenyl)((2S)- piperidin-2-yl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide(Compound 118)

(1) HOBt-H₂O (38 mg) and EDCΗC1 (46 mg) were added to a DMF solution (1 ml) of 3-chloro-4-trifluoromethylpyridine-2- carboxylic acid (45 mg) and stirred at room temperature for 15 minutes. This solution was added to a DMF solution (0.5 ml) of tert-butyl (2S) -2- ( (S) -amino(3- ( l-ethyl-lH-pyrazol-4- yl)phenyl)methyl)piperidine-1-carboxγlate (80 mg) , and the mixture was stirred overnight at room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel . The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=3:2 to 1:1) to obtain tert-butyl (2S) -2- ( (S) -( ( (3-chloro-4-(trifluoromethyl)pyridin-2-yl) carbonyl) amino ) (3- (l-ethyl-lH-pyrazol-4-yl)phenyl)methyl) piperidine-1-carboxylate (99 mg) in a colorless amorphous state.

MS; (ESI pos.) m/z : 592 ([MH-H] + ) IH NMR (600 MHz, CDC13) δ ppm 1.30 - 1.79 (m, 15 H), 1.54 (t, J=7.3 Hz, 3 H), 2.84 - 2.91 (m, 0.2 H), 3.02 - 3.10 (m, 0.8 H), 3.96 - 4.03 (m, 0.8 H), 4.14 - 4.17 (m, 0.2 H), 4.21 (q, J=7.3 Hz, 2 H), 4.54 - 4.59 (m, 0.2 H), 4.71 - 4.76 (m, 0.8 H), 5.44 - 5.55 (m, 1 H), 7.22 - 7.37 (m, 2 H), 7.38 - 7.44 (m, 1 H), 7.50 (br. s., 0.2 H), 7.54 (s, 0.8 H), 7.62 - 7.71 (m, 2 H), 7.74 - 7.80 (m, 1 H), 8.45 (d, J=8.7 Hz, 1 H), 8.57 (d, J=5.0 Hz, 1 H)

(2) 4 N Hydrochloric acid/ethyl acetate (3 ml) was added to an ethyl acetate solution (5 ml) of tert-butyl (2S)-2-((S)-(((3- chloro-4- ( trifluoromethyl)pyridin-2-yl) carbonyl)amino) ( 3- ( l-ethyl-lH-pyrazol-4- yl)phenyl)methyl)piperidine-l-carboxylate (83 mg) and stirred at room temperature for 4 hours . The mixture was concentrated under reduced pressure. Chloroform and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (75 mg) in a pale yellow amorphous state.

Synthesis of 3-chloro-N-{ (R) - [3- ( l-ethyl-lH-pyrazol-4- yl)phenyl][(2R)- piperidin-2-yl]methyl}-4- (trifluoromethyl)pyridine-2- carboxamide(Compound 115)

The title compound was synthesized in the same way as above using tert-butyl (2R) -2- ( (R) -amino(3- (1-ethyl-lH- pyrazol-4-yl)phenyl)methyl)piperidine-l-carboxylate, which was prepared in the same way as in Production Example 17.

Example 10

Synthesis of 3-chloro-N- ( (S) - ( (2S) -piperidin-2-yl) (3-thiophen- 2-ylphenyl) methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide monohydrochloride(Compound 100)

(1) tert-Butyl (2S) -2- ( (S) - ( 3-bromophenyl) ( ( ( 3-chloro-4-

(trifluoromethyl)pyridin-2- yl)carbonyl) amino)methyl)piperidine-l-carboxylate (500 mg) , 2- thiopheneboronic acid (166 mg) , and potassium carbonate (180 mg) were suspended in a mixed solvent (5 ml) of DMF/ethanol

(=2:1). After the reaction vessel was purged with nitrogen gas, PdCl₂(PPh₃) 2 (30.4 mg) was added thereto, and the mixture was stirred at 90⁰C for 7 hours. A saturated aqueous solution of sodium bicarbonate and water were added thereto , followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, hexane/ethyl acetate=4:l to 3:1 and silica gel, hexane/ethyl acetate=7:l to 4:1) to obtain tert-butyl (2S) -2- ( (S) - ( ( (3- chloro-4- (trifluoromethyl)pyridin-

2-y1)carbony1)amino) ( 3-thiophen-2-ylphenyl)methyl)piperidine-

1-carboxylate (273 mg) in a colorless amorphous state.

MS; (ESI pos.) m/z : 580 ([M+H] + )

IH NMR (600 MHz, CDC13) δ ppm 1.29 - 1.78 (m, 15 H) 3.00 - 3.09 (m, 1 H) 3.95 - 4.20 (m, 1 H) 4.50 - 4.75 (m, 1 H) 5.50 - 5.57 (m, 1 H) 7.04 - 7.09 (m, 1 H) 7.26 - 7.41 (m, 4 H) 7.50 - 7.55 (m, 1 H) 7.59 - 7.70 (m, 2 H) 8.45 - 8.50 (m, 1 H) 8.55 - 8.60 (m, 1 H) (2) 4 N Hydrochloric acid/ethyl acetate (1.1 ml) was added to an ethyl acetate solution (5 ml) of tert-butyl (2S) -2- ((S)- ( ( (3-chloro-4- (trifluoromethyl)pyridin-2-yl) carbonyl) amino) ( 3-thiophen-2-ylphenyl)methyl)piperidine-l- carboxylate (245 mg) and stirred at room temperature for 15 hours. 4 N Hydrochloric acid/ethyl acetate (0.5 ml) was further added thereto, and the mixture was further stirred for 22.5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and solidified by the addition of diethyl ether. The precipitate was collected by filtration, then washed with diethyl ether, and dried to obtain the title compound (187 mg) as a colorless solid.

Example 11 Synthesis of 3-chloro-N- ( (S) - (3- (l-ethyl-lH-pγrazol-4- yl)phenyl)((2S)- piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide monomaleate(Compound 107)

3-Chloro-N-( (S) - ( 3- ( l-ethyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4-

(trifluoromethyl)pyridine-2-carboxamide (1.0 g) was dissolved in ethyl acetate (10 ml). Maleic acid (247 mg) was added thereto, and the mixture was stirred overnight at room temperature . The precipitate was collected by filtration and dried under reduced pressure at 70⁰C for 3 hours to obtain the title compound (1.09 g) as a colorless crystal.

Example 12 Synthesis of 3-chloro-N-( (S) - ( 3- ( 1-ethyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl) -4- ( trifluoromethyl)pyridine-2- carboxamide monohydrochloride monohydrate(Compound 114)

3-Chloro-N-((S)-(3-(l-ethyl-lH-pyrazol-4- yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide (10.1 g) was dissolved in isopropanol (100 ml).

To this solution, concentrated hydrochloric acid (3.15 g) was added under ice cooling. After concentration under reduced pressure, the resulting residue was diluted with water (40 ml) and isopropanol (10 ml), refluxed and then allowed to cool, followed by collecting the precipitate by filtration. The resulting crystal was washed with isopropanol-water (1:4) to give the titled compound (10.1 g) as a colorless crystal. Anal. Found: C, 52.64; H, 5.18; N, 12.79; F, 10.18; Cl, 12.94.

The structural formulas of the compounds shown in Examples 1 to 12 and compounds synthesized in the same way are shown in Table 1. Instrumental data thereof are shown in Table 2.

[Table 1]

)

Test Example [Glycine uptake inhibition experiment]

The glycine uptake experiment was conducted according to the method described in Neuron, 8, 927-935, 1992. Glioma T98G cells which expressed human glycine transporter-1 (GIyTl) were used. The T98G cells were seeded at a density of 2.0 x 10⁴ cells/well onto a 96-well plate and cultured overnight in a carbon dioxide incubator. The test compound was dissolved in 100% DMSO and then dissolved in 10 mM HEPES buffer solution (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin. After the medium for cell culture was removed, the test compound and [³H] glycine (final concentration 250 nM) were added to the cells and reacted at room temperature for 15 minutes. After the completion of reaction, the labeled glycine solution was aspirated with a manifold. The cells were then lysed with 0.5 M sodium hydroxide solution. An intracellular glycine amount was determined by measuring radio activity in the cell lysate with a liquid scintillation counter. A glycine uptake amount in the presence of 10 μM ALX5407 is defined as nonspecific uptake, and a specific uptake amount was determined by subtracting the nonspecific uptake amount from a total uptake amount in the absence of 10 μM ALX5407. Glycine uptake inhibitory activity (IC₅₀ value) was calculated from an inhibition curve at test compound concentrations of 10^'10 to 10^"6.

The IC₅₀ values of the compounds of the present invention are illustrated in Table 3. [Table 3 ]

[Industrial Applicability]

The compound of the present invention has glycine transporter-1 (GIyTl) inhibitory activity and is thus effective for the prevention or treatment of glycine transporter-related diseases, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, posttraumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders.

Claims

1. A compound represented by formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein ring A is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms , wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci_₆ alkyl, C₁.₆ haloalkyl, cyano, Ci.₆ alkoxy, halogen, Ci-6 acyl and C₂-₇ alkoxycarbonyl;

Ar¹ is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms , wherein the phenyl , the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, d_₆ alkyl, C₁.₆ haloalkyl, cyano, C₁.₆ alkoxy. Ci-₆ acyl, Ci-₆ haloacyl, Ci_₆ haloalkoxy, C₃_₈ cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy;

R¹ is hydrogen, Ci_₆ alkyl, C₃.₆ alkenyl, or C₃.₈ cycloalkyl, wherein the Ci-₆ alkyl is unsubstituted or substituted with cyano ;

R³ is hydrogen, Cχ._β alkyl, or halogen; and n is 1 or 2.

2. A compound represented by formula [IA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein ring A is a monocyclic or bicycliσ aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms , wherein the aromatic ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci_₆ alkyl, C_x.₆ alkoxy and halogen;

Ar¹ is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, C_x.₆ alkyl, Ci_₆ haloalkyl, cyano, C₁^ alkoxy. Ci-₆ acyl, Ci-₆ haloacyl, C₁-_S haloalkoxy, C₃._a cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy;

R¹ is hydrogen, Ci_₆ alkyl, C₃_₆ alkenyl, or C₃-β cycloalkyl, wherein the Ci_₆ alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.

3. A compound represented by formula [ I ' ] or a pharmaceutically > acceptable salt thereof or a hydrate thereof

wherein

R⁴ is hydrogen, Ci-₆ haloalkyl, cyano or C₁^ acyl;

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C^₆ alkyl, Ci_₆ haloalkyl, cyano, C₁..,; alkoxy, C^₆ acyl, Ci-₆ haloacyl and C₁.₆ haloalkoxy or with methylenedioxy;

R¹ is hydrogen, d-₆ alkyl, C₃.₆ alkenyl, or C₃.₈ cycloalkyl, wherein the Ci_₆ alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.

4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof or a hydrate thereof. wherein R⁴ is hydrogen; and. Ar¹ is phenyl or pyridyl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci-β alkyl, Ci.₆ haloalkyl, cyano, Ci_₆ alkoxy, Ci-₆ acyl, Ci-₆ haloacyl and C₁.₆ haloalkoxy or with methylenedioxy.

5. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein ring A is pyrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, quinolyl, indolyl, thienyl or thiazolyl, wherein ring A is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci-₆ alkyl, Ci_₆ alkoxy and halogen.

6. The compound according to claim 2 represented by formula [II] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein ring A is a monocyclic or bicyclic aromatic ring having 1 or 2 nitrogen atoms as endocyclic atoms , wherein the aromatic ring is unsubstituted or substituted with one substituent selected from the group consisting of Ci_₆ alkyl, halogen and Ci_₆ alkoxy; Ar¹ is phenyl, pyridyl, or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 1 to 3 substituents selected from the group consisting of halogen, Cχ.₆ alkyl, Cχ-6 haloalkyl, Ci_₆ alkoxy and Ci_β haloalkoxy; and n is 1 or 2.

7. The compound according to claim 1 represented by formula [III] or a pharmaceutically acceptable salt thereof or a hydrate thereof

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-₆ alkyl and Ci-₆ haloalkyl;

R² is hydrogen or Ci_₆ alkyl; and n is 1 or 2 , wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.

8. The compound according to claim 7 represented by formula [IIIA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C_x.₆ alkyl and Ci-₆ haloalkyl;

R² is hydrogen or Cχ-₆ alkyl; and n is 1 or 2 , wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.

9. The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of the pyrazolyl in the benzene ring is position 3.

10. The compound according to claim 1 represented by formula [IV] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein R⁵ is hydrogen, halogen or Ci_₆ alkoxy;

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_₆ alkyl and Ci-₆ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4.

11. The compound according to claim 10 represented by formula [IVA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

R⁵ is hydrogen, halogen or Ci-₆ alkoxy;

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-₆ alkyl and Ci-₆ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4.

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof or a hydrate thereof. wherein R⁵ is hydrogen; and Ar¹ is phenyl or pyridyl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_₆ alkyl and Ci-6 haloalkyl.

13. The compound according to claim 10, 11 or 12 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of pyridyl in the benzene ring is position 3.

14. The compound according to claim 1 represented by formula [V] or a pharmaceutically acceptable salt thereof or a hydrate thereof

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Cχ.6 alkyl and Ci-₆ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.

15. The compound according to claim 14 represented by formula [VA] or a pharmaceutically acceptable salt thereof or a hydrate thereof

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci-β alkyl and C₁-I₅ haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.

16. The compound according to claim 14 or 15 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of the pyrimidinyl in the benzene ring is position 3.

17. The compound according to claim 1 represented by formula [VI] or a pharmaceutically acceptable salt thereof or a hydrate thereof

wherein

Ar¹ is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_₆ alkyl and C₁.₆ haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrazinyl in the benzene ring is position 3 or 4.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the substitution position of the pyrazinyl in the benzene ring is position 3.

19. The compound according to any one of claims 1, 2 and 5 to 18 or a pharmaceutically acceptable salt thereof or a hydrate thereof , wherein n is 2.

20. The compound according to claim 3 or 4 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein n is 2.

21. The compound according to any one of claims 1, 2 and 5 to 19 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein configuration of the asymmetric carbon atom at position 2 in the pyrrolidine or piperidine ring is S-configuration, and configuration of the asymmetric carbon atom bound with the nitrogen atom of the amide is also S-configuration .

22. The compound according to claim 3, 4 or 20 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein configuration of the asymmetric carbon atom at position 2 in the pyrrolidine or piperidine ring is S- configuration, and configuration of the asymmetric carbon atom bound with the nitrogen atom of the amide is also S- configuration.

23. The compound according to any one of claims 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is phenyl which has chloro, fluoro or methyl at position 2 and has trifluoromethyl at position 3, 5 or 6 and/or chloro at position 3 or 6.

24. The compound according to any one of claims 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is phenyl which has chloro or methyl at position 2, and trifluoromethyl at position 3 or 5 , and may further have chloro at position 6.

25. The compound according to any one of claims 1, 2, 5 to 19 and 21 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.

26. The compound according to claim 3, 4, 20 or 22 or a pharmaceutically acceptable salt thereof or a hydrate thereof. wherein Ar¹ is pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.

27. The compound according to any one of claims 1 to 3 , 5 to 11 and 13 to 22 or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein Ar¹ is isoquinolin-1-yl.

28. 3-Chloro-N-((S)-(3-(l-methyl-lH-pyrazol-4-yl) phenyl) ( ( 2S) -piperidin-2-yl)methyl) -4- ( trifluoromethyl) pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

29. 3-Chloro-N- ( (S) - (3- ( l-ethyl-lH-pyrazol-4-yl)phenγl)

( (2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

30. A hydrochloride salt of 3-chloro-N- ( (S) - (3- ( 1-ethyl-lH- pyrazol-4-yl)phenyl) ( (2S) -piperidin-2-yl)methyl) -4-

(trifluoromethyl)pyridine-2-carboxamide, or a hydrate thereof .

31. A maleate salt of 3-chloro-N- ( (S) - (3- ( 1-ethyl-lH- pyrazol-4-yl)phenyl) ( ( 2S) -piperidin-2-yl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide, or a hydrate thereof.

32. 3-Chloro-N- ( (S) - ( 2S) -piperidin-2-yl( 3- ( lH-pyrazol- 4-yl)phenyl)methyl) -4- (trifluoromethyl)pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof or a hydrate thereof .

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .

34. The pharmaceutical composition according to claim 33, which is a glycine transporter inhibitor.

35. A pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, drug abuse, convulsion, tremor, and sleep disorders, comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .