RU2294927C2 - Derivatives of piperidine, methods for their preparing, pharmaceutical composition based on thereof, their using and treatment method - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I):

or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R¹ represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R² represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R³)- wherein R³ and R⁴ represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

Description

Field of Invention

The present invention relates to a novel piperidine compound having excellent antagonistic activity against the tachykinin receptor.

BACKGROUND OF THE INVENTION

Tachycinin is the generic name for a group of neuropeptides, and substance P (hereinafter referred to as SP), neurokinin-A, and neurokinin-B, have been previously known in mammals. It is known that these peptides exhibit various types of biological activities due to the binding of their corresponding receptors that exist in vivo (neurokinin-1, neurokinin-2, neurokinin-3). Among them, SP represents one of those peptides that were known before other neuropeptides and have been studied in detail. Its existence was confirmed in an extract obtained from the intestinal tract of a horse in 1931, and it was a peptide comprising 11 amino acids, the structure of which was determined in 1971.

SP is present in the entire peripheral nervous system and has physiological activities, such as vasodilating ability, promotion of vascular permeability, smooth muscle contraction, (stimulation of neurons), salivary activity, diuretic activity, immunological activity, etc., and can also perform neurotransmitter functions of primary sensory neurons. More specifically, it is known that SP secreted from the end of the posterior horn of the spinal cord after a pain impulse transmits pain information to secondary neurons, and that SP secreted from the peripheral ends induces an inflammatory response of the receptors. Based on these facts, it is believed that SP is involved in various types of diseases (e.g., pain, inflammation, allergies, pollacuria, urinary incontinence, respiratory diseases, mental disorders, depression, anxiety, vomiting, etc.), and also that SP is associated with dementia-type Alzheimer's disease [Review: Physiological Reviews, vol.73, pp.229-308 (1993), Journal of Autonomic Pharmacology, vol.13, pp.23-93 (1993)].

To date, as a therapeutic agent for the above diseases (especially for vomiting, depression, disorders of the urinary system, etc.), no compounds have been found that have an excellent antagonistic effect on tachykinin receptors (especially antagonistic action on SP receptors), and at the same time it would have sufficiently satisfactory safety, stability (metabolism, in vivo dynamics and absorption), etc. Therefore, a search was made for a compound that would have an excellent antagonistic effect on tachykinin receptors and would have a sufficiently satisfactory clinical effect as a therapeutic agent.

Accordingly, it is an object of the present invention to provide a compound having excellent antagonistic activity against tachykinin receptors and having a satisfactory clinical effect in terms of safety, stability (metabolism, in vivo dynamics and absorption), etc.

SUMMARY OF THE INVENTION

The present invention relates to a piperidine compound represented by the formula [I]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula :

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroatom where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized,

R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by —N (R ³ ) -, where R ³ represents a hydrogen atom or an optionally substituted alkyl group, R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof.

In the present invention, ring A is an optionally substituted benzene ring, and examples of benzene ring substituents include an alkyl group, a halogen atom, a cyano group, an optionally protected hydroxyl or alkoxy group. Ring A may contain from 1 to 3 of these substituents, which may be the same or different.

In the present invention, ring B is an optionally substituted benzene ring, and examples of benzene ring substituents are a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, alkyl groups, optionally substituted hydroxyl or alkoxy groups. Ring B may contain from 1 to 3 of these substituents, which may be the same or different.

Preferred examples of ring A and ring B in the compound of the present invention are compounds in which ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A ¹ , A ² and A ^{3 are the} same or different, and each represents a hydrogen atom, a halogen atom, an alkyl group, an optionally protected hydroxyl or alkoxy group,

B ¹ , B ² and B ^{3 are the} same or different, and each represents a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, alkyl groups, optionally protected hydroxyl or alkoxy groups. Examples of a trihaloalkyl group are a trifluoromethyl group or a trichloromethyl group, etc. Examples of a heterocyclic group are a tetrazolyl group, etc.

In the present invention, examples of a protecting group for an optionally protected hydroxyl group are conventional protecting groups, such as an optionally substituted arylalkyl group, an optionally substituted silyl group, and an acyl group. Of the above, arylalkyl groups such as a benzyl group and a phenethyl group, substituted silyl groups such as a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group, and acyl groups such as a formyl group, acetyl group, propionyl group, malonyl group, acryloyl group are preferred. and a benzoyl group.

In the present invention, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula:

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized.

Of the above, R ¹ preferably represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula:

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized,

further preferred are an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula:

where R ¹¹ represents a substituted carbonyl group, a substituted sulfonyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized, and R ¹² represents a hydrogen atom, an optionally substituted alkyl group, a substituted carbonyl group substituted with a sulfonyl group or a heterocyclic group having 1-4 atoms selected from the atoms and the nitrogen, oxygen and sulfur atoms as heteroatoms, wherein the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized.

In the present invention, examples of substituents in the optionally substituted alkyl group R ¹ are an alkoxycarbonyl group, a morpholinocarbonyl group, a prilylaminocarbonyl group, a morpholinoaminocarbonyl group, a piperidinocarbonyl group, a substituted alkoxyphenyl group, a dialkylaminocarbonyl group, a hydroxyl group or a hydroxycarbylalkylcarbonylalkylamine.

In the present invention, examples of substituents of the optionally substituted hydroxyl group in R ¹ are

(1) a substituted carbonyl group,

(2) a substituted sulfinyl group,

(3) a substituted sulfonyl group or

(4) an optionally substituted alkyl group.

Examples of substituents of the substituted carbonyl group in the above (1) are an optionally substituted alkyl group, an optionally substituted alkoxy group, a substituted amino group, a monocyclic heterocyclic group containing 1-2 atoms selected from a nitrogen atom and an oxygen atom as heteroatoms (a monocyclic heterocyclic group is optional replaced). An example of a substituent of an optionally substituted alkyl group is a hydroxyl group. Examples of substituents of an optionally substituted alkoxy group are an alkoxy group, a hydroxyl group or a halogen atom. Examples of substituents are alkyl substituted amino group substituted by a group selected from a halogen atom, a dialkylamino group, piperidinyl group, morpholino group, carboxyl group, morpholinocarbonyl group, dialkylaminocarbonyl group, an alkylaminocarbonyl group, alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group and hydroxyl group; a piperidinyl group substituted with a hydroxyalkanoyl group or an alkoxyalkanoyl group; or a dialkylaminosulfonyl group. Examples of a monocyclic heterocyclic group are a morpholino group, a piperazinyl group, an imidazolyl group, a thiomorpholino group, a piperidino group, a furyl group, a tetrahydrothiazolinyl group or a pyrrolidinyl group. Examples of monocyclic heterocyclic substituent groups are an alkyl group which may be substituted with a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, gidroksialkilaminokarbonilnoy group alkoksialkilaminokarbonilnoy group alkiltioalkilaminokarbonilnoy group alkilsulfinilalkilaminokarbonilnoy group alkilsulfonilalkilaminokarbonilnoy group or a morpholino group, an oxo group or a hydroxyl group.

Examples of substituents of a substituted sulfinyl group in the above (2) are an alkyl group or a thienyl group.

Examples of substituents of a substituted sulfonyl group in the above (3) are an alkyl group or a thienyl group.

Examples of substituents of an optionally substituted alkyl group in the above (4) are an optionally substituted hydroxyl group, a dialkylamino group or a monocyclic heterocyclic group containing 1-4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom as hetero atoms (a monocyclic heterocyclic group is optionally substituted ) Examples of substituents of the optionally substituted hydroxyl group are an alkyl group, an alkylsulfonyl group or a tetrahydropyranyl group. Examples of a monocyclic heterocyclic group are a pyridyl group, a piperidinyl group, a morpholino group, an isoxazolyl group, a triazolyl group, a tetrazolyl group or a pyrrolidinyl group. Examples of substituents of a monocyclic heterocyclic group are an alkyl group or a phenyl group.

In the present invention, examples of substituents of a substituted thiol group in R ¹ are a substituted phenyl group, a substituted carbonyl group, or an optionally substituted alkyl group. Examples of a substituent of a substituted phenyl group are a hydroxyl group. Examples of a substituent of a substituted carbonyl group are an alkyl group. Examples of substituents of an optionally substituted alkyl group are an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkoxycarbonylamino group, a hydroxyalkanoylamino group, a morpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino group, an alkanoyloxy group or a hydroxyl group.

In the present invention, examples of substituents of a substituted carbonyl group in R ¹ are a hydroxyl group, an alkoxy group, an optionally substituted amino group or a monocyclic heterocyclic group containing 1-4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom as heteroatoms (a monocyclic heterocyclic group is optional replaced). Examples of substituents of an optionally substituted amino group are (a) a group (s) selected from a pyridyl group, an optionally substituted hydroxyl group (s), a pyrimidyl group, an alkyl pyrido group, a pyrazinyl group, and an alkyl group optionally substituted with a hydroxyl group or cyano group. Examples of a monocyclic heterocyclic group are a piperidino group, a piperazino group, a morpholino group, a thiomorpholino group or a pyrrolidino group.

Examples of substituents of a monocyclic heterocyclic group are an alkyl group, a hydroxyl group, an oxo group, a pyrimidyl group, a pyrazinyl group, an alkylsulfonyl group, an alkanoyl group or a hydroxyalkyl group.

In the present invention, examples of substituents of a substituted sulfinyl group in R ¹ are a hydroxyl group or an optionally substituted alkyl group. Examples of a substituent of an optionally substituted alkyl group are a hydroxyl group.

In the present invention, examples of a substituent of a substituted sulfonyl group in R ^{1 are} an optionally substituted alkyl group. Examples of substituents of an optionally substituted alkyl group are a hydroxyl group or an alkanoyloxy group.

In the present invention, if R ¹ represents a group of the formula:

(1) examples of substituted carbonyl substituents in R ¹¹ and R ¹² are an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, a substituted amino group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, where the heterocyclic group is optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized. Examples of substituents of an optionally substituted alkyl group are an alkylaminocarbonyl group, a dialkylaminocarbonyl group in which its alkyl moiety is optionally substituted with a hydroxyl group, an aminocarbonyl group, an alkoxycarbonylamino group, an alkanoylamino group, an amino group substituted with an alkoxycarbonyl group, an alkylamino group, an alkylamino group, an alkylamino group, an amino group halogen atom, tetrazolyl group, pyridyl group, furyl group, hydroxyl ith group, alkylthio group, 2-oxopyrrolidino group, 2-aminothiazolyl group, 2-thiol-4-alkylthiazolyl group, 2,2-dialkyl-1,3-dioxolanyl group, cycloalkyl group, alkylsulfinyl group, alkylsulfonyl group, thienyl group, group 5 -methyl-2,4 (1H, 3H) -pyrimidinedione, amino group or dialkylamino group. Examples of substituents of an optionally substituted aryl group are a nitro group or an amino group, and examples of an aryl group are a phenyl group, a naphthyl group, a phenanthryl group or an anthracenyl group. Examples of substituents of a substituted amino group are an alkyl group optionally substituted with a group selected from a halogen atom, an alkoxy group and a hydroxyl group, and the amino group is monosubstituted or disubstituted. Examples of a heterocyclic group are a saturated or unsaturated monocyclic or bicyclic aromatic group such as a thienyl group, a furyl group, a tetrahydrofuryl group, a pyranyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, a pyridinyl group, a pyrazinyl group, a pyrazini group , pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazo lidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl phenyl group, quininyl group, quininyl group, quininyl group, quininyl group , cinnolinyl group, quinolyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group na, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, piridopirimidinilnaya group izohromanilnaya group, chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group, etc. Of these heterocyclic groups, it is preferable to use a pyridyl group, a pyrrolidinyl group, a piperazinyl group, a quinolyl group, a piperidinyl group, a pyrimidyl group, a thiazolyl group, a pyrazinyl group, a morpholino group, a thiomorpholino group, an indolyl group, a cinnolinyl group, a cinnolinyl group, a thinnolinyl group, a cinnolinyl group, a thinnolinyl group, a cinnolinyl group, a thinnolinyl group, a tinnolinyl group, a tinnolinyl group, a tinnolinyl group, a thinnolinyl group, a tinnolinyl group, a tinnolinyl group, a tinnolinyl group, a thinnolinyl group, a thinnolinyl group .d. Examples of substituents of the heterocyclic group are a dialkylamino group, an alkoxycarbonyl group, a morpholinoalkyl group, a hydroxyalkyl group, an alkyl group, a benzyloxy group, an alkoxycarbonyl group, an alkanoyl group, a hydroxyl group, an oxo group or a formyl group.

(2) Examples of substituents of the substituted sulfonyl group in R ¹¹ and R ¹² are an optionally substituted alkyl group, a cyanophenyl group, a dialkylamino group or an alkenyl group. Examples of substituents of an optionally substituted alkyl group are a halogen atom, a hydroxyl group, a dialkylamino group optionally substituted with a hydroxyl group, a morpholino group, a piperidino group or a 4-methylpiperazino group.

(3) Examples of substituents of the optionally substituted alkyl group in R ¹¹ and R ¹² are a dialkylaminocarbonyl group, an alkoxy group, a dialkylamino group, a cyano group, a morpholino group, a pyridyl group or a halogen atom.

(4) A heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as heteroatoms, in R ¹¹ and R ¹² are saturated or unsaturated monocyclic or bicyclic aromatic heterocyclic groups such as a thienyl group, a furyl group , pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindin quinolysinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, isoquinolyl group, benzothiazole lilnaya group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, piridopirimidinilnaya group izohromanilnaya group, chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group. Of these heterocyclic groups, it is preferable to use a pyridyl group, a pyrrolyl group, a piperazinyl group, a quinolyl group, a piperidinyl group, a pyrimidyl group, a thiazolyl group, a pyrazinyl group, a morpholino group, an indolyl group, a cinnolinyl group, a furyl group, etc. Examples of substituents of the heterocyclic group are a dialkylamino group, an alkoxycarbonyl group, an alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, etc.

Further, if R ¹¹ and R ¹² form a bond between their ends, with the formation of a neighboring nitrogen atom of a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydropyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a triazolyl group, a triazolyl group, a triazolyl group, a tetrazolyl group, a triazolyl group, a tetrazolyl group, a triazolyl group, groups, then examples of substituents of the heterocyclic group are an alkyl group substituted with an alkoxy group or a hydroxyl group, a piperidinyl group, an alkoxyphene an alkyl group, an alkanoyl group, a hydroxyl group, an oxo group and an amino group.

If the nitrogen atom of the heterocyclic group is oxidized, the state of the oxidized nitrogen atom means a state in which the nitrogen atom is cationized, examples of which are the N-oxomorpholino group or the N-alkyl morpholino group.

In the present invention, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom.

In the present invention, the substituent of the optionally substituted hydroxyl group in R ² is an alkyl group.

In the present invention, the substituent of the optionally substituted amino group in R ² is an alkyl group.

In the present invention, the substituent of an optionally substituted alkyl group in R ² is an alkoxy group.

In the present invention, examples of substituents of a substituted carbonyl group in R ² are a hydroxyl group, an alkoxy group or an alkylamino group.

In the present invention, examples of Z are an oxygen atom or a group —N (R ³ ) -.

In the present invention, examples of R ³ are a hydrogen atom or an optionally substituted alkyl group. Examples of substituents of an optionally substituted alkyl group in R ³ are a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group.

In the present invention, examples of R ⁴ are a hydrogen atom or an optionally substituted alkyl group. Examples of substituents of an optionally substituted alkyl group in R ⁴ are a halogen atom, an alkoxy group or an alkylamino group.

Preferred compounds of the present invention are compounds in which R ¹ represents an optionally substituted alkyl group.

Preferred substituents of the optionally substituted alkyl group are a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group or a hydroxyalkylaminocarbonyloxy group.

As a preferred compound of the present invention, a compound in which R ¹ represents an optionally substituted hydroxyl group can be mentioned. Of these compounds, compounds in which R ¹ is an optionally substituted alkoxy group are preferred. In addition, compounds in which R ¹ is an optionally substituted carbonyloxy group are preferred.

Preferred substituents for the optionally substituted alkoxy group are a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a triazolyl group, a tetrazolyl group optionally substituted with an alkyl group or alkoxy group, and more preferably a hydroxyl group or tetrahydropyranyloxy group. Preferred substituents are optionally substituted by a morpholino carbonyloxy group, an imidazolyl group, an alkylamino group wherein its alkyl moiety is optionally substituted by hydroxyl group, morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, alkanoyloxy group or a carboxyl group; a piperidino group substituted with a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl group, an alkylthioalkylaminocarbonyl group, an alkylsulfinylalkylaminocarbonyl group, an alkylsulfonylalkylalkylaminocarbonyl group or a piperidinylamino group substituted with a hydroxyalkanoyl group or an alkoxyalkanoyl group; a thiomorpholino group in which the sulfur atom is optionally substituted with an oxo group; oxopyrrolidinyl group; oxotetrahydrothiazolinyl group; or a dialkylaminosulfonylamino group, and more preferably a morpholino group; an alkylamino group in which its alkyl moiety is optionally substituted with a hydroxyl group; or a thiomorpholino group in which the sulfur atom is substituted by an oxo group.

As a preferred compound of the present invention, a compound in which R ¹ represents a substituted thiol group can be mentioned.

Preferred substituents for the optionally substituted thiol group are an alkanoyl group or an alkyl group optionally substituted with a hydroxyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkoxycarbonylamino group, a hydroxyalkanoylamino group, a morpholinocarbonylamino group, or a hydroxyalkylaminocarbonylamino amino group. As a preferred compound of the present invention, a compound in which R ¹ represents a substituted carbonyl group can be mentioned.

Preferred substituents of the optionally substituted carbonyl group are alkoxy; an amino group optionally substituted with a pyrimidyl group or an alkyl pyrido group; an alkylamino group in which its alkyl moiety is optionally substituted with a hydroxyl group or a cyano group; di (hydroxyalkyl) amino group; a pyridylamino group in which its pyridyl moiety is optionally substituted with a hydroxyl group; a piperidino group substituted with a hydroxy group or an oxo group; a piperazino group substituted with an oxo group, an alkyl group, an alkylsulfonyl group or an alkanoyl group; morpholino group; thiomorpholino group; or a pyrrolidino group substituted with a hydroxyalkyl group or a hydroxyl group, and more preferably a pyrimidylamino group or a hydroxypiperazino group.

As a preferred compound of the present invention, a compound in which R ¹ represents a substituted sulfinyl group can be mentioned.

Preferred substituents for the optionally substituted sulfinyl group are an alkyl group optionally substituted with a hydroxyl group or a hydroxyl group, and more preferably an alkyl group optionally substituted with a hydroxyl group.

As a preferred compound of the present invention, a compound in which R ¹ is a substituted sulfonyl group can be mentioned.

Preferred substituents of the optionally substituted sulfonyl group are an alkyl group optionally substituted with a hydroxyl group or alkanoyloxy group, and more preferably an alkyl group optionally substituted with a hydroxyl group.

Preferred compounds of the present invention are compounds in which R ¹ represents a group of the formula:

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized.

Of these compounds, preferably a compound in which R ¹¹ represents a substituted carbonyl group and R ¹² represents a hydrogen atom or an alkyl group. Further, preferably, each of the compounds in which R ¹¹ is a correspondingly optionally substituted alkanoyl group, an optionally substituted aminocarbonyl group, a morpholinocarbonyl group, and a piperidinylcarbonyl group substituted with an alkanoyl group. Another preferred example is a compound in which R ¹¹ represents a substituted sulfonyl group and R ¹² represents a hydrogen atom or an alkyl group.

Preferred substituents for the optionally substituted alkanoyl group are an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminocarbonyl group, an alkoxycarbonylamino group, an alkanoylamino group, an amino group substituted with an alkoxycarbonyl group and an alkyl group, an amino group substituted with an alkylene phenyl group and an optionally substituted alkanoyl group , tetrazolyl group, hydroxyl group, alkylthio group, al ilsulfinilnoy group, an alkylsulfonyl group, 2-aminothiazolyl group, 2-oksopirrolidinogruppoy, 2-thiol-4-alkiltiazolidinilnoy group or cycloalkyl group, and more preferably an alkoxy group, a hydroxyl group or a cycloalkyl group. Preferred substituents of the optionally substituted aminocarbonyl group are a halogen atom, a hydroxyl group or an alkyl group optionally substituted with an alkoxy group, and more preferably an alkyl group. Preferred substituents for the optionally substituted sulfonyl group are an alkyl group optionally substituted with a hydroxyl group or halogen, an alkenyl group or a dialkylamino group, and more preferably an alkyl group.

The compounds of the present invention are represented by a compound of the formula [I], wherein ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula

where A ¹ represents an alkyl group, a hydrogen atom, a halogen atom or an alkoxy group, A ² represents a hydrogen atom or a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group, a halogen atom or an alkyl group, B ² represents a trihaloalkyl group, a halogen atom or an alkyl group, B ³ represents a hydrogen atom,

R ¹ represents a hydroxyl group; an alkyl group substituted with a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group, a morpholinoaminocarbonyl group, a hydroxyalkylaminocarbonyloxy group or an alkylpiperazinocarbonyl group; dihydroxyphenylthio group; alkanoylthio group; an alkylthio group optionally substituted with a hydroxyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkoxycarbonylamino group, a hydroxyalkanoylamino group, a morpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino group or an alkanoyloxy group; dialkylthionium group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a dialkylamino group, a pyridyl group, a triazolyl group, a tetrazolyl group, an optionally substituted alkyl group, a piperidino group, a morpholino group, a pyrrolidino group or an alkoxy; thienylsulfonyloxy group; morpholinocarbonyloxy group; an alkylpiperazinocarbonyloxy group; imidazolylcarbonyloxy group; piperidinoalkylaminocarbonyloxy group; morpholinoalkylaminocarbonyloxy group; an alkylaminocarbonyloxy group in which its alkyl moiety is optionally substituted with a hydroxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group or an alkanoyloxy group; dialkylaminoalkylaminocarbonyloxy group; a piperidinocarbonyloxy group substituted with a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl group, an alkylthioalkylaminocarbonyl group, an alkylsulfinylalkylaminocarbonyl group, an alkylsulfonylalkylalkylalkylaminoalkylcarbonyl group; a dialkylaminocarbonyloxy group optionally substituted with a hydroxyl group; a piperidinylaminocarbonyloxy group substituted with a hydroxyalkanoyl group or an alkoxyalkanoyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is optionally substituted with an oxo group; oxopyrrolidinylcarbonyloxy group; oxo-tetrahydrothiazolinylcarbonyloxy group; dialkylaminosulfonylaminocarbonyloxy group; carboxyl group; alkoxycarbonyl group; an aminocarbonyl group optionally substituted with a pyrimidinyl group or a pyrazinyl group; an alkylaminocarbonyl group in which the alkyl moiety is optionally substituted with a hydroxyl group or a cyano group; di (hydroxyalkyl) aminocarbonyl group; a piperidylaminocarbonyl group in which a fragment of the pyridyl group is optionally substituted with a hydroxyl group; an aminocarbonyl group substituted with an alkyl pyrido group; a piperidinocarbonyl group substituted with a hydroxyl group or an oxo group; a piperazinocarbonyl group substituted with an oxo group, an alkyl group, a pyrimidinyl group, a pyrazinyl group, an alkylsulfonyl group or an alkanoyl group; morpholinocarbonyl group; thiomorpholinocarbonyl group; a pyrrolidinocarbonyl group substituted with a hydroxyalkyl group or a hydroxyl group; an alkylsulfinyl group optionally substituted with a hydroxyl group; hydroxysulfinyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group or an alkanoyloxy group; or a group of the formula:

where R ¹¹ represents a hydrogen atom; pyridyl group; an alkanoyl group optionally substituted with a group selected from an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminocarbonyl group, an amino group, an alkoxycarbonylamino group, an alkanoylamino group, an amino group, a substituted alkoxycarbonyl group and an alkyl group, an amino group, an substituted alkylalkanoalkyl group alkoxy groups optionally substituted with a phenyl group, a furyl group, a tetrazolyl group, a hydroxyl group group, alkylthio group, alkyl sulfinyl group, alkyl sulfonyl group, 2-aminothiazolyl group, 2-oxopyrrolidino group, 2,2-dialkyl-1,3 - dioxolanyl group, 2-thiol-4-alkylthiazolinyl group, cycloalkyl group and 5-alkyl-2, 4 (1H, 3H) -pyrimidinedione group; a phenylcarbonyl group optionally substituted with an amino group or nitro group; a pyridylcarbonyl group optionally substituted with an alkyl group or a hydroxyl group; a furylcarbonyl group optionally substituted with a formyl group; morpholinoalkyl group or hydroxyalkyl group; thienylcarbonyl group; quinolylcarbonyl group; an indolylcarbonyl group substituted with an alkyl group; a pyrazinylcarbonyl group optionally substituted with an alkyl group or alkanoyl group; morpholinocarbonyl group; a pyrrolidinylcarbonyl group optionally substituted with a benzyloxy group, an alkoxycarbonyl group, an alkanoyl group, a hydroxyl group or an oxo group; tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group substituted with an alkoxycarbonyl group or an alkanoyl group; a thiomorpholinocarbonyl group in which the sulfur atom is optionally substituted with an oxo group;

3-alkyl-2,4 (1H, 3H) -pyrimidinedione dicarbonyl group; an alkylaminocarbonyl group in which its alkyl moiety is optionally substituted with a halogen atom, a hydroxyl group or an alkoxy group; dialkylaminocarbonyl group; an alkoxycarbonyl group optionally substituted with an alkoxy group, a hydroxyl group or a halogen atom; an alkylsulfonyl group optionally substituted with a group selected from a hydroxyl group, a morpholino group, an alkyl piperazino group, a dialkylamino group, an optionally substituted hydroxyl group and a halogen atom; alkenylsulfonyl group; dialkylaminosulfonyl group; or an alkyl group optionally substituted with a morpholino group, a halogen atom, an alkoxy group, a cyano group, a pyridyl group, a dialkylaminocarbonyl group or a dialkylamino group, and R ¹² represents a hydrogen atom; pyridyl group; pyrazinyl group; or an alkyl group, or —N (R ¹¹ ) (R ¹² ) represents a triazolyl group, a tetrazolyl group, an aminopurinyl group, a morpholino group, a morpholino group in which the nitrogen atom is substituted by an alkyl group, an N-oxomorpholino group, a piperidino group, an optionally substituted piperidino group, pyrrolide a substituted hydroxyl group or an alkoxyalkyl group, an imidazolidinyl group substituted by a hydroxyalkyl group and an oxo group, a hexahydropyrimidinyl group substituted by a hydroxyalkyl group and an oxo group, dioxopyrrolidino group, thiazolidyl group or azacycloheptyl group,

R ² represents a hydrogen atom,

Z represents an oxygen atom or a group represented by —N (R ³ ) -,

R ³ represents an alkyl group optionally substituted with a hydroxyl group or an alkanoyl group,

R ⁴ represents a hydrogen atom or an alkyl group optionally substituted with a hydroxyl group.

Of these compounds, compounds in which R ^{1 is} substituted with a hydroxyl group are preferred; an alkyl group substituted with a dialkylaminocarbonyl group, a morpholinocarbonyl group, a morpholinoaminocarbonyl group or an alkylpiperazinocarbonyl group; dihydroxyphenylthio group; alkanoylthio group; an alkylthio group optionally substituted with a hydroxyl group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a dialkylamino group, a pyridyl group, a triazolyl group, a tetrazolyl group, an optionally substituted alkyl group, a piperidino group, a morpholino group, a pyrrolidino group or an alkoxy; morpholinocarbonyloxy group; an alkylpiperazinocarbonyloxy group; imidazolylcarbonyloxy group; piperidinoalkylaminocarbonyloxy group; morpholinoalkylaminocarbonyloxy group; an alkylaminocarbonyloxy group in which its alkyl moiety is optionally substituted with a hydroxyl group, a morpholinocarbonyl group or a carboxyl group; dialkylaminoalkylaminocarbonyloxy group; a piperidinocarbonyloxy group optionally substituted with a hydroxyl group or hydroxyalkyl group; a dialkylaminocarbonyloxy group optionally substituted with a hydroxyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is optionally substituted with an oxo group; oxopyrrolidinylcarbonyloxy group; oxo-tetrahydrothiazolinylcarbonyloxy group; dialkylaminosulfonylaminocarbonyloxy group; alkoxycarbonyl group; an aminocarbonyl group optionally substituted with hydroxyalkyl; an alkylsulfinyl group optionally substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents a hydrogen atom; an alkanoyl group optionally substituted with a group selected from an amino group, a halogen atom, a dialkylamino group, an alkoxy group, a furyl group, a tetrazolyl group, a hydroxyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a 2-aminothiazolyl group, a 2,2-dialkyl-1,3 group -dioxol, 2-thiol-4-alkylthiazolinyl group, cycloalkyl group and 5-alkyl-2,4 (1H, 3H) -pyrimidinedione group; a phenylcarbonyl group optionally substituted with an amino group or nitro group; pyridylcarbonyl group; a furylcarbonyl group optionally substituted with a formyl group, a morpholinoalkyl group or a hydroxyalkyl group; thienylcarbonyl group; quinolylcarbonyl group; a pyrazinylcarbonyl group optionally substituted with an alkyl group; morpholinocarbonyl group; pyrrolidinocarbonyl group; tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group substituted with an alkoxycarbonyl group; an alkylaminocarbonyl group optionally substituted with a halogen atom, a hydroxyl group or an alkoxy group; dialkylaminocarbonyl group; an alkoxycarbonyl group optionally substituted with an alkoxy group, a hydroxyl group or a halogen atom; an alkylsulfonyl group optionally substituted with a group selected from a hydroxyl group, a morpholino group, an alkyl piperazino group, a dialkylamino group, an optionally substituted hydroxyl group and a halogen atom; alkenylsulfonyl group; dialkylaminosulfonyl group; or an alkyl group optionally substituted with a morpholino group, a halogen atom, an alkoxy group, a cyano group, a pyridyl group, a dialkylaminocarbonyl group or a dialkylamino group, and

R ¹² represents a hydrogen atom; pyridyl group; or an alkyl group.

Further preferred are compounds in which R ¹ represents a hydroxyl group; an alkyl group substituted with a dialkylaminocarbonyl group, a morpholinocarbonyl group, a morpholinoaminocarbonyl group or an alkylpiperazinocarbonyl group; dihydroxyphenylthio group; alkanoylthio group; an alkylthio group optionally substituted with a hydroxyl group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a pyridyl group, a triazolyl group, a tetrazolyl group, an optionally substituted alkyl group or an alkoxy group; morpholinocarbonyloxy group; imidazolylcarbonyloxy group; piperidinoalkylaminocarbonyloxy group; morpholinoalkylaminocarbonyloxy group; an alkylaminocarbonyloxy group optionally substituted with a hydroxyl group; morpholinocarbonyl group or carboxyl group; dialkylaminoalkylaminocarbonyloxy group; a piperidinocarbonyloxy group optionally substituted with a hydroxyl group or hydroxyalkyl group; a dialkylaminocarbonyloxy group optionally substituted with a hydroxyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is optionally substituted with an oxo group; oxopyrrolidinylcarbonyloxy group; oxo-tetrahydrothiazolinylcarbonyloxy group; dialkylaminosulfonylaminocarbonyloxy group; alkoxycarbonyl group; an aminocarbonyl group optionally substituted with a hydroxyalkyl group; an alkylsulfinyl group optionally substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or, a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted by a group selected from an amino group, a halogen atom, an alkoxy group, a furyl group, a tetrazolyl group, a hydroxyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a 2-aminothiazolyl group, 2,2-dialkyl-1, A 3-dioxolanyl group, a 2-thiol-4-alkylthiazolinyl group, a cycloalkyl group and a 5-alkyl-2,4 (1H, 3H) -pyrimidinedione group; a phenylcarbonyl group optionally substituted with an amino group or nitro group; pyridylcarbonyl group; a furylcarbonyl group optionally substituted with a formyl group or a hydroxyalkyl group; quinolylcarbonyl group; morpholinocarbonyl group; pyrrolidinocarbonyl group; tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group substituted with an alkoxycarbonyl group; an alkylaminocarbonyl group optionally substituted with a halogen atom, a hydroxyl group or an alkoxy group; dialkylaminocarbonyl group; an alkoxycarbonyl group optionally substituted with an alkoxy group, a hydroxyl group or a halogen atom; an alkylsulfonyl group optionally substituted with a hydroxyl group or a halogen atom; alkenylsulfonyl group; or thienylsulfonyl group, and

R ¹² represents a hydrogen atom; pyridyl group; or an alkyl group.

Of the compounds of the present invention, compounds in which ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A ¹ represents an alkyl group, a hydrogen atom, a halogen atom or an alkoxy group, A ² represents a hydrogen atom or a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group, a hydrogen atom or an alkyl group, B ² represents a trihaloalkyl group, a hydrogen atom or an alkyl group, B ³ represents a hydrogen atom,

R ¹ represents a hydroxyl group; an alkyl group substituted with a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group or a hydroxyalkylaminocarbonyloxy group; dihydroxyphenylthionyl group; alkanoylthio group; an alkylthio group optionally substituted with a hydroxyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkoxycarbonylamino group, a hydroxyalkanoylamino group, a morpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino group or an alkanoyloxy group; dialkylthionium group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a triazolyl group, a tetrazolyl group, an optionally substituted alkyl group or an alkoxy group; thienylsulfonyloxy group; morpholinocarbonyloxy group; imidazolylcarbonyloxy group; an alkylaminocarbonyloxy group in which its alkyl moiety is optionally substituted with a hydroxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group or an alkanoyloxy group; a piperidinocarbonyloxy group substituted with a hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl group, an alkylthioalkylaminocarbonyl group, an alkylsulfinylalkylaminocarbonyl group, an alkylsulfonylalkylalkylalkylaminoalkylcarbonyl group; a dialkylaminocarbonyloxy group optionally substituted with a hydroxyl group; a piperidinylaminocarbonyloxy group substituted with a hydroxyalkanoyl group or an alkoxyalkanoyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is optionally substituted with an oxo group; oxopyrrolidinylcarbonyloxy group; oxo-tetrahydrothiazolinylcarbonyloxy group; dialkylaminosulfonylaminocarbonyloxy group; carboxyl group; alkoxycarbonyl group; an aminocarbonyl group optionally substituted with a pyrimidinyl group; an alkylaminocarbonyl group in which the alkyl moiety is optionally substituted with a hydroxyl group or a cyano group; di (hydroxyalkyl) aminocarbonyl group; a pyridylaminocarbonyl group in which a fragment of the pyridyl group is optionally substituted with a hydroxyl group; an aminocarbonyl group substituted with an alkyl pyrido group; a piperidinocarbonyl group substituted with a hydroxyl group or an oxo group; a piperazinocarbonyl group substituted by an oxo group, an alkyl group, an alkylsulfonyl group or an alkanoyl group; morpholinocarbonyl group; thiomorpholinocarbonyl group; a pyrrolidinocarbonyl group substituted with a hydroxyalkyl group or a hydroxyl group; an alkylsulfinyl group optionally substituted with a hydroxyl group; hydroxysulfinyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group or an alkanoyloxy group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with (a) a group (s) selected from an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminocarbonyl group, an alkoxycarbonylamino group, an alkanoylamino group, an amino group, a substituted alkoxycarbonyl group and an alkyl group, an amino group, an amino group an alkyl group, an alkoxy group, an optionally substituted phenyl group, a furyl group, a tetrazolyl group, a hydroxyl group, an alkylthio a group, an alkylsulfinyl group, an alkylsulfonyl group, a 2-aminothiazolyl group, a 2-oxopyrrolidino group, a 2,2-dialkyl-1,3-dioxolanyl group, a 2-thiol-4-alkylthiazolinyl group and a cycloalkyl group; a phenylcarbonyl group optionally substituted with an amino group or nitro group; a pyridylcarbonyl group optionally substituted with a hydroxyl group; a furylcarbonyl group optionally substituted with a formyl group or a hydroxyalkyl group; thienylcarbonyl group; an indolylcarbonyl group substituted with an alkyl group; morpholinocarbonyl group; a pyrrolidinylcarbonyl group optionally substituted with a benzyloxy group, an alkoxycarbonyl group, an alkanoyl group, a hydroxyl group or an oxo group; tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group substituted with an alkoxycarbonyl group or an alkanoyl group; a thiomorpholinocarbonyl group in which the sulfur atom is optionally substituted with an oxo group; 3-alkyl-2,4 (1H, 3H) -pyrimidinedione dicarbonyl group; an alkylaminocarbonyl group in which its alkyl moiety is optionally substituted with a halogen atom, a hydroxyl group or an alkoxy group; dialkylaminocarbonyl group; an alkoxycarbonyl group optionally substituted with an alkoxy group, a hydroxyl group or a halogen atom; an alkylsulfonyl group optionally substituted with a group selected from a hydroxyl group and a halogen atom; alkenylsulfonyl group; or a dialkylaminosulfonyl group; and

R ¹² represents a hydrogen atom; pyrazinyl group; or an alkyl group, or

—N (R ¹¹ ) (R ¹² ) represents a triazolyl group, a tetrazolyl group, an aminopurinyl group, a morpholino group in which the nitrogen atom is substituted by an alkyl group, an N-oxomorpholino group, an amidazolidinyl group substituted by a hydroxyalkyl group and an oxo group, a hexahydropyrimidinyl group, a substituted oxo group, or dioxopyrrolidino group,

R ² represents a hydrogen atom,

Z represents an oxygen atom or a group represented by —N (R ³ ) -,

R ³ represents an alkyl group optionally substituted with a hydroxyl group,

R ⁴ represents a hydrogen atom or an alkyl group optionally substituted with a hydroxyl group.

Of these compounds, compounds in which ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A ¹ represents an alkyl group, A ² represents a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group, B ² represents a trihaloalkyl group, B ³ represents a hydrogen atom,

R ¹ represents an alkoxy group substituted with a hydroxyl group or tetrahydropyranyloxy; an alkylaminocarbonyloxy group in which its alkyl moiety is optionally substituted with a hydroxyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is substituted by an oxo group; an alkylthionyl group; alkanoyl group substituted by hydroxyl group; an aminocarbonyl group substituted with (a) a group (s) selected from an alkyl group, a pyrazinyl group and a pyrimidinyl group; a piperazinocarbonyl group substituted with an alkanoyl group; a piperidinocarbonyl group substituted with a hydroxyl group; an alkylsulfinyl group optionally substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with (a) a group (s) selected from an alkoxy group, a hydroxyl group and a cycloalkyl group; alkoxycarbonyl group; a pyridylcarbonyl group substituted with a hydroxyl group; morpholinocarbonyl group; an alkylaminocarbonyl group; or an alkylsulfonyl group; a pyrazinyl group, and

R ¹² represents a hydrogen atom or an alkyl group,

—N (R ¹¹ ) (R ¹² ) represents a triazolyl group, a tetrazolyl group, or an N-oxomorpholino group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

Even more preferred are compounds in which R ¹ is an alkylaminocarbonyloxy group in which its alkyl moiety is substituted with a hydroxyl group; a thiomorpholinocarbonyloxy group in which the sulfur atom is substituted by an oxo group; alkanoyl group substituted by hydroxyl group; a piperazinocarbonyl group substituted with an alkanoyl group; a piperidinocarbonyl group substituted with a hydroxyl group; an alkylsulfinyl group substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group substituted by a hydroxyl group, and

R ¹² represents a hydrogen atom.

In the present invention, compounds selected from the following compounds (A) to (BK) or their pharmaceutically acceptable salts are particularly preferred.

(A) (2R, 4S) -1- [N- (1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-methylpropionylamino) piperidine,

(B) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylaminopiperidine,

(C) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine,

(D) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {2- (2-tetrahydropyranyloxy) ethoxy} piperidine,

(E) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 -methoxyacetylaminopiperidine,

(F) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 -methoxycarbonylaminopiperidine,

(G) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylamino-2- (4-fluoro-2- methylphenyl) piperidine,

(H) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 methanesulfonylaminopiperidine,

(I) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyethoxy) piperidine,

(J) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 hydroxyacetylaminopiperidine,

(K) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (3-hydroxypropoxy) piperidine,

(L) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (2-cyclopropyl-2-hydroxyacetylamino) -2 - (4-fluoro-2-methylphenyl) piperidine,

(M) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxy-2-methylpropionylamino) piperidine,

(N) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino) piperidine,

(O) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine,

(P) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 methanesulfinyl piperidine,

(Q) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 methanesulfonylpiperidine,

(R) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine,

(S) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-methoxypropionylamino) piperidine,

(T) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (N-methanesulfonyl-N-methylamino) piperidine,

(U) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyethylaminocarbonyloxy) piperidine,

(V) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (3-hydroxy-3-methylbutyrylamino) piperidine,

(W) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfinyl) piperidine,

(X) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 hydroxyacetylaminopiperidine,

(Y) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -2-hydroxypropionylamino) piperidine,

(Z) (2R, 4S) -1- {N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino) piperidine,

(AA) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl ) piperidine,

(AB) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyethanesulfinyl) piperidine,

(AC) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(S) - ((S) -2-hydroxypropane) sulfinyl) piperidine,

(AD) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(R) - ((S) -2-hydroxypropane) sulfinyl} piperidine

(AE) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl ) piperidine,

(AF) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -2-hydroxypropanesulfonyl) piperidine,

(AG) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-methylethanesulfonyl) piperidine,

(AH) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxy-2-methylpropanesulfinyl) piperidine,

(AI) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(S) - ((S ) -2-hydroxypropane) sulfinyl} piperidine,

(AJ) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(R) - ((S ) -2-hydroxypropane) sulfinyl) piperidine,

(AK) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(R) - ((R ) -2-hydroxypropane) sulfinyl} piperidine,

(AL) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - {(S) - ((R ) -2-hydroxypropane) sulfinyl} piperidine,

(AM) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -2-hydroxypropanesulfonyl ) piperidine,

(AN) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino ) piperidine,

(AO) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino ) piperidine,

(AP) (2R, 4S) -4- (4-acetylpiperazinocarbonyl) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine,

(AQ) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethanesulfinyl) piperidine,

(AR) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothiomorpholinocarbonyloxy) piperidine,

(AS) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfonyl) piperidine,

(AT) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethanesulfonyl) piperidine,

(AU) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (4-hydroxypiperidinocarbonyl) piperidine,

(AV) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine,

(AW) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -2-hydroxypropionyl ) piperidine,

(AX) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-pyrazine -2-ylaminocarbonyl) piperidine,

(AY) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (pyrazin-2-ylamino) piperidine ,

(AZ) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-pyrazine -2-ylamino) piperidine,

(BA) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-methylethylthionyl) piperidine,

(BB) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-triazoryl) piperidine,

(BC) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-tetrazolyl) piperidine,

(BD) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (N-oxomorpholino) piperidine,

(BE) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-15 fluoro-2-methylphenyl) - 4- (N-oxomorpholino) piperidine,

(BF) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine,

(BG) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxypyridin-5-ylcarbonylamino ) piperidine,

(BH) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (N-pyrimidin-4-ylaminocarbonyl) piperidine,

(BI) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (N-methyl-N-pyrimidin-4-ylaminocarbonyl) piperidine,

(BJ) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyacetylamino) piperidine or

(BK) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-methylethylthio) piperidine.

In the present invention, compounds selected from the following (a) to (s) or their pharmaceutically acceptable salts are more preferred.

(a) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxy-2-methylpropionylamino) piperidine,

(b) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino) piperidine,

(c) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine,

(d) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (3-hydroxy-3-methylbutyrylamino) piperidine,

(e) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino) piperidine,

(f) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl ) piperidine,

(g) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl ) piperidine,

(h) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -2-hydroxypropanesulfonyl ) piperidine,

(i) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino ) piperidine,

(j) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino ) piperidine,

(k) (2R, 4S) -4- (4-acetylpiperazinocarbonyl) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine,

(1) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothiomorpholinocarbonyloxy) piperidine,

(m) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfonyl) piperidine,

(n) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethanesulfonyl) piperidine,

(o) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (4-hydroxypiperidinocarbonyl) piperidine,

(p) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine,

(q) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -2-hydroxypropionyl ) piperidine,

(r) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyacetylamino) piperidine or

(s) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-methylethylthio) piperidine.

Among the compounds of the present invention, preferred compounds include compounds in which ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula:

where A ¹ represents an alkyl group, A ² represents a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group or a halogen atom, B ² represents a trihaloalkyl group or a halogen atom, B ³ represents a hydrogen atom,

R ¹ represents a hydroxyl group; an alkyl group substituted with a dialkylaminocarbonyl group or a morpholinocarbonyl group, an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a triazolyl group or a tetrazolyl group optionally substituted with an alkyl group; morpholinocarbonyloxy group; hydroxyalkylaminocarbonyloxy group; imidazolylcarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group or a 5-alkyl-2,4 (1H, 3H) -pyrimidinedione group; pyridylcarbonyl group; furylcarbonyl group; thienylcarbonyl group; morpholinocarbonyl group; alkoxycarbonyl group or alkylsulfonyl group;

R ¹² represents a hydrogen atom; or an alkyl group, or —N (R ¹¹ ) (R ¹² ) represents a triazolyl group, a morpholino group in which the nitrogen atom is substituted by an alkyl group, or an N-oxomorpholino group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

Among these compounds, compounds in which R ¹ represents a hydroxyl group are preferred; an alkyl group substituted with a dialkylaminocarbonyl group or a morpholinocarbonyl group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group, a triazolyl group or a tetrazolyl group optionally substituted with an alkyl group; morpholinocarbonyloxy group; hydroxyalkylaminocarbonyloxy group; imidazolylcarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group or a 5-alkyl-2,4 (1H, 3H) -pyrimidinedione group; pyridylcarbonyl group; furylcarbonyl group; thienylcarbonyl group; morpholinocarbonyl group; alkoxycarbonyl group; alkylsulfonyl group;

R ¹² represents a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, compounds in which R ¹ represents a hydroxyl group are more preferred; an alkoxy group substituted with a hydroxyl group or a triazolyl group; hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group; and

R ¹² represents a hydrogen atom; or an alkyl group, or —N (R ¹¹ ) (R ¹² ) represents a morpholino group in which the nitrogen atom is substituted by an alkyl group, a piperazino group substituted by an N-oxomorpholino group, an alkyl group or an alkanoyl group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

More preferred are compounds in which R ¹ is a hydroxyl group; an alkoxy group substituted with a hydroxyl group or a triazolyl group; hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group;

R ¹² represents a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, other preferred compounds are compounds in which R ¹ represents a hydroxyl group; an alkoxy group optionally substituted with a hydroxyl group, an alkylsulfonyloxy group or a tetrazolyl group; hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group; furylcarbonyl group; morpholinocarbonyl group; alkoxycarbonyl group; or an alkylsulfonyl group; and

R ² represents a hydrogen atom; or an alkyl group, or —N (R ¹¹ ) (R ¹² ) represents a triazolyl group or a tetrazolyl group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

Examples of other preferred compounds are compounds in which ring A represents a benzene ring of the formula

and ring B represents a benzene ring of the formula:

where A ¹ represents an alkyl group, A ² represents a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group, B ² represents a trihaloalkyl group, B ³ represents a hydrogen atom,

R ¹ represents a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group; or an alkoxycarbonyl group; and

R ¹² represents a hydrogen atom; or an alkyl group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

Among other preferred compounds, preferred compounds in which ring A represents a benzene ring of the formula:

and ring B represents a benzene ring of the formula

where A ¹ represents an alkyl group, A ² represents a halogen atom, A ³ represents a hydrogen atom, B ¹ represents a trihaloalkyl group, B ² represents a trihaloalkyl group, B ³ represents a hydrogen atom,

R ¹ represents a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group, and

R ¹² represents a hydrogen atom; or an alkyl group, or —N (R ¹¹ ) (R ¹² ) represents a morpholino group in which the nitrogen atom is substituted by an alkyl group, or an N-oxomorpholino group,

R ² represents a hydrogen atom,

Z represents a group represented by —N (R ³ ) -,

R ³ represents an alkyl group,

R ⁴ represents a hydrogen atom or an alkyl group.

More preferred are compounds in which R ¹ is a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionally substituted with a hydroxyl group; alkylsulfonyl group; an alkylaminocarbonyl group substituted with a hydroxyl group; a piperidinocarbonyl group substituted with a hydroxyl group; or a group of the formula:

where R ¹¹ represents an alkanoyl group optionally substituted with a hydroxyl group, and R ¹² represents a hydrogen atom; or an alkyl group.

The compound [I] of the present invention can be used for pharmaceutical purposes either in free form or in the form of a pharmaceutically acceptable salt.

As pharmaceutically acceptable salts of the compounds [I] of the present invention, mention may be made, for example, of inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromate; and salts of organic acids, etc., such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, succinate and tartrate.

In addition, the compounds [I] of the present invention or their pharmaceutically acceptable salts include any of their internal salts, solvates and hydrates, etc.

Optical isomers may be present in the compounds [I] of the present invention due to the presence of an asymmetric carbon atom, and the present invention includes any of these optical isomers and mixtures thereof. In the present invention, among these optical isomers, compounds with an R configuration in position 2 of the piperidine ring (attachment position of ring A) are preferred, and compounds with an R configuration in position 2 of piperidine ring (attachment position of ring A) and with S configuration in position 4 (accession position R ¹ ).

Compounds [I] or their pharmaceutically acceptable salts of the present invention have an excellent antagonistic effect on the tachykinin receptor, especially antagonistic action on the SP receptor, so that they can be useful as safe drugs for the prevention and treatment of inflammatory or allergic diseases (for example, atopic dermatitis, dermatitis, herpes, psoriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, ra seeded sclerosis, conjunctivitis, ophthalmia, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough and, in addition, diseases of the central nervous system (e.g. schizophrenia, Parkinson's disease, depression, anxiety, psychosomatic disorders, dependence from morphine, dementia (e.g., Alzheimer's disease, etc.), etc.), digestive diseases (e.g., intestinal hypersensitivity, ulcerative colitis, Crohn's disease, disorders (e.g., gastritis, stomach ulcers, etc.) D.) associated with urease-positive Spirillum (on example, helicobacter pylori, etc.), etc.), bouts of nausea, vomiting, disorders of the urinary system (e.g., pollakiuria, urinary incontinence, etc.), circulatory disorders (e.g., angina pectoris, hypertension, heart failure , thrombosis, etc.) and immune system disorders, etc. in mammals (e.g., mice, Mongolian gerbils, ferrets, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).

In particular, since the compounds [I] or their pharmaceutically acceptable salts, which are the active ingredients of the present invention, are readily transferred to the brain, and at the same time, due to their low toxicity, show almost no side effects, they can be used as therapeutic or prophylactic agents for diseases of the central nervous system, such as vomiting, depression, etc., or disorders of the urinary system, such as pollacnuria, etc.

Measurements regarding the compounds of the present invention or their pharmaceutically acceptable salts can be carried out in accordance with the method disclosed in European Journal of Pharmacology, vol. 254, pages 221-227 (1994) regarding neurokinin-1 receptor binding, and in accordance with the method disclosed in European Journal of Pharmacology) vol. 265, pages 179-183 (1994) with respect to their action against the induction of neurokinin-1 receptors, and in accordance with the method disclosed in British Journal of Pharmacology vol. 119, pages 931-936 (1996) regarding their effectiveness against vomiting; in addition, in accordance with the method disclosed in Journal of Urology, vol. 155, No. 1, pages 355-360 (1996) regarding inhibition of pollacnuria.

The compounds of formula [I] or their pharmaceutically acceptable salts of the present invention can be administered orally or parenterally, and they can be prepared in the form of appropriate preparations using commonly used pharmaceutical carriers for oral or parenteral administration. As such pharmaceutical carriers, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.) can be mentioned. ), lubricants (magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.), disintegrants (potato starch, etc.) and wetting agents (anhydrous sodium lauryl sulfate, etc.), etc.

In addition, if these pharmaceutical preparations are administered orally, they can be prepared in the form of solid preparations, such as tablets, granules, capsules, powders, or in the form of liquid preparations, such as solutions, suspensions and emulsions. On the other hand, if they are administered parenterally, for example, they can be administered in the form of injection solutions or solutions for infusion using distilled water for injection, physiological solutions, aqueous glucose solutions, etc., or they can be administered in the form of suppositories and etc.

The dose of the compound [I] or its pharmaceutically acceptable salt of the present invention may vary depending on the route of administration, age, weight or condition of the patient, etc., and, for example, in the case of oral administration, the compound is usually administered in a dose of from 0.1 to 20 mg / kg per day, particularly preferably 0.1 to 10 mg / kg per day, and in the case of parenteral administration, usually at a dose of 0.01 to 10 mg / kg per day, particularly preferably 0.01 to 1 mg / kg per day.

[Method A]

The target compound [I] of the present invention can be obtained, for example, by reacting a compound of the formula [II]:

where ring A represents an optionally substituted benzene ring, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group of the formula:

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, as heteroatoms, where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized, or

R ¹¹ and R ¹² taken together with the adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazolyl group and a purinyl group, where the heterocyclic group is optionally substituted and a nitrogen atom a heterocyclic group is optionally oxidized,

R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom,

with a compound of the formula [III]:

where ring B represents an optionally substituted benzene ring, R ³ represents a hydrogen atom or an optionally substituted alkyl group, and R ⁴ represents a hydrogen atom or an optionally substituted alkyl group,

in the presence of urea.

[Method B]

Among the target compounds [I] of the present invention,

compounds of the formula [I-a]:

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings,

can be obtained, for example, by reducing a compound of formula [IV]:

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings,

[Method C]

Among the compounds of the present invention, the compound of formula [I-b]:

where ring A, ring B, R ¹¹ , R ¹² , R ² , Z, R ³ and R ⁴ have the above meanings,

can be obtained by reacting a compound of formula [IV]

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings,

with a compound of the formula [V]:

where X ¹ represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or a magnesium atom, and R ¹¹ and R ¹² have the above meanings.

[Method D]

Among the compounds of the present invention, the compound of formula [I-c]:

where ring A, ring B, R ² , Z, R ³ and R ⁴ are as defined above, and R ¹³ is an optionally substituted carboxyl group,

can be obtained by reacting a compound of formula [IV]

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings,

with the compound of the formula [VI]:

where X ² represents a leaving group, and R ¹³ has the above meanings,

and recovering the resulting compound of formula [VII]:

where ring A, ring B, R ¹³ , Z, R ³ and R ⁴ have the above meanings.

[Method E]

Among the compounds of the present invention, a compound of the formula [I ″]:

where ring A, ring B, R ¹ , R ² and R ⁴ have the above meanings,

can be obtained by reacting the compounds of formula [II]:

where the ring A, R ¹ and R ² have the above meanings,

with the compound of the formula [III ']:

where the ring B and R ⁴ have the above meanings,

in the presence of a urea bond forming agent.

These methods [Method A-Method E] can be carried out as described below.

[Method A]

The reaction of compound [II] with compound [III] can be carried out in a suitable solvent in the presence of a urea bond forming agent. Examples of urea-forming agents are compounds of the formula:

where W ¹ and W ^{2 are the} same or different, and each represents a leaving group and the like.

W ¹ and W ² may be the same or different, and each represents an imidazolyl group, a halogen atom, a phenoxy group, and the like. Particularly preferred are 1,1'-carbonyldiimidazole, phosgene and the like. and carbonyldihalides, such as 1,1'-carbonyldiimidazole, triphosgene or phosgene, etc. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly. This reaction can occur, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C.

Further, in this reaction, compound [I] can also be obtained by reacting compound [II]

with a urea bond forming agent of the formula:

where W ¹ and W ^{2 are the} same or different, and each represents a leaving group,

resulting in a compound of the formula [VIII-a]:

where the ring A, R ¹ , R ² and W ² have the above meanings,

then converting the compound [VIII-a] into its reactive derivative, and carrying out its interaction with the compound [III],

or, alternatively, compound [I] can be prepared by reacting compound [III] and an urea bond forming agent of the formula:

where W ¹ and W ² have the above meanings,

resulting in a compound of the formula [VIII-b]:

where ring B, R ³ , R ⁴ and W ² have the above meanings,

then converting the compound [VIII-b] into its reactive derivative, and interacting with the compound [II].

As reactive derivatives, compounds can be mentioned in which W ² provides the group represented by the formula:

in the compound [VIII-a] or in the compound [VIII-b], and the like.

The reaction of compound [II] or compound [III] with a urea bond forming agent can proceed, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

The reaction, which will lead to the conversion of compound [VIII-a] or compound [VIII-b] into its reactive derivative, can be carried out using an agent providing the derivative, such as methyl iodide, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

The reaction of each reactive derivative with compound [III] or compound [II] can be carried out in the presence of a base, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, triethylamine, etc., can be used as the base, and any solvent can be used as long as it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

[Method B]

The reduction of compound [IV] can be carried out in a suitable solvent in the presence of a reducing agent. As the reducing agent, sodium borohydride and the like can be preferably used, for example, sodium borohydride, aluminum hydride such as diisobutylaluminium hydride, etc. Further, any solvent can be used, provided that it does not adversely affect the course of the reaction, for example, ethanol, tetrahydrofuran, dichloromethane, etc. can be used accordingly. This reaction can be carried out, for example, at a temperature of from -70 ° C to a boiling point under reflux, preferably at a temperature of from -70 ° C to 20 ° C.

[Method C]

The reaction of compound [IV] with compound [V] can be carried out in a suitable solvent by subjecting the compounds to reductive amination. Such a reductive amination reaction can be carried out by hydrogenation under acidic conditions in the presence of a reducing agent, such as sodium borohydride, triacetoxin sodium borohydride, sodium cyanoborohydride or a reduction catalyst such as palladium. As the group [X ¹ ] in the compound [V], for example, a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or a magnesium atom can be mentioned, and a hydrogen atom and a hydroxyl group are preferred. Any solvent can be used, provided that it does not adversely affect the course of the reaction, for example, dichloromethane, acetic acid, ethanol, methanol, etc. can be used accordingly. As the salt of compound [V], hydrochloride, acetate, etc., can be used appropriately. The reaction in question can occur, for example, at a temperature of from -10 ° C to 80 ° C, preferably at a temperature of from 0 ° C to 30 ° C.

[Method D]

The reaction of compound [IV] with compound [VI] can be carried out in a suitable solvent, optionally in the presence of a base. As the leaving groups [X ² ] of the compound [VI], diethylphosphono group, triphenylphosphinyl group, etc. can be mentioned. As the bases, for example, potassium tert-butoxide, triethylamine, sodium hydroxide, etc. can be mentioned, and potassium tert-butoxide, triethylamine, and the like are preferred. Further, any solvent can be used, provided that it does not adversely affect the course of the reaction, for example, tetrahydrofuran, dichloromethane, etc. can be used accordingly. The reaction in question can occur, for example, at a temperature of from -30 ° C to 80 ° C, preferably at a temperature of from -20 ° C to 30 ° C.

Further, the reduction of compound [VII] can be carried out in the usual way, by hydrogenation in the presence of reduction catalysts such as palladium, etc. Suitable solvents are methanol, ethanol, etc. The reaction in question can occur, for example, at a temperature of from 0 ° C to 50 ° C.

[Method E]

The reaction of compound [II] with compound [III '] can be carried out in the presence of a urea bond forming agent in a suitable solvent. As the agents forming the urea bond, you can specify those that are represented by the formula:

where W ¹ and W ^{2 are the} same or different, and each represents a leaving group.

As W ¹ and W ² , regardless of whether they are the same or different, an imidazolyl group, a halogen atom or a phenoxy group and the like can be mentioned. It is particularly preferable to use 1,1'-carbonyldiimidazole, phosgene and, for example, carbonyldihalides, such as 1,1'-carbonyldiimidazole, triphosgene, phosgene, etc. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly. The reaction in question can occur, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C.

Further, the compound [I ″) can be obtained by reacting the compound [II] with a urea bond forming agent of the formula:

where W ¹ and W ^{2 are the} same or different, and each represents a leaving group, obtaining a compound of formula [VIII-a]:

where the ring A, R ¹ R ² and W ² have the above meanings,

then converting the compound [VIII-a] into its reactive derivative and reacting it with the compound [III '], or, alternatively, the compound [I' '] can be obtained by reacting the compound [III'] with a urea bond forming agent of the formula:

where W ¹ and W ² have the above meanings, obtaining the compound of formula [VIII ']:

where the ring B, R ⁴ and W ² have the above meanings,

then converting the compound [VIII '] into its reactive derivative and interacting with the compound [II].

Examples of reactive derivatives are, for example, compounds in which W ² provides a group represented by the formula:

in compound [VIII-a] or in compound [VIII '].

The reaction of compound [II] or compound [III '] with a urea bond forming agent can proceed, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

The reaction of converting compound [VIII-a] or compound [VIII '] into their reactive derivatives can be carried out using an agent providing such a derivative, such as methyl iodide, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, any solvent may be used, provided that it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

The reaction of each reactive derivative with compound [III] or compound [II] can be carried out in the presence of a base, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. Further, triethylamine, etc., can be used as the base, and any solvent can be used as long as it does not adversely affect the course of the reaction, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used accordingly.

The compound [I] of the present invention can also be obtained by converting the R ¹ group and the R ³ group ^{of the} compound obtained by the above method into the desired substituent. The method for converting substituents can be selected appropriately depending on the types of substituents needed; and you can use the following methods (methods a-q).

(method a)

The compound [I] in which R ¹ represents a group containing a substituted hydroxyl group (for example, an optionally substituted alkoxy group, a substituted carbonyloxy group or an alkylsulfonyloxy group, etc.) in the formula [I] can be prepared by alkylating, acylating or sulfonylating in a conventional manner corresponding a compound containing a hydroxyl group as R ¹ . For example, alkylation may occur at a temperature of from -10 ° C to 80 ° C, acylation may occur at a temperature of 5 ° C to 80 ° C, and sulfonylation may occur at a temperature of 5 ° C to 80 ° C.

(method b)

The compound [I] in which R ¹ represents a group containing a substituted amino group in the formula [I] can be obtained by conventionally replacing the corresponding compound containing an amino group as R ¹ with substituent (s) of the amino group (for example, an alkoxycarbonyl group such as tert-butoxycarbonyl, an arylalkoxycarbonyl group, such as a benzyloxycarbonyl group, etc., an alkanoyl group, such as a formyl group, acetyl group, propionyl group, etc., by an alkyl group, such as methyl I am a group, an ethyl group, a propyl group, etc., an alkylsulfonyl group, such as a methanesulfonyl group, an ethanesulfonyl group, etc., an alkenylsulfonyl group, such as a vinylsulfonyl group, etc., by a heterocyclic group, such as a pyridyl group etc., etc.). Alternatively, this compound can be prepared using a carbamate synthesis reagent, such as N, N'-succinimidyl carbonate, etc., by reacting, for example, with alkoxyalkyl alcohol, etc. Substitution is conveniently carried out in the usual way, depending on the types of substituents, by alkylation, acylation, sulfonylation, arylation, etc. Further, by replacing a hydrogen atom with an amino group, a disubstituted compound can be obtained. The reaction in question can proceed at a temperature of from -20 ° C to 50 ° C.

Further, if the compound [I], in which R ¹ represents a group containing a substituted amino group, contains a urea bond, it can be obtained by reacting the corresponding amine compound with an urea-forming agent in a manner analogous to the method [method A] or , by the method disclosed in Japanese Provisional Patent Publication No.10-195037.

Further, the compound [I], in which R ¹ represents a group containing a substituted amino group in the formula [I], can be obtained by adding a compound containing an amino group to the corresponding compound containing a carbon-carbon double bond at R ¹ . The reaction in question can be carried out at the boiling point of the solvent, or in the absence of a catalyst.

(method c)

The compound [I], in which R ¹ represents a group containing an amino group in the formula [I], can be obtained by removing the protective group from the corresponding compound containing a substituted amino group at R ¹ . The removal of the protective group can be carried out in the usual way (for example, treatment with an acid, treatment with a base, catalytic reduction, etc.). Among the reactions considered, a reaction carried out by treatment with an acid can proceed at a temperature of from 5 ° C to 120 ° C, a reaction carried out by treatment with a base can proceed at a temperature of from 5 ° C to 40 ° C, and a catalytic reduction reaction can proceed at a temperature of 10 ° C to 40 ° C.

Further, a compound [I] in which R ¹ represents a group containing an amino group in the formula [I] can be obtained by reducing a corresponding compound containing a nitro group at R ¹ . Recovery can be carried out in the presence of acid, by reacting with chloride of tin, zinc, etc. For example, the reaction in question can be carried out at the boiling point of the solvent.

Further, a compound [I] in which R ¹ represents a group containing an amino group in the formula [I] can be obtained by subjecting the corresponding compound containing a carboxyl group to R ¹ to a Curtius rearrangement, etc. Curtius rearrangement can be carried out, for example, according to the method disclosed in Advanced Organic Chemistry, vol.4, page 1054. That is, it can be carried out by converting the carboxyl group to an acid chloride using thionyl chloride, etc. and then, by azidizing it with sodium azide, etc., followed by hydrolysis.

(method d)

The compound [I], in which R ¹ represents a group containing a hydroxyl group in the formula [I], can be obtained by removing in the usual way the protective group of the corresponding compound containing a substituted hydroxyl group at R ¹ . Removal of the protective group can be accomplished using acid treatment, base treatment, catalytic reduction, etc. depending on the type of protecting group. The reaction in question can occur, for example, at a temperature of from 0 ° C to 80 ° C, particularly preferably from 5 ° C to 50 ° C.

Further, the compound [I], in which R ¹ represents a group containing a hydroxyl group in the formula [I], can be obtained by reducing the corresponding compound containing a formyl group at R ¹ . The reduction can be carried out by reacting the compound in the presence of a reducing agent, such as sodium borohydride, etc. The reaction in question can occur, for example, at a temperature of from -80 ° C to 80 ° C, particularly preferably from -70 ° C to 20 ° C.

Further, the compound [I] in which R ¹ represents a group containing a hydroxyl group in the formula [I] can be obtained by reducing the corresponding compound containing an ester or carboxyl group at R ¹ . The reduction can be carried out by subjecting the compound to a reaction in the presence of a reducing agent, such as lithium aluminum hydride, etc. The reaction in question can occur, for example, at a temperature of from -50 ° C to 200 ° C, particularly preferably from -20 ° C to 60 ° C.

(method e)

In the event that R ¹ in the formula [I] represents a hydroxyl group and contains an asymmetric center at the connecting part, the configuration of the compound can be changed to the opposite configuration, for example, according to the method of Mitsunobu and others, as disclosed in Synthesis, pages 1 to 28, 1981. More specifically, the conversion can be carried out by reacting the compound in the presence of triphenylphosphine, benzoic acid and diethyl azodicarboxylate in a suitable solvent. The reaction in question can occur, for example, at a temperature of from 0 ° C to 60 ° C, particularly preferably from 5 ° C to 40 ° C.

(method f)

The compound [I] in which R ¹ represents a group containing an optionally substituted thiol group in the formula [I] can be obtained by reacting the corresponding compound containing a hydroxyl group at R ¹ with a corresponding compound containing a thiol group, for example, by the method Mitsunobu et al., As disclosed in Synthesis, pages 1 to 28, 1981. More specifically, the reaction can be carried out by reacting the compound in the presence of triphenylphosphine and diethyl azodicarboxylate in a suitable solvent. The reaction in question can occur, for example, at the boiling point of the solvent by heating.

The compound [I] in which R ¹ represents a group containing an optionally substituted thiol group in the formula [I] can be obtained by reacting the corresponding compound [I] containing a halogen atom of R ¹ with a corresponding compound containing a thiol group. The reaction in question can occur, for example, at a temperature of from -50 ° C to 150 ° C, particularly preferably from 10 ° C to 100 ° C.

In addition, the compound [I] in which R ¹ represents an alkylthio group-containing group can be prepared by alkylating the corresponding compound [I] containing a thiol group on R ¹ or the corresponding compound containing a protected thiol group (for example, an acetylated thiol group) . The reaction in question can proceed in the presence of a base, for example, at a temperature of from -10 ° C to 80 ° C, particularly preferably from 5 ° C to 50 ° C.

(method g)

The compound [I] in which R ¹ in the formula [I] represents a group containing a substituted amino group can be obtained by subjecting the corresponding compound [I] containing a hydroxyl group to R ¹ , an amination reaction, for example, according to the method of Mitsunobu and others, as disclosed in Synthesis, pages 1 to 28 1981.

(method h)

The compound [I] in which R ¹ in the formula [I] represents a group containing a free carboxyl group can be obtained by subjecting the corresponding compound [I] containing an esterified carboxyl group to R ¹ to a deesterification reaction in the usual way (for example, by hydrolysis with a base, such as sodium hydroxide, etc., acid treatment with hydrogen chloride, hydrogen bromide, etc., reduction in a hydrogen atmosphere using palladium (palladium black), palladium-carbon, etc., depending on the type ester residue ka). In deesterification reactions, for example, hydrolysis using a base can proceed at a temperature of from 5 ° C to 70 ° C, acid treatment is carried out at a temperature of from 5 ° C to 80 ° C, recovery can occur at a temperature of from 10 ° C to 40 ° C .

(method i)

The compound [I] in which R ¹ in the formula [I] represents an amide bond group can be prepared by reacting the corresponding compound [I] containing a free carboxyl group on R ¹ with the corresponding amine, or by reacting the corresponding compound [ I] containing a free amino group at R ¹ , with the corresponding carboxylic acid, in the presence or absence of a condensing agent. As the condensing agent, 1,1'-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, isobutyl chloroformate or N-methylmorpholine, etc., which are usually used in the reaction to form amide bond using carboxylic acid and amine. The reaction in question can occur, for example, at a temperature of from -20 ° C to 50 ° C.

(method j)

The compound [I] in which R ¹ in the formula [I] represents a group containing a heterocyclic group whose nitrogen atom is substituted by an oxo group (nitrogen atom is oxidized) (for example, an N-oxomorpholino group, etc.) can be obtained by treating the corresponding compound [ I] containing a heterocyclic group at R ¹ , an oxidizing agent (for example, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, oxone, etc.). The reaction in question can occur, for example, at a temperature of from 5 ° C to 50 ° C.

(method k)

The compound [I] in which R ¹ in the formula [I] represents a group containing a heterocyclic group, the nitrogen atom of which is oxidized, different from the above compound (method j) (for example, N-alkyl-4-morpholino group, etc. ), can be obtained by reacting the corresponding compound [I] containing a heterocyclic group at R ¹ with an alkyl halide. The reaction in question can occur, for example, at a temperature of from 20 ° C to 80 ° C.

(method l)

The compound [I] in which R ¹ in the formula [I] represents an alkyl group can be obtained by conventionally alkylating the corresponding compound [I] in which R ³ represents a hydrogen atom. An alkyl group may be substituted. The reaction in question can occur, for example, at a temperature of from 20 ° C to 80 ° C.

(method m)

The compound [I] in which R ¹ in the formula [I] represents a group containing a group whose sulfur atom is monosubstituted with an oxo group (for example, a sulfinyl group, etc.) can be obtained by treating the corresponding compound [I] containing a thio group at R ¹ , an oxidizing agent (e.g., 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxon, etc.). The reaction in question can proceed, for example, at a temperature of from -80 ° C to 150 ° C, particularly preferably from 0 ° C to 40 ° C.

(method n)

The compound [I] in which R ¹ in the formula [I] represents a group containing a group whose sulfur atom is disubstituted by oxo groups (for example, a sulfonyl group, etc.) can be obtained by treating the corresponding compound [I] containing a thio group at R ¹ , an oxidizing agent (for example, 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxon, etc.). The reaction in question can proceed, for example, at a temperature of from -80 ° C to 150 ° C, particularly preferably from 0 ° C to 40 ° C.

(method o)

The compound [I] in which R ¹ in the formula [I] represents an amino group, can be obtained by subjecting the corresponding compound [I] containing a carbonyl group at R ¹ to a reductive amination reaction. The reaction in question can be carried out by the above method [Method C].

(method p)

The compound [I] in which R ¹ in the formula [I] represents a sulfinic acid group can be prepared by reacting the corresponding compound [I] containing an alkyl sulfinyl group at R ¹ , for example, according to the method disclosed in Synlett, April , pages 375 to 377, 1997.

(method q)

The compound [I] in which R ¹ in the formula [I] represents a group containing an imidazolidinyl group or a hexahydropyrimidinyl group can be obtained by carrying out the cyclization reaction of the corresponding compound [I] containing an aminoalkylamino group at R ¹ , for example, in the presence of a condensing agent such like 1,1'-carbonyldiimidazole, etc. The reaction in question can occur, for example, at a temperature of from -20 ° C to 50 ° C.

As solvents that can be used in the above reactions from (method a) to (method q), any solvent can be used as long as it does not adversely affect the course of the reaction, for example, solvents suitably selected from dioxane can be used, dimethyl ether of ethylene glycol, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, alcohol, dichloromethane, carbon tetrachloride, 1,3-dimethyl-2-imidazolidine, acetic acid, d ethyl ether, methoxyethane, dimethylsulfoxide, acetonitrile, water and mixtures thereof.

Incidentally, the compound [IV], used in the present invention as a starting material, is a new compound, and can be obtained, for example, as shown below in the diagram:

where R ⁵¹ represents an alkyl group, R ⁶¹ represents a protecting group for an amino group, R ⁵² represents an alkyl group that may form a bond at its end, X ³ represents a leaving group, X ⁴ represents a leaving group, and ring A, ring B, R ³ and R ⁴ have the above meanings.

Thus, the condensation reaction of the pyridine compound [IX] and the Grignard reagent [X] is carried out, and then the amino group is protected to obtain the compound [XI]. Then, the resulting compound was reduced to give compound [XII]. Further, the carbonyl group of compound [XII] is protected with ketal to give compound [XIII], the protective group at the amino group is removed to give compound [XIV]. Then, a condensation reaction of compound [XIV] and compound [XV] is carried out to obtain compound [XVI], then reacting with compound [XVII], or a condensation reaction of compound [XIV] and compound [III] is carried out to obtain compound [XVIII], and removing his protective group, receive the compound [IV].

Compound [IV] contains an asymmetric carbon atom, and due to this asymmetric carbon, optical isomers exist. Using the optical isomer of the above compound [XIV], the desired optical isomer of the compound [IV] can be obtained.

The optical isomer of compound [XIV] can be obtained by subjecting the racemic mixture of compound [XIV] to optical isomers in the usual manner. Separation into optical isomers can be accomplished, for example, by reacting compound [XIV] with an N-acyl optically active amino acid or an N-sulfonyl optically active amino acid, producing two types of diastereoisomeric salts, and isolating and collecting one of the diastereoisomeric salts using the difference in their solubility.

Examples of the acyl groups of N-acyl optically active amino acids are the acetyl group, propionyl group, tosyl group or benzyloxycarbonyl group, and examples of optically active amino acids are L-phenylalanine, L-leucine, L-glutamine, L-methionine, L-valine, L threonine, D-phenylalanine or D-phenylglycine.

Further, the compound [II], used in the present invention as a starting material, is a new compound, and can be obtained, for example, as shown in the diagram below:

where ring A, ring R ¹¹ , R ¹² , R ⁶¹ and X ¹ have the above meanings.

Thus, compound [XII] and compound [V] are subjected to a reductive amination reaction to give compound [XIX] and removing the protective group of its amino group, compound [II-a] is obtained. The reductive amination reaction can be carried out similarly to the method of [Method C].

Upon receipt of the aforementioned compound [IV], each of the intermediate compounds is not limited to those shown in the reaction scheme, and their salts or their reactive derivatives can be successfully used, provided that they do not adversely affect the course of the reaction.

Further, among the starting materials [II] of the present invention, the compound [II-b] can be obtained, for example, as shown below in the scheme:

where R ⁵³ represents an alkyl group, X ³ represents a halogen atom, and ring A has the above meanings.

That is, the pyridine compound [XX] and the compound [XXI] are condensed, and the obtained compound [XXII] is reduced to give the compound [II-b].

Further, among the starting materials of the present invention, the compound of formula [II-c]:

where the symbols have the above meanings, you can get the following method.

where the symbols have the above meanings.

That is, the compound [XII] is reduced to obtain the compound [XXIII] and the protective group is removed from the amino group of the obtained compound [XXIII] to give the compound [II-c].

Although there are optical isomers of compound [II-c], in a manner analogous to the above method for resolving into optical isomers for compound [XIV], it can be obtained by resolving the racemic mixture into optical isomers.

Further, in the preparation of a compound or starting materials of the present invention, if the starting materials or intermediates contain a functional group, suitable protective groups can be introduced for each of the functional groups in a conventional manner, in addition to the above method, and if their presence is optional, these protective groups can be deleted.

As used herein, the term “alkyl group” means, for example, a branched or unbranched alkyl group containing 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a tert-butyl group, an isopentyl group, and t .d., preferably a group containing 1-4 carbon atoms. The term alkenyl group means, for example, a branched or unbranched alkenyl group containing 2-7 carbon atoms, such as a vinyl group, an aryl group, a propenyl group, an isopropenyl group, etc., preferably a group containing 1-4 carbon atoms. The term alkoxy group means a branched or unbranched alkoxy group containing 1-6 carbon atoms, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, etc., preferably a group containing 1-4 carbon atoms. The term alkanoyl group means a branched or unbranched alkanoyl group containing from 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, tert-butylcarbonyl group, etc., preferably a group containing 1 -4 carbon atoms. The term lower cyclic alkyl group means a cycloalkyl group containing 3-8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc., with those groups containing 3- 6 carbon atoms. Further, halogen atoms are represented by a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.

EXAMPLES

The present invention will now be described in more detail with reference to examples and comparative examples, but the present invention is not limited to these examples.

Example 1

(1) 1.43 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine is dissolved in 30 ml of methanol, and 114 mg sodium borohydride. The mixture was stirred at room temperature for 3 hours. An aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and after stirring the mixture, the layers were separated. The organic layer was washed with water and brine, dried, and then the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: acetone = 4: 1) to obtain 0.99 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2 -methylphenyl) -4-hydroxypiperidine as shown in table 1 below.

(2) 200 mg of the above compound (1) is then purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 18 mg (a) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N -methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 125 mg (b) cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 1 below.

Example 2

200 mg of (2R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) is dissolved in 10 ml of tetrahydrofuran) -4-oxopiperidine, 60 mg of sodium borohydride are added and the mixture is refluxed. While continuously boiling the mixture under reflux, a mixed solvent of 1 ml of methanol and 5 ml of tetrahydrofuran was added dropwise to the mixture. After 5 hours, the reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried, and then the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to obtain 33 mg (a) (2R, 4R) -1- [N- {1- (S) - (3,5 -bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 160 mg (b) (2R, 4S) -1- [N- (1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 2 below.

Example 3

Use (2R) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and work up as described in Example 2 to obtain (a) (2R, 4R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and (b) (2R, 4S) - 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 2 below.

Example 4

150 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 5 ml of dimethylformamide and 40 mg of sodium hydride (60%) are added. ) at 0 ° C. 0.2 ml of methyl iodide was added to the solution at 0 ° C, and the mixture was stirred at room temperature for 16 hours. Then water and ethyl acetate are added to the solution, the mixture is stirred and the layers are separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 72 mg of (a) cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4-methoxypiperidine and 36 mg (b) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4-methoxypiperidine, as shown below in table 3.

Example 5

Use 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 2-picolyl chloride hydrochloride and work up as described in Example 4 above to give 1 - {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyridylmethoxy) piperidine, as shown in table 4 below.

Example 6

In 2 ml of a toluene solution containing 98 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, add 57.6 mg of hydrochloride dimethylaminoethyl chloride, 12.5 mg of tetrabutylammonium bromide and 1 ml of a 10M aqueous solution of sodium hydroxide at room temperature. After the mixture was stirred at room temperature for 2 hours, stirring was further carried out at 60 ° C. for 16 hours. After completion of the reaction, ethyl acetate and an aqueous sodium bicarbonate solution were added to the reaction mixture, and the layers were separated. The organic layer was washed further with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1). The resulting oily substance was treated with a 4M solution of hydrochloric acid in ethyl acetate. The resulting precipitates were collected by filtration and dried, yielding 53 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (1-dimethylaminoethoxy) -2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as presented below in table 4.

Example 7

The hydrochloride of 1- (2-chloroethyl) piperidine and 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine is treated according to the method of example 6, obtaining 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-piperidylethoxy) piperidine hydrochloride, as shown in Table 4 below.

Example 8

100 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine is dissolved in 3 ml of dichloromethane, 0.03 ml of piperidine and 0.018 are added ml of acetic acid and the mixture is stirred. 129.7 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried and the solvent was removed using distillation under reduced pressure. The residue was then purified using a NH-silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4-piperidinopiperidine and cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine. Each of the compounds obtained is dissolved in 1 ml of chloroform, respectively, and 0.2 ml of a 4M solution of hydrochloric acid in ethyl acetate is added. After stirring briefly, the mixture was concentrated under reduced pressure to obtain 58 mg of (a) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 hydrochloride of piperidinopiperidine and 16 mg of (b) cis-1- {N- (3,5-bis-trifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine hydrochloride, as presented below in table 5.

Examples 9 to 44

Use the appropriate starting materials, which are processed according to the method of example 8, to obtain the compounds shown below in tables 6 to 18.

Example 45

2.45 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and 3.85 g of acetate are dissolved in 20 ml of acetic acid ammonium and add 5 g of sodium sulfate. The mixture was stirred at room temperature for one hour. Then, 1.18 g of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, a 2M aqueous sodium bicarbonate solution, chloroform and water are added. The mixture was stirred for 0.5 hour and the layers were separated. The aqueous layer was extracted again with chloroform, the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 10: 1). The resulting oily substance was treated with a solution of a 4M solution of hydrochloric acid in ethyl acetate and concentrated under reduced pressure. Then, the concentrate was thoroughly triturated with isopropyl ether to obtain 1.16 g of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride, as presented below in table 19.

Example 46

Use (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, which is treated according to the method of example 45 to obtain the hydrochloride ( 2R) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 19 below.

Example 47

In 20 ml of a dichloromethane solution containing 1.06 g of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, add 0, 42 ml of triethylamine and 660 mg of dibutyloxycarbonate and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 130 mg of (a) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 120 mg (b) cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, as shown in table 20 below.

Example 48

100 mg of trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine is treated with a 4M solution of hydrochloric acid in ethyl acetate. Ether and hexane were added, and the resulting precipitates were collected by filtration, washed with hexane and dried in vacuo to obtain 56 mg of trans-4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) piperidine as shown in table 21 below.

Example 49

Using cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, which is treated according to the method of example 48, obtaining cis hydrochloride -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 21 below.

Example 50

60 mg of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 1.2 ml of dichloromethane, 0.02 ml is added triethylamine and 0.013 ml of propionyl chloride under ice cooling, and the mixture was stirred under ice cooling for 20 minutes. The reaction mixture was poured into saturated saline and the layers were separated. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried and the solvent was removed using distillation. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 9: 1) to obtain 40 mg of (a) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4- fluoro-2-methylphenyl) -4-propionylaminopiperidine and 27 mg (b) cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 β-propionylaminopiperidine, as shown below in table 22.

Examples 51 to 69

The corresponding starting materials were used, which were processed according to the method of Example 50 to give the compounds shown in Tables 23 to 33 below.

Example 70

0.056 ml of triethylamine are successively added to 4 ml of a dichloromethane solution containing 98 mg of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 0.028 ml of acetyl chloride at 0 ° C and the mixture was stirred at 5 ° C for 0.5 hour. After completion of the reaction, an aqueous solution of sodium bicarbonate and chloroform are added, the mixture is stirred and the layers are separated. The aqueous layer was again extracted with chloroform, the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 4: 1) and dried in vacuo to give 86 mg of 4-acetylamino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2 - (4-fluoro-2-methylphenyl) piperidine in powder form, as shown below in table 34.

Example 71

4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and nicotine chloride hydrochloride are used, which are treated according to the method of Example 70 to obtain 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-pyridylcarbonylamino) piperidine, as shown in table 34 below.

Example 72

To 3 ml of a dimethylformamide solution containing 124 mg of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, 44 mg of N- tert-butoxycarbonylglycine, 58 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 13.5 mg of 1-hydroxy-1H-benzotriazole and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, an aqueous solution of sodium bicarbonate and chloroform are added, the mixture is stirred and the layers are separated. The aqueous layer was again extracted with chloroform, the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) and treated with a 4M solution of hydrochloric acid in ethyl acetate. The mixture was concentrated under reduced pressure. The precipitates formed are washed with isopropyl ether, collected by filtration and dried in vacuo to obtain 83 mg of 4-aminoacetylamino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl hydrochloride ) piperidine, as shown below in table 35.

Example 73

Use 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and N, N-dimethylglycine, which are processed according to the method of example 72, obtaining 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-dimethylaminoacetylamino-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride, as shown in table 35 below.

Example 74

To 25 ml of an ethanol solution containing 320 mg of cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-nitrobenzoyl) aminopiperidine add 480 mg of tin dichloride and the mixture is refluxed for 4 hours. After completion of the reaction, ethanol was removed using distillation under reduced pressure. Diethyl ether and a 2M aqueous sodium hydroxide solution were added and the layers were separated. The organic layer was washed again with a 2M aqueous sodium hydroxide solution and then washed with water. This organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1), and the resulting oily substance was treated with a 4M solution of hydrochloric acid in ethyl acetate. The reaction mixture was concentrated under reduced pressure and triturated with isopropyl ether to obtain 152 mg of cis-4- (4-aminobenzoyl) amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine, as shown below in table 36.

Example 75

To 60 ml of a tetrahydrofuran solution containing 3.91 g of N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine, 2.34 g of 1,1'-carbonyldiimidazole was added and the mixture was stirred at 40 ° C during the night. After the solvent was removed using distillation, ethyl acetate was added. All organic layers were washed with water and brine and dried. White crystals obtained by removing the solvent by distillation under reduced pressure were collected using diisopropyl ether. The resulting white crystals were dissolved in 60 ml of acetonitrile and 3.5 ml of methyl iodide was added. After the reaction proceeds at 60 ° C. for 2 hours, the solvent is removed using distillation under reduced pressure. 224 mg of the residue was dissolved in 2 ml of dichloromethane, 100 mg of cis-2- (4-fluoro-2-methylphenyl) -4- (propanoylamino) piperidine and 0.11 ml of triethylamine were added under ice cooling, and the mixture was stirred at room temperature overnight . The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with water and brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 3) to obtain 83.5 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine, as shown in table 37 below.

Examples 76 to 84

Use the appropriate starting materials, which are processed according to the method of example 75, obtaining the compounds shown below in tables 37 to 39.

Example 85

To 1 ml of an ethyl acetate solution containing 212 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, add 2 ml of a 4M solution of hydrochloric acid in ethyl acetate under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes. After the solvent was removed using distillation under reduced pressure, chloroform and a 2M aqueous sodium hydroxide solution were added to the residue. The layers were separated, the aqueous layer was extracted with chloroform, the combined organic layers were dried and the solvent was removed using distillation under reduced pressure to obtain 177 mg (2R, 4S) -4-amino-1- [N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 40 below.

Example 86

Use (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert -butoxycarbonylaminopiperidine, which is treated according to the method of example 85, obtaining (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2 - (4-fluoro-2-methylphenyl) piperidine, as shown below in table 40.

Example 87

To 2 ml of a dichloromethane solution containing 253 mg of (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine and 0.139 ml of triethylamine, add 0.071 ml of methanesulfonyl chloride under ice-cooling and the mixture is stirred for one hour. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with chloroform, the combined organic layers were washed, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 243 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-4-methanesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 41 below.

Example 88

Use (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and ethanesulfonyl chloride, which are treated according to the method of example 87, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethanesulfonylamino 2- (4-fluoro-2-methylphenyl) piperidine as shown in table 41 below.

Example 89

To 1 ml of a dimethylformamide solution containing 58.4 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-methanesulfonylamino-2 - (4-fluoro-2-methylphenyl) piperidine, 4.6 mg of sodium hydride are added under ice-cooling. The mixture was stirred for 30 minutes, 0.010 ml of methyl iodide was added, and then the mixture was stirred for one hour. The reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, and the solvent was removed using distillation under reduced pressure. The residue was then purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 36.7 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl } -N-methyl] aminocarbonyl-4- (N-methanesulfonyl-N-methyl) amino-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 41 below.

Example 90

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethanesulfonylaminopiperidine which is treated according to the method of example 89, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4- (N-methyl N-ethanesulfonyl) aminopiperidine, as shown below in table 41.

Example 91

To 20 ml of a toluene solution containing 985 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 129 mg of tetrabutylammonium bromide and 10 ml of a 10M aqueous sodium hydroxide solution are added at room temperature 1.21 ml of 2- (2-bromoethoxy) tetrahydropyran, the temperature of the mixture is raised to 60 ° C-70 ° C and the mixture is stirred overnight. 2.42 ml of 2- (2-bromoethoxy) tetrahydropyran is then added and the mixture is stirred overnight. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 3: 2) to obtain 1.12 g (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (tetrahydropyran-2-yloxy) ethoxy} piperidine, as shown in table 42 below.

Example 92

To 30 ml of a methanol solution containing 1.04 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (tetrahydropyran-2-yloxy) ethoxy} piperidine, add 64 mg of p-toluenesulfonic acid monohydrate and the mixture is stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, then the residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 1: 1) to obtain 703 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine, as shown in table 42 below.

Example 93

To 2 ml of a tetrahydrofuran solution containing 53.6 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine, 13.8 mg of 4H- [1,2,4] triazole and 24.4 mg of triphenylphosphine, add 0,092 ml of a 40% solution of diethyl azodicarboxylate in toluene under ice cooling. The temperature of the mixture was raised to room temperature and the mixture was stirred overnight. Then the temperature was raised to 50 ° C, 24.4 mg of triphenylphosphine was added and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with brine, dried and the solvent was removed using distillation. The residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 1: 1 and chloroform: methanol = 19: 1) to obtain 43.2 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) - N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (1,2,4) triazolylethoxy} piperidine, as shown in table 42 below.

Examples 94 and 95

The corresponding starting materials are processed according to the method of example 93, obtaining the compounds shown below in table 42.

Example 96

To 2 ml of a dichloromethane solution containing 215 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2 -hydroxyethoxy) piperidine and 0.084 ml of triethylamine, add 0.037 ml of methanesulfonyl chloride under ice-cooling, and the mixture is stirred for 30 minutes. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with brine, dried, and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 2: 1) to obtain 189 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine, as shown in table 42 below.

Example 97

(1) To 1 ml of a dichloromethane solution containing 61.5 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine and 0.028 ml of triethylamine, add 0.013 ml of morpholine under ice cooling and the mixture is refluxed under heating overnight. Next, add 1 ml of morpholine and the mixture is stirred for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried, and the solvent was removed using distillation. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) and NH-silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 36.3 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethoxy) piperidine.

(2) In 1.0 ml of chloroform, 30.7 mg of the above compound (1) is dissolved and 0.02 ml of a 4M solution of hydrochloric acid in ethyl acetate is added. The mixture was stirred for some time and concentrated under reduced pressure to obtain 35.3 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4- (2-morpholinoethoxy) piperidine, as shown below in table 42.

Example 98

Use (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine and diethylamine, which treated according to the method of Example 97 (1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (2-diethylaminoethoxy) -2- (4-fluoro- 2-methylphenyl) piperidine as shown in table 42.

Example 99

200 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine is dissolved in 2 ml of dichloromethane, then add 0.1 ml of ethyl isocyanate and 0.1 ml of triethylamine, and the mixture was stirred under heating at 60 ° C. for 3 days. The reaction mixture was cooled to room temperature, water and chloroform were added, and the layers were separated. The aqueous layer was again extracted with chloroform and the combined organic layers were dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 78 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) - N-methyl} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 42 below.

Example 100

200 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 2 ml of dichloromethane, then successively 0.1 ml of morpholine-4-carboxylic acid chloride and 0.1 ml of triethylamine are added and the mixture is stirred under heating at 60 ° C. for 3 days. Then the reaction mixture was cooled to room temperature, water and chloroform were added, and the layers were separated. The aqueous layer was again extracted with chloroform and the combined organic layers were dried over sodium sulfate. Then, the solvent was removed using distillation under reduced pressure, the residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 68 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) - N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonyloxypiperidine, as shown in Table 42 below.

Example 101

248 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine is dissolved in 5 ml of tetrahydrofuran, then add 81 mg of 1,1'-carbonyldiimidazole and the mixture was stirred under heating at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water and chloroform were added, and the layers were separated. The aqueous layer was again extracted with chloroform, and then the combined organic layers were washed with water. The organic layer was dried over sodium sulfate and the solvent was removed using distillation under reduced pressure. The resulting concentrated residue was purified using an NH silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 135 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4- (1-imidazolyl) carbonyloxypiperidine, as shown in table 42 below.

Example 102

(1) In 3 ml of acetonitrile, 298 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ( 1-imidazolyl) carbonyloxypiperidine, then 0.06 ml of methyl iodide was added and the mixture was stirred under heating for one hour. The solution was cooled to room temperature and the solvent was removed using distillation under reduced pressure. To the residue were added 2.5 ml of methylene chloride, 0.11 ml of 4-methylpiperazine and 0.14 ml of triethylamine, and the mixture was stirred at room temperature for 16 hours. An aqueous solution of sodium bicarbonate and chloroform were added to the reaction mixture, and the mixture was stirred for 30 minutes. The layers are separated, the resulting organic layer is washed further with water and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified using an NH silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-methylpiperazino) carbonyloxypiperidine.

(2) The above compound (1) is treated with a 4M solution of hydrochloric acid in ethyl acetate to obtain 78 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (4) hydrochloride -methylpiperazino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 43 below.

Examples 103 to 105

Use the appropriate starting materials, which are processed according to the method of examples 102 (1) and (2), obtaining the compounds shown below in table 43.

Example 106

(1) 5 g of cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 10.5, are dissolved in 100 ml of tetrahydrofuran, g of triphenylphosphine and 4.88 g of benzoic acid, then 18.3 ml of a 40% toluene solution of diethyl azodicarboxylate are successively added under ice-cooling, and the mixture is stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred for 30 minutes. The solution was stratified, the resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 4.36 g of trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-benzoyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 1.4 g of the compound (1) obtained above are dissolved in 10 ml of methanol, then 325 mg of potassium carbonate is added and the mixture is stirred at room temperature for 16 hours. After the solution was concentrated under reduced pressure to remove the solvent, water and ethyl acetate were added and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 0.68 g of trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro) -2-methylphenyl) -4-hydroxypiperidine, as shown below in table 44.

Example 107

To 10 ml of tetrahydrofuran, 98 mg of trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 70 mg [1,2] , 4] triazole and 262 mg of triphenylphosphine, then 0.48 ml of a 40% toluene solution of diethyl azodicarboxylate is added and the mixture is stirred at reflux for 16 hours. After completion of the reaction, an aqueous solution of sodium bicarbonate and ethyl acetate are added and the mixture is stirred for 30 minutes. The reaction layer was separated, the resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 46 mg of cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2 -methylphenyl) -4- (1,2,4-triazolyl) piperidine, as shown below in table 44.

Example 108

Cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 4,6-dihydroxy-2-mercaptopyrimidine are used, which are treated according to the method of example 107, obtaining the compound as shown below in table 45.

Example 109

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine which is treated according to the method of Example 106 (1) and (2) to obtain (2R, 4R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown below in table 46 .

Examples 110 to 112

Use the appropriate starting materials, which are processed according to the method of example 107, obtaining the compounds shown below in table 46.

Example 113

(1) 30 ml of a tetrahydrofuran solution containing 1.2 ml of triethylphosphonoacetate are ice-cooled and sodium hydride is slowly added. Maintaining the same temperature, the mixture was stirred for 30 minutes and 30 ml of a tetrahydrofuran solution containing 3.02 g of (2R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} was added dropwise. -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine. The mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain (2R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl -4-ethoxycarbonylmethylidene-2- (4-fluoro-2-methylphenyl) piperidine as a colorless liquid.

(2) The compound (1) obtained above is dissolved in 50 ml of methanol, 500 mg of palladium-on-charcoal is added, and the mixture is stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was removed and methanol was removed using distillation under reduced pressure; the residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 3.23 g of 2R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N- methyl] aminocarbonyl-4-ethoxycarbonylmethyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 46 below.

Example 114

(1) 3.23 g of (2R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethyl-2- is dissolved in 20 ml of methanol (4-fluoro-2-methylphenyl) piperidine and 5.73 ml of a 2M aqueous sodium hydroxide solution are added. The mixture was stirred at room temperature overnight. After the mixture was neutralized with 2M hydrochloric acid, methanol was removed by distillation under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was removed using distillation under reduced pressure to obtain 2.97 g of (2R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxymethyl-2- (4-fluoro-2-methylphenyl) piperidine as a yellow powder.

(2) 200 mg of the above compound (1) is dissolved in 2 ml of dimethylformamide, 84 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 65 mg of 1-hydroxy-1H-benzotriazole and 0.037 ml of morpholine are added and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried, the solvent was removed by distillation to obtain a residue, which was purified using an NH silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 138 mg (2R) -1- [N- {1- ( R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylmethylpiperidine, as shown in table 46 below.

Examples 115 to 117

Use the appropriate starting materials, which are processed according to the method of example 114 (2), obtaining the compounds shown below in table 46.

Example 118

(1) 1.49 g of (2R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro) is dissolved in 10 ml of ethanol -2-methylphenyl) -4-oxopiperidine and 226 mg of hydroxylamine hydrochloride and 267 mg of sodium acetate are added. The mixture was stirred overnight. Ethanol was removed using distillation under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine and dried. The solvent was removed using distillation under reduced pressure to give the compound as a gum.

(2) The compound (1) obtained above is dissolved in 50 ml of methanol and 844 mg of nickel chloride are added. The mixture was cooled on ice and 224 mg of sodium borohydride was slowly added. After stirring the mixture overnight, it was concentrated under reduced pressure, water and ethyl acetate were added, and the layers were separated. The organic layer was washed with brine and dried. The solvent was removed by distillation under reduced pressure to obtain 1.44 g of (2R) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl- 2- (4-fluoro-2-methylphenyl) piperidine, as shown below in table 47.

Example 119

Use (2R) -1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, which is treated according to the method of Example 119 (1) and (2) to obtain (2R) -4-amino-1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as follows in table 47.

Example 120

Use (2R) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, which is treated according to the method of example 50, obtaining (a) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) -4- (2-pyrazinylcarbonylamino) piperidine and (b) (2R, 4R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyrazinylcarbonylamino) piperidine, as shown in table 47 below.

Example 121

In 2 ml of an acetonitrile solution containing 80 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4-morpholinopiperidine, add 0.034 ml of methyl iodide and the mixture was stirred at 60 ° C overnight. The solvent was removed by distillation, and the yellow powder precipitated was dried, yielding 98 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-4-morpholinio) piperidinium iodide, as shown in table 48 below.

Example 122

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine which is treated according to the method of example 121, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4- (N-methyl-4-morpholino) piperidinium iodide, as shown in table 48 below.

Example 123

In 2 ml of a dichloromethane solution containing 80 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4-morpholinopiperidine, 34 mg of 3-chloroperbenzoic acid are added and the mixture is stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried, and the solvent was removed using distillation under reduced pressure. The white powder precipitated was dried, yielding 79 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine, as shown in table 48 below.

Example 124

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine which is treated according to the method of example 123, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4- (N-oxomorpholino) piperidine, as shown below in table 48.

Examples 125 to 127

Use the appropriate starting materials, which are processed according to the method of example 8, to obtain the compounds shown below in table 49.

Examples 128 to 136

Use the appropriate starting materials, which are processed according to the method of example 50, obtaining the compounds shown below in tables 49-51.

Example 137

263 mg of (2R) -4-amino-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 2 ml of dichloromethane at room temperature 52 μl of 2-chloroethylisocyanate and 167 μl of triethylamine are added and the mixture is stirred for 2 hours. A saturated sodium bicarbonate solution was added to the solution, the dichloromethane layer was isolated and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 109 mg of (2R) -4- (2-chloroethyl) ureido-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 51.

Example 138

2.65 g of (2R) -4-amino-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride are dissolved in 20 ml of dimethylformamide and 1 g of 5-formylfuran-2-carboxylic acid and 1.92 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.6 g of 1-hydroxy-1H-benzotriazole and 1.4 ml of triethylamine are added. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, an aqueous solution of citric acid and ethyl acetate are added and the layers are separated. The organic layer was further washed with brine, and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using an NH silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 289 mg of (a) (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl -4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine and 185 mg (b) (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 52 below.

Examples 140 to 168

Use the appropriate starting materials, which are processed according to the method of example 138, to obtain the compounds as shown in tables 53-57 below.

Example 169

In 1 ml of tetrahydrofuran, 80 mg of (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine, 25.7 mg of 1,1-carbonyldiimidazole is added under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes. To a solution of 19 μl of 2-aminoethanol under ice-cooling, 44 μl of triethylamine was added and the mixture was stirred at room temperature for 22 hours. The solvent was removed by distillation, water and dichloromethane were added to the residue, and the layers were separated. The organic layer was washed with brine, dried and concentrated. Isopropyl ether was added to the residue, and white crystals precipitated were collected by filtration to obtain 74 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) ureidopiperidine, as shown below in table 57.

Examples 170 to 173

Use the appropriate starting materials, which are processed according to the method of example 169, obtaining the compounds shown as shown below in table 57.

Examples 174 to 177

Use the appropriate starting materials, which are processed according to the method of example 87, obtaining the compounds shown as shown below in table 58.

Example 178

In 10 ml of dichloromethane, 1.01 g of (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine and 0.558 ml of triethylamine, while cooling with ice, 0.314 ml of 2-chloroethanesulfonyl chloride is added and the mixture is stirred for 4 hours. The solution was poured into water, the layers were separated, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 725 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-4-ethylenesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 58 below.

Example 179

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine , which is treated according to the method of example 178, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (1-ethylene sulfonyl- 1-methylamino) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 58.

Examples 180-181

Use the appropriate starting materials, which are processed according to the method of example 87, obtaining the compounds shown below in table 59.

Examples 183-184

Use the appropriate starting materials, which are processed according to the method of example 89, obtaining the compounds shown below in table 59.

Example 185

Use (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 2-methoxyethyl chloride, which are treated according to the method of example 91, obtaining (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) -4- (2-methoxyethoxy) piperidine as shown in table 59 below.

Examples 186 to 189

Use the appropriate starting materials, which are processed according to the method of examples 91 and 92, obtaining the compounds shown below in tables 59 and 60.

Example 190

Use (2R, 4S) -1- {N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ( 2-hydroxyethoxy) piperidine and methanesulfonyl chloride, which are processed according to the method of example 96, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl -2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine, as shown below in table 60.

Examples 191 to 196

Use the appropriate starting materials, which are processed according to the method of example 97, obtaining the compounds shown below in tables 60 and 61.

Examples 197-198

Use the appropriate starting materials, which are processed according to the method of example 101, obtaining the compounds shown below in table 62.

Examples 199 to 205

Use the appropriate starting materials, which are processed according to the method of examples 102 (1) or 102 (1) and (2), obtaining the compounds shown below in table 63.

Example 206

Use (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine, which is treated according to the method of example 123, obtaining (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxopiperidino) piperidine, as described below in table 65.

Example 207

124 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4- fluoro-2-methylphenyl) piperidine, 3.8 mg of sodium borohydride are added and the mixture is stirred at room temperature for 2 hours. An aqueous sodium bicarbonate solution was added to the solution, the mixture was stirred for 10 minutes and concentrated, then ethanol was removed using distillation. Ethyl acetate and water were added to the residue, and the layers were separated. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 68 mg (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4- (5-hydroxymethylfuran-2-yl) carbamoylpiperidine, as shown in table 65 below.

Example 208

124 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-) is dissolved in 4 ml of dichloroethane. fluoro-2-methylphenyl) piperidine, 44 μl of morpholine and 2.9 μl of acetic acid, 106 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium carbonate and chloroform were added to the solution, the resulting mixture was stirred for 10 minutes and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using an NH silica gel chromatography column (n-hexane: ethyl acetate = 1: 1). The resulting oily substance was treated with a 4M solution of hydrochloric acid in ethyl acetate to obtain 78 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl hydrochloride ) -4- (5-morpholinomethylfuran-2-yl) carbamoylpiperidine, as shown below in table 65.

Example 209

In a mixture of 3.3 ml of toluene and 0.4 ml of dichloromethane, 197 mg (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2- methylphenyl) -4-hydroxypiperidine and 78 mg of 1,1'-carbonyldiimidazole are added. The mixture was stirred at 60 ° C for 4 hours. Distilled water was added, the mixture was extracted with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 3.7 ml of acetonitrile, 100 μl of methyl iodide was added and the mixture was stirred at 50 ° C for 3 hours. The solution was concentrated under reduced pressure, 3.6 ml of toluene and 156 μl of thiomorpholine were added to the residue, and the mixture was stirred at 70 ° C. for 16 hours. Distilled water was added, the mixture was extracted with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1 to 1: 2) to give 197 mg (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4-thiomorpholino-carbonyloxy piperidine, as shown below in table 65.

Examples 210 to 212

Use the appropriate starting materials, which are processed according to the method of example 209, obtaining the compounds shown below in table 65.

Example 213

62 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine are dissolved in 1.9 ml of dichloromethane under ice cooling, 22 mg of 3-chloroperbenzoic acid was added and the mixture was stirred at 0 ° C for 30 minutes. The solution was extracted by adding 0.1 M aqueous sodium hydroxide and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: acetone = 4: 1) to obtain 63 mg (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4- (1-oxothiomorpholino) carbonyloxypiperidine, as shown below in table 65.

Example 214

79 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine is dissolved in 2.4 ml of dichloromethane 68 mg of 3-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 4 hours. The solution was extracted by adding 0.1 M aqueous sodium hydroxide solution and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: acetone = 4: 1) to obtain 76 mg (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (1 , 1-dioxothiomorpholino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 65 below.

Example 215

78 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-) is dissolved in 1 ml of tetrahydrofuran methylphenyl) -4- (2,2,5-trimethyl [1,3] dioxolan-5-yl) carbamoylpiperidine and 0.5 ml of a 2M aqueous hydrochloric acid solution are added under ice-cooling. After 15 minutes, the temperature was raised to room temperature and the mixture was further stirred for 30 minutes. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 2: 1) to obtain 64 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1,1-di (hydroxymethyl) ethyl} carbamoylpiperidine, as shown in table 66 below.

Example 216

In 1 ml of dichloromethane, 50.5 mg of (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine and 25.2 mg of methyl isocyanate are added under ice-cooling. After the temperature of the mixture was raised to room temperature, the mixture was stirred for 30 minutes. The solution was poured into water, the dichloromethane layer was isolated and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 47.9 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylureidopiperidine, as shown in table 66 below.

Example 217

Use (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and tert-butyl isocyanate, which are treated according to the method of example 216, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- tert-butylureido-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 66.

Example 218

In 1 ml of dichloromethane, 50.5 mg of (2R, 4S) -4-amino-1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine and 42 μl of triethylamine and 18 μl of dimethylcarbamoyl chloride are added under ice cooling. After the temperature of the mixture was raised to room temperature, the mixture was stirred overnight. The solvent was poured into water, the dichloromethane layer was isolated and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 39: 1) to obtain 41.8 mg (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (3,3-dimethylureido) -2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 66 below.

Examples 219 to 224

Use the appropriate starting materials, which are processed according to the method of example 216, obtaining the compounds shown below in table 67.

Example 225

(1) Using 80 mg of (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro) -2-methylphenyl) piperidine, which is treated according to the method of example 216, obtaining (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2 - (4-fluoro-2-methylphenyl) -4- (4-methylpiperazinocarbamoyl) piperidine.

(2) The compound (1) obtained above is dissolved in 1 ml of ethyl acetate, 0.5 ml of a 4M solution of hydrochloric acid in ethyl acetate is added under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling. The solvent was removed using distillation under reduced pressure, and diethyl ether was added. The white crystals precipitated were collected by filtration to obtain 80 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) -4- (4-methylpiperazinocarbamoyl) piperidine as shown in table 67 below.

Example 226

In 2 ml of dichloromethane, 100 mg of (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine, 33 μl of triethylamine and 19 μl of methyl chloroformate are added under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes. The solution was poured into water and the dichloromethane layer was isolated and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 80 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxycarbamoylpiperidine, as shown in table 66 below.

Examples 227 to 229

Use the appropriate starting materials, which are processed according to the method of example 226, obtaining the compounds shown below in table 68.

Example 230

22 mg of 2-ethoxyethanol are dissolved in 1.2 ml of acetonitrile, and 94 mg of N, N'-disuccinimidyl carbonate and 0.1 ml of triethylamine are added to this, and the mixture is stirred at room temperature for 1.5 hours. The solvent was removed by distillation, saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, and extracted. The organic layer was washed with brine, dried and concentrated. The residue was dissolved in 0.8 ml of dichloromethane, 80 mg of (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl- 2- (4-fluoro-2-methylphenyl) piperidine and 33 μl of triethylamine and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the solution and extracted. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 19: 1) to obtain 85 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-4- (2-ethoxyethoxy) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 68 below.

Example 231

3-Hydroxy-3-methylbutanol and (2R, 4S) -4-amino-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 4-fluoro-2-methylphenyl) piperidine, which is processed according to the method of example 230, obtaining (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxy-3-methylbutoxy) carbamoylpiperidine, as shown in table 68 below.

Example 232

(1) 119 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro) is dissolved in 1 ml of tetrahydrofuran -2-methylphenyl) -4-vinylsulfonylaminopineridine. 26 μl of morpholine is added at room temperature and the mixture is refluxed with heating. After 5 hours, 26 μl of morpholine was added and the mixture was further refluxed under heating for 2.5 hours. The solution was concentrated and the residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 129 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl } -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethyl) sulfonylaminopiperidine.

(2) 34.1 mg of the above compound (1) is dissolved in 1 ml of chloroform, and 25 μl of a 4M solution of hydrochloric acid in ethyl acetate is added. The mixture was concentrated to give 33.1 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4- (2-morpholinoethyl) sulfonylaminopiperidine, as shown in table 69 below.

Examples 233 to 238

Use the appropriate starting materials, which are processed according to the method of example 232 (1) and (2), obtaining the compounds shown below in table 69.

Example 239

101 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl- are dissolved in a mixture of 1.6 ml of dimethylformamide and 0.2 ml of dichloromethane. 2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, add 39 mg of (S) - (-) - 2-pyrrolidone-5-carboxylic acid, 58 mg of 1-ethyl-3- (3-dimethylaminopropyl) hydrochloride carbodiimide and 12 mg of 4- (dimethylamino) pyridine and the mixture was stirred at room temperature for 6 hours, after which stirring was continued at 60 ° C. for 4 days. A 5% aqueous citric acid solution was added to the solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was purified using a silica gel chromatography column (chloroform: acetone = 4: 1 to 2: 1) to obtain 64 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4 - ((2S) -5-oxopyrrolidin-2-yl} carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 70 below.

Example 240

(1) 179 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl are dissolved in a mixture of 3.2 ml of toluene and 0.4 ml of dichloromethane ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 69 mg of 1,1'-carbonyldiimidazole are added and the mixture is stirred at 60 ° C. for 3 hours. Distilled water was added and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 3.2 ml of acetonitrile, 88 μl of methyl iodide was added and the mixture was stirred at 50 ° C. for 3 hours. After the solution is concentrated, 3.2 ml of toluene and 114 μl of triazolidine are added and the mixture is stirred at 70 ° C. for 16 hours. Distilled water was added and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1 to 1: 2) to obtain 141 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1,3-tetrahydrothiazol-3-yl) carbonyloxypiperidine.

(2) 62 mg of the above compound (1) were dissolved in 2 ml of dichloroethane, 22 mg of 3-chloroperbenzoic acid was added under ice cooling, and the mixture was stirred at 0 ° C for one hour. A saturated aqueous sodium bicarbonate solution was added to the mixture and extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using thin-layer chromatography on silica gel (chloroform: acetone = 4: 1) to obtain 42 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxo-1,3-tetrahydrothiazol-3-yl) carbonyloxypiperidine, as shown in table 70 below.

Example 241

(1) 101 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4) is dissolved in 1.9 ml of toluene -fluoro-2-methylphenyl) -4-hydroxypiperidine, add 46 μl ethyl ester ethyl acetate isocyanate and one drop of acetic acid and the mixture is stirred at 70 ° C. for 16 hours. The solution was concentrated and the residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1 to 1: 1) to obtain 124 mg (2R, 4S) -1- [N- {1- (S) - (3,5 bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 106 mg of the above compound (1) are dissolved in a mixture of 1.35 ml of tetrahydrofuran and 0.15 ml of methanol, 92 μl of a 2M aqueous sodium hydroxide solution are added and the mixture is stirred at room temperature for 1 hour. After the solution was concentrated, a 10% aqueous citric acid solution was added, and the precipitates were collected by filtration and washed with water to obtain 92 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl } -N-methyl] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 70 below.

Example 242

61 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- ( 4-fluoro-2-methylphenyl) piperidine, 9 μl of morpholine, 15 mg of 1-hydroxybenzotriazole monohydrate and 19 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride are added and the mixture is stirred at room temperature for a day. Distilled water was added to the solution, the mixture was extracted with chloroform, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 50 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylmethylaminocarbonyloxypiperidine, as shown in table 70 below.

Example 243

In 1.9 ml of toluene, 101 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro- 2-methylphenyl) -4-hydroxypiperidine, 37 μl of chlorosulfonyl isocyanate are added and the mixture is stirred at room temperature for 10 minutes. 207 μl of diethylamine was added and the mixture was stirred at room temperature for one hour. Distilled water was added to the solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to give 116 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-4-diethylaminosulfonylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 70 below.

Example 244

Use (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and (S) - (-) - 2-pyrrolidone-5-carboxylic acid, which is treated according to the method of example 239, obtaining (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4 - {(2S) -5 -oxopyrrolidin-2-yl} carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 70 below.

Example 245

264 mg of (2R) -4-amino-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, 80 mg, are dissolved in 2 ml of toluene 2-bromopyridine, 12 mg of palladium acetate, 32 mg of 2,2'-bis (diphenylphosphino) -1,1'-bisnaphthyl and 48 mg of sodium tert-butoxide, and the mixture was stirred at 80 ° C. for 16 hours. The solution was cooled to room temperature, ethyl acetate and aqueous sodium bicarbonate were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using an NH silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 68 mg of (a) (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl -2- (4-fluoro-2-methylphenyl) -4- (2-pridylamino) piperidine and 56 mg (b) (2R, 4R) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pridylamino) piperidine as shown in table 71 below.

Examples 246-247

Use the appropriate starting materials, which are processed according to the method of example 245, obtaining the compounds shown below in tables 71 and 72.

Examples 248-249

Use the appropriate starting materials, which are processed according to the method of example 75, obtaining the compounds shown below in table 72.

Example 250

(1) 800 mg of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-ethyl] aminocarbonyl-4-ethoxycarbonyl-2- is dissolved in 5 ml of tetrahydrofuran (4-fluoro-2-methylphenyl) piperidine, add 5 ml of a 2M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 3 days. An aqueous solution of citric acid was added to the reaction mixture to acidify it, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried. The solution was concentrated to give 700 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro -2-methylphenyl) piperidine.

(2) 110 mg of the above compound (1) is dissolved in dimethylformamide, 96 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, 30 mg of 1-hydroxybenzotriazole, 0.1 ml of 40% aqueous ammonium solution are added and the mixture was stirred at room temperature for 3 hours. An aqueous solution of citric acid and ethyl acetate were added to the solution, and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 87 mg (2R, 4S) -4-aminocarbonyl-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 73 below.

Examples 251 to 253

Use the appropriate starting materials, which are processed according to the method of examples 250 (1) and (2) or 250 (2), obtaining the compounds shown below in table 73.

Example 254

(1) 2 g of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro) are dissolved in 40 ml of tetrahydrofuran -2-methylphenyl) -4-hydroxypiperidine, add 1.59 g of carbon tetrabromide and 1.26 g of triphenylphosphine and the resulting mixture was stirred at room temperature for 2 hours. 80 ml of diethyl ether was added to the solution, and after stirring the mixture, insoluble matter precipitated was removed by filtration. The organic layer was concentrated and the residue was purified using a silica gel chromatography column (n-hexane: ethyl acetate = 10: 1) to obtain 1.26 g of (2R, 4R) -1- [N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-bromo-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 1.14 g of the above compound (1) was dissolved in 20 ml of dimethylformamide, 1.14 g of potassium thioacetate was added and the mixture was stirred at 80 ° C for 2 hours. Then the solution was cooled to room temperature, an aqueous solution of citric acid and ethyl acetate were added, and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (n-hexane: ethyl acetate = 6: 1) to obtain 920 mg (2R, 4S) -4-acetylthio-1- [N- {1- (S) - (3,5- bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 74 below.

Examples 255-256

Use the appropriate starting materials, which are processed according to the method of example 254 (1) and (2), obtaining the compounds shown below in table 74.

Example 257

880 mg of (2R, 4S) -4-acetylthio-1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine, methyl iodide and 5 ml of a 1M aqueous solution of sodium hydroxide are added and the mixture is stirred at room temperature for 2 hours. An aqueous citric acid solution was added to the solution until neutralized, and methanol was removed using distillation. Ethyl acetate and brine were added to the residue, and the layers were separated. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (n-hexane: ethyl acetate = 6: 1) to give 560 mg (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylthiopiperidine, as shown in table 74 below.

Examples 258 to 263

Use the appropriate starting materials, which are processed according to the method of example 257, obtaining the compounds shown below in tables 74 and 75.

Examples 264 to 270

Use the appropriate starting materials, which are processed according to the method of example 213, obtaining the compounds shown below in tables 76-77.

Examples 271 to 278

Use the appropriate starting materials, which are processed according to the method of example 214, obtaining the compounds shown below in tables 78 -79.

Examples 279 to 312

Use the appropriate starting materials, which are processed according to the method of example 138, obtaining the compounds shown below in tables 80-87.

Example 313

To 4.2 ml of a 4M solution of hydrochloric acid in ethyl acetate, 361 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4 - [{(2S, 4R) -4 -benzyloxy-1-tert-butyloxycarbonylpyrrolidin-2-ylcarbonyl} amino] -2- (4-fluoro-2-methylphenyl) piperidine and the mixture was stirred for 1 hour at room temperature. After evaporation in vacuo, the residue was triturated with hexane and the solvent was removed by decantation. The residue was dissolved in 4 ml of methylene chloride, and 158 ml of triethylamine and 36 ml of acetyl chloride were added to the mixture under ice-cooling. After stirring for 1 hour while cooling with ice, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified using a silica gel chromatography column (chloroform: methanol = 49: 1 to 19: 1) to obtain 304 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- 4 - {[(2S, 4R) -4-benzyloxy-1-acetylpyrrolidin-2-ylcarbonyl] amino} -2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 86.

Examples 314 to 316

Use the appropriate starting materials, which are processed according to the method of example 313, obtaining the compounds shown below in tables 86 and 87.

Examples 317-318

Use the appropriate starting materials, which are processed according to the method of example 113 (2), obtaining the compounds shown below in table 87.

Example 319

98 mg of (2R, 4S) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 1.8 ml of toluene 24 mg of succinic anhydride and 0.033 ml of triethylamine are added and the mixture is refluxed for 18 hours. The mixture was cooled to room temperature and then water was added. The mixture was extracted with ethyl acetate, the organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 79 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (2 , 5-dioxopyrrolino) -2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 87 below.

Examples 320 to 330

Use the appropriate starting materials, which are processed according to the method of example 209, obtaining the compounds shown below in tables 88-90.

Example 331

The corresponding starting materials were used, which were processed according to the method of Example 113 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4- (ethoxycarbonylmethyl) piperidine as shown in table 91 below.

Example 332

2.03 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethoxycarbonylmethylpiperidine is dissolved in 20 ml of tetrahydrofuran, 450 mg of lithium aluminum hydride are added under ice-cooling, and the mixture is stirred for one hour. 2 ml of water are added slowly and after stirring the mixture for 10 minutes, 5 ml of a 1M aqueous solution of sodium hydroxide is added and the mixture is further stirred for 10 minutes. The white precipitate formed is removed, diethyl ether and water are added to the filtrate, and the layers are separated. The organic layer was washed further with water, dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1 to 3: 2) to give 830 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) piperidine, as shown in table 91 below.

Example 333

The corresponding starting materials were used, which were processed according to the method of Example 245 to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4- (N-pyrazin-2-ylamino) piperidine as shown in table 91 below.

Example 334

In 2 ml of N, N-dimethylformamide, 114 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- is dissolved (N-pyrazin-2-ylamino) piperidine, 10 mg of sodium hydride (40% mixture in oil) is added with ice cooling, after stirring the mixture for 5 minutes, 0.013 ml of methyl iodide is added and the mixture is stirred at room temperature for 2 hours. Water and ethyl acetate were added to the solution, after stirring the mixture for 10 minutes, the layers were separated. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified using an NH silica gel chromatography column (hexane: ethyl acetate = 85: 15 to 1: 1) to give 98 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-pyrazin-2-yl-N-methylamino) piperidine, as shown in table 91 below.

Example 335

8.0 g of (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 40 ml of dichloromethane, 10 are added ml of an ethanol solution of methylamine (35%, about 8M), 2 ml of acetic acid and 4.24 g of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 16 hours. A 2M aqueous solution of sodium carbonate and chloroform were added to the solution, and after stirring the mixture for 30 minutes, the layers were separated. The aqueous layer was further extracted with chloroform, the combined organic layers were dried and concentrated under reduced pressure. The residue was purified using a NH-silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain a mixture of (a) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine and (b) (2R, 4R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro -2-methylphenyl) -4-methylaminopiperidine.

(2) The above mixture (1) was dissolved in 40 ml of dichloromethane, 4.4 g of ditret-butyl dicarbonate were added and the mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure and the residue was purified using a silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 4.2 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (tert-butoxycarbonyl-N-methylamino) piperidine.

(3) The above compound (2) is treated with a 4M solution of hydrochloric acid in ethyl acetate and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of hexane and ethyl acetate to obtain 3.6 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl hydrochloride ) -4-methylaminopiperidine, as shown below in table 91.

Example 336

(1) 2.12 g of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine are used, which are treated according to the method of Example 248 to obtain 3.8 g (2R, 4S ) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

(2) The compound (1) obtained above is treated according to the method of Example 250 (1) to obtain 2.3 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} amino-4- carboxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 91 below.

Examples 337 to 340

Use the appropriate starting materials, which are processed according to the method of example 250 (2), obtaining the compounds shown below in table 91.

Example 341

Use (1) 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting materials, which are processed according to the method of example 248, and purified using a chromatographic column with silica gel (hexane: ethyl acetate = 4: 1), obtaining (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethoxycarbonylpiperidine .

(2) Use the above compound (1), which is processed according to the method of example 250 (1), obtaining (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} - N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 92 below.

Examples 342 to 349

Use (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting materials, which are processed according to the method of example 250 (2), obtaining the compounds shown below in table 92.

Example 350

In 12 ml of tetrahydrofuran, 1.62 g of (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- ( 4-fluoro-2-methylphenyl) piperidine, 2 ml of borane dimethyl sulfide complex (about 10 M) was added dropwise and the resulting mixture was stirred at room temperature for 16 hours. 10 ml of methanol was added to the reaction mixture, and the mixture was stirred for 0.5 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 1.32 g (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine, as shown in table 93 below.

Examples 351 to 352

Use (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine and the corresponding starting materials, which are processed according to the method of example 209, obtaining the compounds shown below in table 93.

Example 353

Use 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting materials, which are processed according to the method of example 341, obtaining (2R, 4S) -1- [N- {1- (R) - (3 , 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 94 below.

Examples 354 to 365

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting materials, which are processed according to the method of example 250 (2), obtaining the compounds shown below in tables 94 and 95.

Example 366

132 mg of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4- fluoro-2-methylphenyl) piperidine, add 0.027 ml of oxalic acid dichloride and one drop of N, N-dimethylformamide, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5 ml of tetrahydrofuran and 0.12 ml of 2-aminopyrazine are added to the residue, and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified using an NH-silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 63 mg (2R, 4S) -1- [N- {1- (R) - (3 , 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyrazylaminocarbonyl) piperidine, as shown in table 96 below.

Example 367

Use (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine, which is treated according to the method of example 350, obtaining (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro -2-methylphenyl) -4-hydroxymethylpiperidine, as shown below in table 96.

Example 368

In a mixture of 20 ml of toluene and 20 ml of acetic anhydride, 1.07 g of the compound of Example 268 is dissolved, 165 mg of sodium acetate is added and the mixture is stirred while continuing to boil under reflux for 16 hours. After the reaction mixture was cooled to room temperature, an aqueous solution of sodium bicarbonate was slowly added until the formation of foam ceased. Water and ethyl acetate were added to the mixture, and the layers were separated. The aqueous layer was further extracted with ethyl acetate, the combined organic layers were dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 980 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4-acetoxymethylthiopiperidine as shown in table 97 below.

Example 369

Use (2R, 4S) -4-acetoxymethylthio-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, which is treated according to the method of example 214, obtaining (2R, 4S) -4-acetoxymethylsulfonyl-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 97 below.

Example 370

200 mg of (2R, 4S) -4-acetoxymethylsulfonyl-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro) are dissolved in 10 ml of tetrahydrofuran and 5 ml of an aqueous solution of sodium hydroxide -2-methylphenyl) piperidine and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 2M hydrochloric acid and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to obtain 80 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4-hydroxysulfinylpiperidine, as shown below in table 97.

Example 371

130 mg of the compound of Example 261 was dissolved in 2.5 ml of acetonitrile, and 0.5 ml of methyl iodide was added thereto, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated and the residue was washed with diethyl ether to give 117 mg (2R, 4S) - [1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine -4-yl] dimethylsulfonium iodide, as shown below in table 97.

Example 372

10.7 g of (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 100 ml of tetrahydrofuran, 20 are added ml of pyridine and 20 ml of acetic anhydride and the mixture was stirred at room temperature for 5 hours. An aqueous solution of sodium bicarbonate and diethyl ether were added to the reaction mixture, and the mixture was stirred for one hour. The layers are separated, then the organic layer is washed twice with water, dried and concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, 1.5 g of sodium borohydride was added under ice-cooling, and the mixture was stirred for 0.5 hour. An aqueous solution of ammonium chloride was added to the reaction mixture, and, after stirring the mixture for 30 minutes, the solvent was removed using distillation under reduced pressure. Water was added to the residue, and the solution was extracted twice with chloroform. The combined organic layers were dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 9.6 g (2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 98 below.

Examples 373 to 376

Use (2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and the corresponding starting materials, which are processed according to the method of example 209, obtaining the compounds as shown below in table 98.

Example 377

600 mg of (2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) is dissolved in 5 ml of methanol ) piperidine, add 5 ml of a 2M aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. A 2M aqueous hydrochloric acid solution was added to the reaction mixture to neutralize, and the mixture was extracted twice with chloroform. The combined organic layers were dried, concentrated under reduced pressure and purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 550 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 99 below.

Examples 378 to 381

Use the appropriate starting materials, which are processed according to the method of example 377, obtaining the compounds shown below in table 99.

Example 382

Use (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-4-thiomorpholinocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, which is treated with the method of example 213, obtaining (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-4- (1-oxo-thiomorpholino) carbonyloxy-2- (4-fluoro- 2-methylphenyl) piperidine as shown in table 99 below.

Example 383

(1) Use (2R, 4S) -1- {N-acetoxypropyl-N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, which is treated according to the method of example 254 (1) and (2), obtaining (2R, 4S) -1- {N-acetoxypropyl-N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-acetylthiopiperidine .

(2) The compound (1) obtained above is used, which is processed according to the method of Example 257 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro -2-methylphenyl) -4- (2-propylthio) piperidine.

(3) The compound (2) obtained above is used, which is processed according to the method of Example 213 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro -2-methylphenyl) -4- (propan-2-sulfinyl) piperidine, as shown in table 99 below.

Example 384

Use (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-propylthio) piperidine, which is treated with the method of example 214, obtaining (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (propane-2-sulfonyl ) piperidine, as shown below in table 99.

Example 385

Using 148 mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and the corresponding starting material, which are treated according to the method of comparative example 6 to obtain 36 mg (2R, 4S) -1- {N- (3,5-dimethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 100 below.

Example 386

The corresponding starting materials were used, which were processed according to the method of Example 385 to obtain (2R, 4S) -1- {N- (3,5-dichlorobenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 100 below.

Example 387

676 mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-acetoxyethylaminocarbonyloxy) piperidine hydrochloride is dissolved in 10 ml of tetrahydrofuran, 0.28 ml of triethylamine is added and the mixture is stirred for 30 minutes. 330 mg of 1,1'-carbonyldiimidazole was added to the reaction mixture, and the mixture was stirred at 65 ° C. for 2 hours. The solvent was removed using distillation under reduced pressure, and the residue was dissolved in 5 ml of dichloromethane. The mixture was washed with water and brine and dried. The mixture was evaporated in vacuo and the residue was dissolved in 5 ml of acetonitrile. 1 ml of methyl iodide was added to the solution, and the mixture was stirred at 60 ° C. for 2 hours. The solvent was removed using distillation under reduced pressure. The residue was dissolved in 20 ml of tetrahydrofuran, 600 mg of N- {1- (3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methylamine and 0.5 ml of triethylamine were added, and the mixture was stirred at 70 ° C. for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the layers were separated. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 780 mg of a mixture of compound (a) (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- [N- {1- (S ) - (3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and compound (b) (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy ) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as described below in table 101.

Example 388

122 mg of the compound of Example 387 are dissolved in 2 ml of methanol, 1 ml of a 2M aqueous sodium hydroxide solution is added and the mixture is stirred at room temperature for 16 hours. The reaction mixture was neutralized with a 6M aqueous hydrochloric acid solution and the solvent was removed using distillation under reduced pressure. Chloroform and water are added to the residue and the layers are separated. The aqueous layer was further extracted with chloroform, the combined organic layers were dried and concentrated under reduced pressure. The residue was dried in vacuo to give 88 mg of a mixture of compounds (a) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methyl] aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) - 2-hydroxyethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 101 below.

Example 389

(1) 4.92 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 is dissolved in 50 ml of dichloromethane β-hydroxypiperidine, 2.43 g of carbodiimidazole is added to the solution at room temperature, and the mixture is stirred for 1.5 hours. Water was added to the reaction mixture, and the layers were separated with dichloromethane. The organic layer was washed with brine, dried and the solvent was removed using distillation under reduced pressure to obtain 5.99 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolylcarbonyloxy) piperidine.

(2) In a toluene solution (12 ml) of N, N-dimethylformamide (5 ml), 1.17 g of the above compound (1) was dissolved, 0.925 ml of ethyl nipecotate was added at room temperature, and the mixture was stirred overnight. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and brine, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified using a silica gel chromatography column (chloroform: methanol = 39: 1) to obtain 1.24 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) ) -N-methyl} aminocarbonyl-4- (4-ethoxycarbonylpiperidinocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 102.

Example 390

1.08 g of the compound of Example 389 is dissolved in 15 ml of ethanol, 4.8 ml of a 1M solution of potassium hydroxide in ethanol is added at room temperature. After the temperature of the mixture was raised to 50 ° C, the mixture was stirred for 3 hours. A 2M aqueous hydrochloric acid solution was added to the reaction mixture, and ethanol was removed using distillation under reduced pressure. Water and chloroform are added and the layers are separated by chloroform. The organic layer was washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 1.05 g (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (4-carboxypiperidinocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 102 below.

Example 391

64.8 mg of the compound of Example 390 and 18.6 mg of ethanolamine are dissolved in 1 ml of dichloromethane, 48.6 mg of carbodiimidazole are added at room temperature and the mixture is stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic layer was dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 17.8 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {4- (2-hydroxyethylaminocarbonyl) piperidinocarbonyloxy} piperidine as shown in Table 102.

Examples 392 to 398

Using the compound of example 390 and the corresponding starting materials, which are processed according to the method of example 391, obtaining the compounds shown below in tables 102-103.

Example 399

(1) 1.17 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 is dissolved in 12 ml of toluene - (1-imidazolylcarbonyloxy) piperidine, 1.14 g of 4-amino-1-benzylpiperidine is added at room temperature and the mixture is stirred for 3 days. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and brine, and dried. The solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 0.89 g of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (1-benzylpiperidin-4-yl) aminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 890 mg of the above compound (1) was dissolved in 10 ml of methanol, 400 mg of palladium-on-charcoal and one drop of concentrated hydrochloric acid were added, and the mixture was stirred under a hydrogen atmosphere for 4.5 hours. Then the reaction mixture was filtered and the filtrate was evaporated in vacuo, the residue was crystallized (ethyl acetate-hexane) to give 802 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4- (4-piperidinyl) aminocarbonyloxypiperidine.

(3) 14.2 mg of 3-hydroxy-3-methylbutanoic acid was dissolved in 2 ml of dichloromethane, 21.1 mg of carbodiimidazole was added at room temperature, and the mixture was stirred at room temperature overnight. 61.9 mg of the above compound (2) was added to the reaction mixture, and the mixture was further stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 57.5 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl} aminocarbonyloxypiperidine, as shown in table 104 below.

Examples 400 to 402

The compound of example 399 (2) and the corresponding starting materials are processed according to the method of example 399 (3), obtaining the compounds as shown below in table 104.

Example 403

(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-ethyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine obtained by treating the compound of comparative example 11 ( 2) according to the method of example 215, process according to the method of example 209, obtaining the compound shown in table 105 below.

Example 404

The corresponding starting material was treated according to the method of Example 209 to give the compound shown in Table 105 below.

Example 405

The compound of Example 404 was processed according to the method of Example 213 to give the compound shown in Table 105 below.

Example 406

The compound of example 404 was processed according to the method of example 214 to obtain the compound shown in table 105 below.

Examples 407 to 413

The corresponding starting materials are processed according to the method of example 257, obtaining the compound shown below in tables 106-107.

Example 414

1.17 g of (2R, 4S) -4-acetylthio-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 50 ml of methanol and 1.17 g of tert-butyl 2-bromoethyl carbamate was added at room temperature. Then 25 ml of a 1M aqueous sodium hydroxide solution are added dropwise. The reaction mixture was stirred for 5 minutes, the solvent was removed using distillation under reduced pressure, the mixture was extracted with dichloromethane, washed with brine and dried. The solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 710 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (2 tert-butoxycarbonylaminoethylthio) -2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 107 below.

Example 415

(1) To 681 mg of the compound of Example 414, 2 ml of a 4M solution of hydrochloric acid in ethyl acetate was added under ice-cooling, and the mixture was stirred at room temperature for one hour. The solvent was removed by distillation, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform. The organic layer was dried and the solvent was removed by distillation under reduced pressure to obtain 612 mg of (2R, 4S) -4- (2-aminoethylthio) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- hydrochloride 2- (4-fluoro-2-methylphenyl) piperidine, as shown below in table 107.

(2) 55.2 mg of the above compound (1) and 9.1 mg of glycolic acid are dissolved in 1 ml of N, N-dimethylformamide, 24.9 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 19 are added. 9 ml of N-hydroxybenzotriazole monohydrate and the mixture was stirred at room temperature overnight. Ethyl acetate was added, the mixture was washed with water and brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 28.8 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- (1-hydroxyacetylamino) ethylthio} piperidine, as shown in table 107 below.

Examples 416 to 419

The compound of example 415 (1) and the corresponding starting materials are processed according to the method of example 415 (2), obtaining the compound shown in table 108 below.

Example 420

55.2 mg of the compound of Example 415 (1) was dissolved in 1 ml of N, N-dimethylformamide, 9.1 mg of carbodiimidazole was added and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and brine, and dried. The solvent was removed by distillation, the residue was dissolved in 1 ml of acetonitrile and 0.025 ml of methyl iodide was added. The mixture was stirred at 50 ° C. overnight. Then add 0.025 ml of methyl iodide and the mixture is stirred at the same temperature overnight. After removal of N, N-dimethylformamide and methyl iodide using distillation under reduced pressure, 1 ml of toluene and 0.040 ml of morpholine are added and the mixture is stirred at room temperature for 5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 38.0 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl)} aminocarbonyl-2 - (4-fluoro-2-methylphenyl) -4- (2-morpholinocarbonylaminoethylthio) piperidine, as shown in table 108 below.

Example 421

The compound of Example 415 (1) and the corresponding starting material were treated according to the method of Example 420 to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2 methylphenyl) -4- (2- (2-hydroxymethylamino) carbonylaminoethylthio) piperidine as shown in table 108 below.

Example 422

The corresponding starting materials were used, which were processed according to the method of Example 213 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4- {4- (2-methylsulfinyl-ethylaminocarbonyl) piperidinocarbonyloxy} piperidine as shown in table 108 below.

Example 423

The corresponding starting materials were used, which were processed according to the method of Example 214 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) - 4- {4- (3-methylsulfonylpropylaminocarbonyl) piperidinocarbonyloxy} piperidine, as shown in table 108 below.

Examples 424-425

Use the appropriate starting materials, which are processed according to the method of example 209, obtaining the compounds shown below in table 109.

Example 426

82.0 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- are dissolved in 1.5 ml of dichloromethane (2-Methylthioethylaminocarbonyloxy) piperidine, 99.5 mg of metachloroperbenzoic acid are added at room temperature and the mixture is stirred for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the layers were separated with ethyl acetate. The organic layer was washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 48.6 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylsulfonylethylaminocarbonyloxy) piperidine as shown in table 109 below.

Example 427

(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-methylthiopropylaminocarbonyloxy) piperidine is treated according to the method of Example 426 to obtain (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-ethylsulfonylpropylaminocarbonyloxy) piperidine, as represented below in table 109.

Examples 428 to 431

The corresponding starting materials are processed according to the method of example 169, obtaining the compounds shown in table 110 below.

Examples 432-433

The corresponding starting materials are processed according to the method of example 213, obtaining the compounds shown below in table 111.

Examples 434-435

The corresponding starting materials are processed according to the method of example 25,214, obtaining the compounds shown below in table 111.

Example 436

130 mg of imidazole-1-carboxylic acid amide N- (3,5-bistrifluoromethylbenzyl) -N- (2-methoxyethyl) amide are dissolved in 2.8 ml of acetonitrile, 411 μl of methyl iodide are added and the mixture is stirred at 50 ° C for 3 hours . The reaction mixture was concentrated under reduced pressure. The residue was suspended in 2.7 ml of dichloromethane, 89 mg (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and 50 μl of triethylamine were added and the mixture was stirred at room temperature for 20 hours A 5% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 19: 1) to obtain 63 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (2-methoxyethyl)} aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 112 below.

Example 437

94 mg of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine are dissolved in 2.7 ml of dichloromethane, 163 mg of 3 - [(3,5-bistrifluoromethylbenzyl) methylcarbamoyl] -1-methyl- 3H-imidazol-1-iodide and 50 μl of triethylamine and the mixture was stirred at room temperature for 18 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 19: 1) to obtain 84 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methoxyphenyl ) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 112 below.

Example 438

201 mg of N - [(1S) -1- (3,5-bistrifluoromethylphenyl) ethyl] -N-methylamide imidazole-1-carboxylic acid are dissolved in 5.2 ml of acetonitrile, 137 μl of methyl iodide are added. After the mixture was stirred at 50 ° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 4.5 ml of dichloromethane, 132 mg of 4- (2-hydroxyethylcarbamoyloxy) -2-phenylpiperidine and 84 μl of triethylamine were added, and the mixture was stirred at room temperature for 18 hours. A 5% aqueous citric acid solution was added to the reaction mixture, the mixture was extracted with chloroform, the organic layer was dried and concentrated under reduced pressure. The residue was purified using thin-layer chromatography on silica gel (chloroform: acetone = 4: 1) to give 75 mg (2R, 4R) -1- [N - {(S) -1- (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine, as shown in table 112 below.

Example 439

(1) 127 mg of 1- (3,5-bistrifluoromethylphenyl) ethyl imidazole-1-carboxylate is dissolved in 3 ml of acetonitrile, 448 μl of methyl iodide are added. The mixture was stirred at 50 ° C. for 3 hours and the reaction mixture was concentrated. The residue was suspended in 2.7 ml of dichloromethane, 102 mg of 2 - [(2R, 4S) -2- (4-fluoro-2-methylphenyl) piperidin-4-yloxycarbonylamino] ethyl acetate and 50 μl of triethylamine were added and the mixture was stirred at room temperature in within 18 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified using thin-layer chromatography on silica gel (hexane: ethyl acetate = 1: 1) to obtain 43 mg (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1 - {(S) -1- (3,5-bistrifluoromethylphenyl ) ethyl} hydroxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

MS (m / z): 623 [M ⁺ +1]

(2) 43 mg of the above compound (1) are dissolved in a mixture of 0.9 ml of tetrahydrofuran and 0.1 ml of methanol, 103 μl of a 1M aqueous sodium hydroxide solution are added and the mixture is stirred at room temperature for one hour. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 19: 1) to obtain 37 mg (2R, 4S) -1 - {(S) -1- (3,5-bistrifluoromethylphenyl) ethyl} hydroxycarbonyl-2- ( 4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 112 below.

Example 440

50 mg of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine are dissolved in 2.4 ml of N, N-dimethylformamide, 0.044 ml of triethylamine and 99.3 are added in a nitrogen atmosphere at room temperature. mg N- (3,5-bistrifluoromethylbenzyl) -N-methylaminocarbonyl chloride. The reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was poured into water and the mixture was extracted twice with ethyl acetate. The organic layers are combined and washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1 to 1: 2) to obtain 128 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- 2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown below in table 113.

Example 441

560 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 2.0 ml of dichloromethane, 1.5 ml of a dichloromethane solution containing 0.22 ml of pyridine and 0.314 ml of phenylchloroformate are added in a nitrogen atmosphere under ice-cooling. The reaction mixture was stirred at a temperature of from 0 ° C to 5 ° C for 3.5 hours and then stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted twice with dichloromethane. The organic layers were combined and washed twice with a 1M aqueous hydrochloric acid solution and then washed with saturated saline. The organic layer was dried and concentrated. The residue was dissolved in 11 ml of N, N-dimethylformamide, 0.274 ml of ethanolamine was added in a nitrogen atmosphere and at room temperature, and the mixture was stirred at 60 ° C. for 26 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers are combined, washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 39: 1) to obtain 493 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4 -fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 113 below.

Example 442

1.0 g of (2R) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 8 ml of dichloromethane, add 0.31 ml of triethylamine and 466 mg of di-tert-butyloxycarbonate and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layers are combined, washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 481 mg of (a) (2R, 4R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2 - (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 516 mg (b) (2R, 4S) - 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl 2- (4 -fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine as shown in table 113 below.

Example 443

700 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert- are dissolved in 3.5 ml of ethyl acetate. butoxycarbonylaminopiperidine, 3.5 ml of a 4M solution of hydrochloric acid in ethyl acetate are added under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes. The solvent was removed by distillation, ethyl acetate was added to the residue and filtered. Chloroform and a 2M aqueous sodium hydroxide solution were added to the collected substances, and the layers were separated. The aqueous layer was extracted with chloroform. The combined organic layers were dried and concentrated to give 489 mg (2R, 4S) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown below in table 113.

Examples 444 to 449

Use the appropriate starting materials, which are processed according to the method of example 138, obtaining the compounds shown below in table 114.

Examples 450-451

Use the appropriate starting materials, which are processed according to the method of example 102 (1), obtaining the compounds shown below in table 114.

Examples 452 to 469

Use the appropriate starting materials, which are processed according to the method of example 250, to obtain the compounds shown below in tables 115-117.

Example 470

52.8 mg of (2R, 4S) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) hydrochloride are dissolved in 1 ml of dichloromethane piperidine, 0.017 ml of triethylamine and 24.3 mg of 1,1-carbodiimidazole are added at room temperature and the mixture is stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were washed with brine, dried and concentrated. The residue is dissolved in 1 ml of acetonitrile, 0.025 ml of methyl iodide is added and the mixture is stirred at 60 ° C. overnight. The reaction mixture was concentrated and the residue was dissolved in 1 ml of a solution of toluene in acetonitrile (7: 3), 24.4 mg of ethanolamine was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 53.1 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylamino) piperidine, as shown in table 118 below.

Examples 471 to 480

Use the appropriate starting materials, which are processed according to the method of example 470, obtaining the compounds shown below in tables 118-119.

Example 481

490 mg of (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and 312 mg of 2- are dissolved in 10 ml of dichloromethane. (2-aminoethylamino) ethanol, 0.086 ml of acetic acid and 669 mg of sodium triacetoxyborohydride are added at room temperature, and the mixture is stirred overnight. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with brine, dried and concentrated to give 581 mg (2R, 4RS) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (2-hydroxyethylamino) ethylamino} piperidine [(2R, 4S) :( 2R, 4R) = 74: 26]. In 2 ml of dichloromethane, 116 mg of (2R, 4RS) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- ( 2-hydroxyethylamino) ethylamino} piperidine, 39 mg of 1,1-carbodiimidazole is added at room temperature and the mixture is stirred for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain (a) 75.5 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl -2- (4-fluoro-2-methylphenyl) -4- [3- (2-hydroxyethyl) -2-oxoimidazolidin-1-yl] piperidine and (b) 22.6 mg (2R, 4R) -1- { N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- [3- (2-hydroxyethyl) -2-oxoimidazolidin-1-yl] piperidine, as presented below in table 120.

Examples 482 to 486

Use the appropriate starting materials, which are processed according to the method of example 481, obtaining the compounds shown below in tables 120 to 122.

Example 487

12.4 ml of ethylene glycol are dissolved in 1 ml of dichloromethane and 32.4 mg of 1,1-carbodiimidazole is added at room temperature. The mixture was stirred at room temperature for 7.5 hours and 52.8 mg of (2R, 4S) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2 hydrochloride was added to the mixture. - (4-fluoro-2-methylphenyl) piperidine and 0.021 ml of triethylamine. The mixture was stirred for 4 days and the reaction mixture was concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 9: 1) to obtain 16.4 mg (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyloxycarbonylamino) piperidine, as shown in table 123 below.

Example 488

(1) 58 mg of triphosgene are dissolved in 3 ml of dichloromethane, and 2 ml of a dichloromethane solution containing 138 mg of N- {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl is added dropwise thereto. } -N-methylamine and 0.21 ml of triethylamine and then the mixture is heated to 0 ° C. The mixture was concentrated and the residue was dissolved in 2 ml of dichloromethane. To the mixture was added dropwise 2 ml of a dichloromethane solution containing 135 mg of (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine and 0.084 ml of triethylamine, and the mixture was stirred at room temperature in for one day. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: acetone = 10: 1) to obtain 44 mg (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -1- [N- {2-methoxy-5- (5- trifluoromethyltetrazol-1-yl) benzyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

MS (m / z): 652 [M ⁺ +1]

(2) 44 mg (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -1- [N- {2-methoxy-5- (5) are dissolved in 0.9 ml of a mixed solution (tetrahydrofuran: methanol = 8: 1) -trifluoromethyltetrazol-1-yl) benzyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, 0.101 ml of a 1M aqueous solution of sodium hydroxide was added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers are dried over magnesium sulfate and concentrated. The residue was purified using thin-layer chromatography on silica gel (chloroform: methanol = 19: 1) to obtain 36 mg (2R, 4S) -1- [N- {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 124 below

Comparative Example 1

To the Grignard reagent obtained from 14.2 g of magnesium, 93.1 g of 2-bromo-5-fluorotoluene and 500 ml of tetrahydrofuran, 50 ml of 4-methoxypyridine was added dropwise at a temperature of −20 ° C. under a nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was then cooled to −50 ° C. and 85 ml of benzyl chlorocarbonate was added dropwise, while maintaining the temperature at −40 ° C. or lower. After completion of the dropwise addition, the temperature of the reaction mixture was slowly raised, 200 g of ice was added at −15 ° C., and the mixture was stirred for 30 minutes. Then 200 ml of a 5M aqueous citric acid solution were added and the mixture was stirred at room temperature for one hour. Tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. 200 ml of ethyl acetate was added to the residue, and the mixture was extracted twice. The organic layers were combined and washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and the solvent was removed using distillation under reduced pressure. The residue was collected by filtration and washed with isopropyl ether to obtain 146.5 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine, as shown in table 125 below.

Reference Example 2

190 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine are dissolved in 4600 ml of acetic acid, 91 g of zinc powder are added and the mixture is stirred at room temperature in within 24 hours. Insoluble matters were removed from the reaction mixture by filtration, and the solvent was removed using distillation under reduced pressure. 400 ml of ethyl acetate was added to the residue, the mixture was washed with aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified using a silica gel chromatography column (ethyl acetate: hexane = 2: 1) to obtain 166 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine as presented below in table 125.

Reference Example 3

To 132 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was added 650 ml of methanol, 84 ml of trimethoxymethane and 2 g of strongly acidic IR-120 resin (manufactured by Japan Organo Co., Ltd.) and a mixture stirred at room temperature for 3 days. Insoluble matter was removed from the reaction mixture by filtration, and the solvent was removed by distillation under reduced pressure to obtain 146 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine, as shown in table 125 below.

Reference Example 4

To 300 ml of ethanol, 30 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3.0 g of 10% palladium-on-charcoal were added and the mixture was stirred under a hydrogen atmosphere at room temperature. within 3 hours. Insoluble matters were removed from the reaction mixture by filtration, and the solvent was removed using distillation under reduced pressure. 300 ml of ethyl acetate are added to the residue. Under ice-cooling, 20 ml of a 4M solution of hydrochloric acid in ethyl acetate are slowly added dropwise. The crystals were collected by filtration and washed with ethyl acetate. After drying, the crystals were added to a mixture of dichloromethane-aqueous sodium carbonate and the mixture was stirred. After the organic layer was isolated, the aqueous layer was further extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, the solvent was removed using distillation under reduced pressure to obtain 16.7 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine, as shown in table 125 below.

Reference Example 5

To 130 ml of a suspension in ethyl acetate, 10.1 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3.18 g of LN-acetylvaline were added 35 ml of methanol, the mixture was warmed to dissolve and then cooled to room temperature . After 3.5 hours, the precipitated crystals were collected by filtration and washed with 20 ml of ethyl acetate. The resulting crystals were dried under reduced pressure. Then 50 ml of chloroform was added, the mixture was washed with 30 ml of a 2M aqueous sodium hydroxide solution and 30 ml of saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated crystals were further concentrated under reduced pressure to obtain 2.94 g of (2R) -2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine (degree of optical purity: 97.0 % ee) as shown in table 125 below.

Reference Example 6

To 36 ml of a tetrahydrofuran solution of 5.0 g of N- (3,5-bistrifluoromethylbenzyl) -N-methylamine, 3.47 g of 1,1'-carbonyldiimidazole was added and the mixture was stirred at 65 ° C for 20 minutes. The solvent was removed using distillation under reduced pressure, and dichloromethane was added. The entire organic layer was washed with brine, dried, and the solvent was removed using distillation. The residue was dissolved in 26 ml of acetonitrile and 4.84 ml of methyl iodide was added. The mixture was stirred at 60 ° C for 2 hours. The solvent was removed using distillation under reduced pressure, and the residue was dissolved in 80 ml of dichloromethane. Under ice cooling, 5.17 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3 ml of triethylamine are added and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried and the solvent was removed using distillation. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 3) to obtain 9.7 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2 -methylphenyl) -4,4-dimethoxypiperidine, as shown below in table 126.

Reference Example 7

9.7 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine are dissolved in 180 ml of tetrahydrofuran, and ice-cooling is added 70 ml of a 1M aqueous solution of sulfuric acid and the mixture was stirred at room temperature for one hour. After adjusting the pH of the mixture to 8-9 using a 1M aqueous sodium hydroxide solution, tetrahydrofuran was removed using distillation. Water and ethyl acetate were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried. The solvent was removed using distillation. Diisopropyl ether was added to the obtained residue, and white crystals were collected by filtration to obtain 7.86 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- oxopiperidine, as shown below in table 126.

Reference Example 8

To 60 ml of a tetrahydrofuran solution 3.91 g of N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine was added 2.34 g of 1,1'-carbonyldiimidazole and the mixture was stirred at 40 ° C. overnight. The solvent was removed from the reaction mixture by distillation, ethyl acetate was added, the entire organic layer was washed with water and brine, and dried. The solvent was removed by distillation, and the resulting white crystals were collected by filtration using diisopropyl ether. The resulting white crystals were dissolved in 60 ml of acetonitrile, 3.4 ml of methyl iodide were added and the mixture was stirred at 60 ° C for 2 hours. The solvent was removed using distillation under reduced pressure, and the residue was dissolved in 40 ml of dichloromethane. Under ice cooling, 3.47 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3.82 ml of triethylamine are added and the mixture is stirred at room temperature overnight. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried, and the solvent was removed using distillation under reduced pressure. The residue was dissolved in 90 ml of tetrahydrofuran, while cooling with ice, 30 ml of a 1M aqueous solution of sulfuric acid was added thereto, and the mixture was stirred at room temperature for 5 hours. After adjusting the pH of the mixture to 8-9 using a 1M aqueous sodium hydroxide solution, tetrahydrofuran was removed using distillation. Water and ethyl acetate were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1) to obtain 2.12 g (2R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, as shown in table 126 below.

Comparative Examples 9 to 11

Use the appropriate starting materials, which are processed according to the method of comparative example 8, to obtain the compounds shown below in tables 126-127.

Reference Example 12

16.7 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 140 ml of ethanol, 3.74 g of hydroxylamine hydrochloride and 4.41 g of sodium acetate are added and the mixture is stirred at room temperature in within 2 hours. Ethanol is removed under reduced pressure. Water and ethyl acetate were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and the solvent was removed under reduced pressure. The residue was dissolved in 500 ml of methanol, 23.2 g of nickel chloride hexahydrate was added, after stirring the mixture, 3.7 g of sodium borohydride was slowly added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. Methanol was removed using distillation under reduced pressure, aqueous ammonia and dichloromethane were added to the residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was separated into layers and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried and the solvent was removed using distillation. The residue was dissolved in 480 ml of dichloromethane, 8.2 ml of triethylamine and 5.1 ml of propionyl chloride were added under ice-cooling, and the resulting mixture was stirred under ice-cooling for one hour. The reaction mixture was poured into saturated saline and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 1: 1) to obtain 6.43 g of (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine and 5, 65 g of (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine, as shown in table 127 below.

Reference Example 13

Use 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and isobutyroyl chloride, which are treated according to the method of comparative example 12, obtaining (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2- methylphenyl) -4-isobutanoylaminopiperidine; and (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-isobutanoylaminopiperidine, as shown in table 128 below.

Reference Example 14

1.73 g of trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine is dissolved in 17 ml of ethanol, 280 mg of palladium-on-carbon (moisture content 50.9%) is added and the mixture is stirred in a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through celite and ethanol was removed using distillation. The residue was purified using an NH-silica gel chromatography column (chloroform: hexane: ethyl acetate = 5: 5: 2) to obtain 772 mg of trans-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine, as shown in the table below 129.

Comparative Examples 15 to 17

Use the appropriate starting materials, which are processed according to the method of comparative example 14, obtaining the compounds shown below in tables 129-130.

Reference Example 18

110 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 900 ml of ethanol, 24.8 g of hydroxylamine hydrochloride and 29.3 g of sodium acetate are added and the mixture is stirred at room temperature for 5 hours. Ethanol was removed using distillation, and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was dissolved in 2.4 L of methanol and 92.5 g of nickel chloride hexahydrate was added. After stirring, 18.4 g of sodium borohydride was slowly added to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. Methanol was removed by distillation, aqueous ammonia and dichloromethane were added to the residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was separated into layers and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried and the solvent was removed using distillation. The residue was dissolved in 1.2 L of dichloromethane, 45.2 ml of triethylamine and 74.5 ml of di-tert-butyl dicarbonate were added under ice cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into saturated brine, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried and the solvent was removed using distillation under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 36.7 g of (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 37.9 g (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, as shown in table 131 below.

Reference Example 19

37.0 g of cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine is dissolved in 350 ml of ethanol, 5.5 g of palladium-on-carbon are added (moisture content 50.9% ) and the mixture is stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through celite and ethanol was removed by distillation to obtain 25.8 g of cis-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, as shown in table 132 below.

Reference Example 20

To 1.34 g of 3-hydroxyl-2-hydroxymethyl-2-methylpropionic acid and 13 ml of acetone dimethyl acetal were added 95 mg of paratoluenesulfonic acid monohydrate at room temperature and the mixture was stirred for 6 hours. Then 95 mg of paratoluenesulfonic acid monohydrate was added and the mixture was stirred overnight. The resulting solution was concentrated, poured into water and extracted. The aqueous layer was extracted with chloroform. The combined organic layers were washed with brine, dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 19: 1) to obtain 333 mg of 2,2,5-trimethyl [1,3] dioxolane-5-carboxylic acid, as shown in table 132 below.

Reference Example 21

In 400 ml of tetrahydrofuran, 31.5 g of 2-chloro-isonicotinic acid are dissolved and 32.5 g of 1,1'-carbonyldiimidazole are added. The mixture was stirred under ice cooling for one hour. 50 ml of ethanol was added to the solution, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the residue was dried in vacuo to give 35.6 g of ethyl 2-chloroisonicotinate, as shown in table 132 below.

Reference Example 22

In a mixed solvent consisting of 250 ml of toluene and 50 ml of ethanol, 20 g of ethyl 2-chloroisonicotinate and 20 g of 2-methyl-4-fluorophenylboronic acid and 5.8 g of palladium tetrakistriphenylphosphine and 250 ml of 2M aqueous sodium carbonate are dissolved and the mixture stirred at 50-70 ° C for 2 hours. The solution was cooled to room temperature and extracted by adding ethyl acetate and water. The organic layer was washed further with water, dried over magnesium sulfate and concentrated. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 6: 1) to obtain 24.8 g of 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) pyridine, as shown in table 132 below.

Reference Example 23

5.2 g of 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) pyridine and 1.5 g of platinum oxide are dissolved in 200 ml of ethanol, and 15 ml of concentrated hydrochloric acid are added to the solution. The mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. 200 ml of water are added, the mixture is stirred for 30 minutes and then insoluble materials are removed by filtration through celite. Insoluble materials are washed with ethanol, the filtrate and the liquid used in the washing are combined and concentrated. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue. After confirming that the aqueous solution becomes sufficiently basic, carry out the extraction. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated to give 3.6 g of 2,4-cis-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 132 below. .

Reference Example 24

(1) In a mixture of 50 ml of ethyl acetate and 50 ml of diethyl ether, 7.4 g of 2,4-cis-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 4.0 g of N-p are dissolved with heating -toluenesulfonyl-D-phenylalanine. The solvent was concentrated by heating, 30 ml of diisopropyl ether was added and the mixture was stirred. The precipitated crystals are removed, the mother liquor is washed with concentrated aqueous ammonia, dried and concentrated under reduced pressure. 4.0 g of N-p-toluenesulfonyl-1-phenylalanine was added to the residue, 50 ml of ethyl acetate and 30 ml of diisopropyl ether were added and dissolved under heating, the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried, yielding 4.0 g of the N-p-toluenesulfonyl-1-phenylalanine salt (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) - 4-piperidine.

(2) The compound (1) obtained above is dissolved in an aqueous solution of ammonia, and after confirming that the solution has become sufficiently basic, it is extracted twice with chloroform. The combined organic layers were dried and concentrated under reduced pressure to obtain 2.6 g of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine (optical purity: 96% ee), as presented below in table 133.

Reference Example 25

(1) 7.5 g of 3-aminopropanol and 16 g of tert-butyldimethylsilyl chloride are dissolved in 50 ml of N, N-dimethylformamide, 6.8 g of imidazole are added and the mixture is stirred at room temperature for 16 hours. 11 g of citric acid were added to the reaction mixture, and after the mixture was stirred at room temperature for one hour, the mixture was concentrated under reduced pressure. To the residue was added a 2M aqueous sodium hydroxide solution and diethyl ether, and the layers were separated. The organic layer was dried and concentrated under reduced pressure. The residue and 12.1 g of 3,5-bistrifluoromethylbenzaldehyde are dissolved in 300 ml of dichloromethane, 21.2 g of sodium triacetoxyborohydride and 2.9 ml of acetic acid are added and the mixture is stirred at room temperature for 3 hours. A 2M aqueous solution of sodium carbonate was added to the reaction mixture. The mixture was stirred for 30 minutes and extracted twice with chloroform. The combined organic layers were dried, concentrated under reduced pressure, and purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 20 g of 3-tert-butyldimethylsiloxypropyl-3,5-bistrifluoromethylbenzylamine.

(2) Using 12.5 g of the above compound (1) and the compound of comparative example 5, which are processed according to the method of comparative example 6, getting 19 g (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-tert-butyldimethylsiloxypropyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine.

(3) Using 19.0 g of the above compound (2), which is processed according to the method of comparative example 7, obtaining 19 g (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, as shown in table 133 below.

Reference Example 26

4.8 g of the compound of comparative example 5 are dissolved in 40 ml of dichloromethane, 4.4 g of di-tert-butyl dicarbonate are added and the mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100 ml of acetone, 200 mg of acid resin (IR-120) was added and the mixture was stirred at room temperature for 3 days. After removing the resin from the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified using a silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 3.9 g of (R) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine.

(2) 3.9 g of the above compound (1) was dissolved in 20 ml of ethanol, 400 mg of sodium borohydride was added at a temperature of -20 ° C, and the mixture was stirred for one hour. An aqueous solution of ammonium chloride was added to the reaction mixture, and ethanol was removed using distillation. Ethyl acetate and water were added to the residue, the layers were separated, and then washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1) to obtain 3.1 g (2R, 4S) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine .

(3) Using 3.1 g of the above compound (2) and the corresponding starting material, which are treated according to the method of comparative example 209, obtaining 2.3 g (2R, 4S) -1-tert-butoxycarbonyl-2- (4-fluoro -2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine.

(4) 2.3 g of the above compound (3) are dissolved in 20 ml of a 4M solution of hydrochloric acid in ethyl acetate, and the solution is stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The residue was dried, yielding 1.5 g of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-acetoxyethylaminocarbonyloxy) piperidine hydrochloride.

(5) 1.5 g of the above compound (4) are dissolved in 25 ml of a 1M aqueous sodium hydroxide solution, and the solution is extracted twice with chloroform. The combined organic layers were dried and concentrated under reduced pressure. The residue was dried, yielding 1.5 g of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 133 below.

Reference Example 27

4.8 g of 3,5-bistrifluoromethylbenzaldehyde are dissolved in 250 ml of acetonitrile, 6.6 g of trimethylsulfonium iodide, 3.2 g of ground potassium hydroxide and 0.5 ml of water are added and the mixture is stirred at 65 ° C-70 ° C for 16 hours in the presence of alumina beads. After completion of the reaction, insoluble matters are removed. Ethyl acetate and water are added to the filtrate, and the layers are separated. The organic layer was washed, dried and concentrated under reduced pressure. To the residue was added 50 ml of a 40% solution of methylamine in methanol and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified using an NH-silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 1.23 g of 1- (3,5-bistrifluoromethylphenyl) -2-hydroxyethylamine as shown in table 133 below.

Reference Example 28

(1) 2.45 g of 3,5-bistrifluoromethylbenzaldehyde, 835 mg of 2-methoxyethylamine and 687 μl of acetic acid are dissolved in 43 ml of dichloromethane, 3.12 g of sodium triacetoxyborohydride are added and the mixture is stirred at room temperature for one hour under nitrogen. The reaction mixture was washed with a 0.5M aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using an NH-silica gel chromatography column (hexane: ethyl acetate = 19: 1 to 9: 1) to obtain 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.

MS (m / z): 302 [M ⁺ +1] ⁺

(2) 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine are dissolved in a mixed solution of 37 ml of toluene and 4 ml of methylene chloride, 1.78 g of 1,1'-carbonyldiimidazole is added and the mixture is stirred at 60 ° C. for 3 hours . Distilled water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: acetone = 9: 1 to 2: 1) to obtain 3.45 g of imidazole-1-carboxylic acid 3,5-bistrifluoromethylbenzyl-2-methoxyethylamide, as shown in Table 133 below.

Reference Example 29

(1) 3.94 g of 2-bromo-5-fluorophenol and 1.62 ml of methyl iodide are dissolved in 15 ml of N, N-dimethylformamide, and 5.08 g of potassium carbonate are slowly added under ice-cooling. The mixture was stirred at room temperature for 3 hours. Then the insoluble matters are removed by filtration, distilled water is added to the filtrate, the mixture is extracted with diethyl ether and washed with brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 19: 1 to 9: 1) to obtain 4.10 g of 1-bromo-4-fluoro-2-methoxybenzene.

MS (m / z): 204/206 (M ⁺ +1).

(2) 486 mg of magnesium and trace amounts of iodine are added to 7 ml of tetrahydrofuran, a solution of 4.10 g of the above compound (1) in 16 ml of tetrahydrofuran is added dropwise to obtain Grignard reagent. To the solution is added dropwise a solution of 1.96 g of 4-methoxypyridine in 7 ml of tetrahydrofuran at a temperature of −60 ° C. or lower. Then, a solution of 3.75 g of benzyl chloroformate in 18 ml of tetrahydrofuran is added dropwise and the mixture is stirred for 3 hours. The temperature of the mixture was raised to room temperature and 40 ml of a 5% aqueous citric acid solution was added to the mixture. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1 to 1: 2) to obtain 3.15 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-oxo-3,4 dihydro-2H-pyridine.

MS (m / z): 356 [M ⁺ +1]

(3) In a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuran, 3.15 g of the above compound (2) are dissolved, 706 mg of sodium borohydride is added and the mixture is stirred at room temperature for 6 hours. The reaction mixture was concentrated and distilled water was added to the residue. The mixture was extracted with chloroform, the organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: acetone = 19: 1 to 9: 1) to obtain 1.62 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-hydroxypiperidine.

MS (m / z): 360 [M ⁺ +1]

(4) 1.62 g of the above compound (3) was dissolved in 20 ml of toluene, 876 mg of 1,1'-carbonyldiimidazole was added and the mixture was stirred at 60 ° C for one hour. 1.09 ml of ethanolamine was added and the resulting mixture was stirred at 60 ° C for 6 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: acetone = 4: 1 to 1: 1) to obtain 1.81 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine.

MS (m / z): 447 [M ⁺ +1]

(5) 1.81 g of the above compound (4) was dissolved in 20 ml of methanol, 90 mg of 10% palladium-on-charcoal was added, and the mixture was stirred at room temperature for one hour under a hydrogen atmosphere. After insoluble matters were removed by filtration, the filtrate was concentrated. Diethyl ether was added to the residue, and the precipitates collected were collected by filtration to obtain 1.30 g of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 134 below.

Reference Example 30

(1) 5.46 g of 4-methoxypyridine is dissolved in 40 ml of tetrahydrofuran, and 55 ml of a 1M solution of phenylmagnesium bromide-tetrahydrofuran is added dropwise in a nitrogen atmosphere at −60 ° C. or lower. Then, a solution of 10.24 g of benzyl chloroformate in 50 ml of tetrahydrofuran was added dropwise and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature and 120 ml of 5% aqueous citric acid solution was added. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated. Diisopropyl ether was added to the residue and the precipitates were collected by filtration to obtain 8.51 g of 1-benzyloxycarbonyl-4-oxo-2-phenyl-3,4-dihydro-2H-pyridine.

MS (m / z): 308 [M ⁺ +1]

(2) 8.48 g of the above compound (1) was dissolved in 260 ml of acetic acid, 3.61 g of zinc powder was added, and the mixture was stirred at room temperature for 18 hours. Then 1.8 g of zinc powder was added, after stirring the mixture at room temperature for 6 hours, 1.8 g of zinc powder was further added and the mixture was stirred at 50 ° C. for 3 days. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried and concentrated to give 8.54 g of 1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine.

MS (m / z): 310 [M ⁺ +1]

(3) 619 mg of the above compound (2) are dissolved in 15 ml of tetrahydrofuran, and 4 ml of a 1M solution of diisobutylaluminium hydride in toluene under nitrogen atmosphere at -60 ° C or lower is added dropwise. The mixture is stirred for 10 minutes. 667 μl of a 6M aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was concentrated. Distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 2: 1 to 1: 1) to obtain 553 mg of 1-benzyloxycarbonyl-4-hydroxy-2-phenylpiperidine.

MS (m / z): 312 [M ⁺ +1]

(4) To a mixed solution of 14 ml of toluene and 1.6 ml of dichloromethane, 511 mg of the above compound (3) was added, 319 mg of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at 60 ° C. for 2 hours. 396 μl of ethanolamine was added to the mixture, and the resulting mixture was stirred at 60 ° C. for 3 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: acetone = 9: 1 to 2: 1) to obtain 462 mg of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine.

MS (m / z): 399 [M ⁺ +1]

(5) 430 mg of the above compound (4) were dissolved in 10 ml of methanol, 30 mg of 10% palladium-on-charcoal was added, and the mixture was stirred at room temperature for 5 days in a hydrogen atmosphere. Insoluble materials were removed by filtration and the filtrate was concentrated to obtain 348 mg of 4- (2-hydroxyethylaminocarboxyoxy) -2-phenylpiperidine, as shown in table 134 below.

Reference Example 31

(1) 2.61 g of 3,5-bistrifluoromethylacetophenone was dissolved in 47 ml of ethanol, 478 mg of sodium borohydride was added and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was concentrated. The residue was extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 9: 1 to 4: 1) to obtain 2.51 g of 1- (3,5-bistrifluoromethylphenyl) ethanol.

MS (m / z): 258 [M ⁺ +1]

(2) In a mixed solution of 40 ml of toluene and 4 ml of acetonitrile, 2.49 g of the above compound (1) are dissolved, 1.72 g of 1,1'-carbonyldiimidazole are added and the mixture is stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried, concentrated under reduced pressure to obtain 3.40 g of 1- (3,5-bistrifluoromethylphenyl) ethyl imidazole-1-carboxylate, as shown in table 134 below.

Reference Example 32

Trace amounts of iodine are added to 1.74 g of magnesium and 40 ml of tetrahydrofuran, and 10.4 g of 2-bromo-5-fluorotoluene is added dropwise in a nitrogen atmosphere at room temperature over 40 minutes. The reaction mixture was refluxed under heating for one hour to obtain a Grignard reagent solution. 5.46 g of 4-methoxypyridine was added dropwise to the resulting Grignard reagent solution over 20 minutes under nitrogen at -40 ° C. After completion of the dropwise addition, the mixture is stirred at a temperature of from -40 ° C to -30 ° C for 30 minutes. Then the reaction mixture was cooled to -40 ° C, while maintaining the temperature at -40 ° C or lower, a solution of 12 g of di-tert-butyl dicarbonate in 20 ml of tetrahydrofuran was added dropwise. After completion of the dropwise addition, the temperature of the reaction mixture was slowly raised. At a temperature of −15 ° C., ice is added to the mixture and the mixture is stirred for 20 minutes. An aqueous citric acid solution is then added and the mixture is stirred at room temperature for 40 minutes. Tetrahydrofuran was removed using distillation, ethyl acetate was added to the resulting residue, and extracted twice. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting crystals were collected by filtration using diisopropyl ether to obtain 11.9 g of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3,4-dihydro-2H- pyridine, as shown below in table 134.

Reference Example 33

To 6.0 ml of ethanol, 916 mg of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine and 110 mg of 10% palladium-on-carbon are added (moisture content 50.5%) and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. After insoluble matters were removed by filtration, the solvent was removed using distillation. The residue was dissolved in 15 ml of toluene and the solution was cooled to -78 ° C. To the resulting solution, 1.8 ml of butyllithium aluminum hydride (65% by weight solution in toluene) was slowly added dropwise under a nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred at a temperature of from -78 ° C to -60 ° C for one hour. A 1 M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred for 10 minutes. The resulting precipitates were isolated by filtration through celite and extracted twice with ethyl acetate. The organic layers are combined and washed with saturated aqueous ammonia and brine. The organic layer was dried and concentrated under reduced pressure. After adding 7.5 ml of ethyl acetate to the residue, 7.5 ml of a 4M solution of hydrochloric acid in ethyl acetate was slowly added dropwise under ice-cooling. The crystals were collected by filtration and washed with ethyl acetate. After drying, the crystals are added to a mixture of ethyl acetate-1M aqueous sodium hydroxide and stirred. The organic layer was isolated and the aqueous layer was extracted three times with ethyl acetate. The organic layers are combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 471 mg of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine, as shown in table 134 below.

Reference Example 34

831 ml of triphosgene are dissolved in 3.0 ml of dichloromethane and a solution of 1.08 g of N- (3,5-bistrifluoromethylbenzyl) -N-methylamine and 1.76 ml of triethylamine in 5.0 ml of dichloromethane are added dropwise over 10 minutes, in nitrogen atmosphere under ice cooling. The reaction mixture was stirred at a temperature of from 0 ° C to 5 ° C for 30 minutes The solvent was removed using distillation, and the residue was dried. Water and dichloromethane were added to the residue, and the mixture was extracted twice with dichloromethane. The organic layers are combined, washed with brine and dried. Then, the solvent was removed using distillation. The residue was purified using a silica gel chromatography column (from hexane to hexane: ethyl acetate = 10: 1) to obtain 760 mg of N- (3,5-bistrifluoromethylbenzyl) -N-methylaminocarbonyl chloride, as shown in table 134 below.

Reference Example 35

24.5 g of 3,5-bistrifluoromethylbenzaldehyde are dissolved in 20 ml of methanol and 60 ml of ethylamine (2M solution in tetrahydrofuran) are added under ice-cooling. Then, 4.38 g of sodium borohydride was slowly added and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture and concentrated under reduced pressure. The residue was extracted with dichloromethane, the organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (hexane: ethyl acetate = 4: 1 to chloroform: methanol = 9: 1) to obtain 6.35 g of N- (3,5-bistrifluoromethylbenzyl) -N-ethylamine, as shown in the table below 135.

Reference Example 36

(1) 1.34 g of magnesium and trace amounts of iodine are added to 20 ml of tetrahydrofuran, and a solution of 9.50 g of 2-bromotoluene in 45 ml of tetrahydrofuran is added dropwise to obtain a Grignard reagent. To the Grignard reagent obtained, a solution of 5.46 g of 4-methoxypyridine in 20 ml of tetrahydrofuran in a nitrogen atmosphere at a temperature of -60 ° C or lower is added dropwise. Then, a solution of 10.24 g of chlorobenzyl formate in 50 ml of tetrahydrofuran is added dropwise at a temperature of -40 ° C and the mixture is stirred for 3 hours. The temperature of the mixture was raised to room temperature and 120 ml of 5% aqueous citric acid solution was added. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated under reduced pressure. The residue was crystallized using diisopropyl ether, and the crystals were collected by filtration to obtain 11.15 g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine.

MS (m / z): 322 [M ⁺ +1]

(2) 11.15 g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine are dissolved in a mixed solution of 125 ml of ethanol and 35 ml of tetrahydrofuran, 2.76 g of borohydride are added sodium and the mixture is stirred at room temperature for a day. 1.38 g of sodium borohydride are then added and the mixture is stirred at room temperature for a day. The reaction mixture was concentrated under reduced pressure, and distilled water was added to the residue. The mixture was extracted with chloroform, the organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: acetone = 49: 1 to 9: 1) to obtain 6.18 g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine.

MS (m / z): 326 [M ⁺ +1]

(3) 1.63 g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine was dissolved in 21 ml of toluene, 973 mg of 1,1'-carbonyldiimidazole was added and the mixture was stirred at 60 ° C for one hour. 1.21 ml of ethanolamine was added to the solution, and the mixture was stirred at 60 ° C. for 6 hours. Distilled water was added to the reaction mixture and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: acetone = 9: 1 to chloroform: methanol = 19: 1) to obtain 1.34 g of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine.

MS (m / z): 413 [M ⁺ +1]

(4) 1.33 g of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine was dissolved in 30 ml of methanol, 70 mg of 10% palladium-on-carbon was added and the mixture was stirred at room temperature in for 14 hours in a hydrogen atmosphere. After insoluble matters were removed by filtration, the filtrate was concentrated to obtain 880 mg of 4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine, as shown in table 135 below.

Reference Example 37

(1) 25 g of 4-fluoro-1-bromobenzene are used, which is treated according to the method of comparative example 1 to obtain 22.3 g of 1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-oxo-3,4-dihydro-2H pyridine.

(2) 20 g of the above compound (1) are dissolved in 400 ml of ethanol, 7.6 g of sodium borohydride are added and the mixture is stirred at -20 ° C for 2 hours. After completion of the reaction, an aqueous solution of citric acid is slowly added to the mixture until the formation of foam ceases. The solvent was removed using distillation under reduced pressure, and the layers were separated by adding water and chloroform. The aqueous layer was then extracted with chloroform, the combined organic layers were dried and concentrated under reduced pressure. The residue was purified using a silica gel chromatography column (chloroform: ethyl acetate = 10: 1) to obtain 6.3 g of a mixture of (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine and ( b) (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine.

(3) Using 6.2 g of the above compound (2), which is treated according to the method of comparative example 209, obtaining 7.3 g of a mixture of (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4-fluorophenyl) - 4- (2-hydroxyethylaminocarbonyloxy) piperidine; and (b) (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine.

(4) Using 6.3 g of the above compound (3), which is processed according to the method of comparative example 4, obtaining 2.6 g of a mixture of (a) (2R, 4S) -2- (4-fluorophenyl) -4- (2 -hydroxyethylaminocarbonyloxy) piperidine; and (b) (2S, 4R) -2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in Table 135 below.

Reference Example 38

0.639 g of N-tosyl-D-phenylalanine is dissolved in 5 ml of methanol and the solution is heated to 59 ° C, and then 1.3 ml of a methanol solution containing 0.418 g of 2- (4-fluoro-2-methyl) phenyl-4 is added dropwise. -hydroxypiperidine. After crystals are formed within 20 minutes after the start of crystallization, another methanol solution of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine is added dropwise to the mixture over 5 minutes. The mixture was cooled from 59 ° C to 30 ° C for one hour and then crystals formed within 1.5 hours. The resulting crystals were removed by filtration and washed with chilled methanol, air dried at 60 ° C overnight to obtain 0.325 g of the salt of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine N-tosyl- D-phenylalanine. 0.62 ml of a 2M aqueous solution of hydrogen chloride was added to the obtained salt, the mixture was extracted with ethyl acetate. 0.3 ml of a 5M aqueous sodium hydroxide solution was added to the aqueous layer, and then extracted four times with ethyl acetate. The organic layer was dried, concentrated under reduced pressure to obtain 0.129 g of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine, as shown below in table 136.

Reference Example 39

2.72 g of 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde are dissolved in 40 ml of dichloromethane, 2.5 ml of an 8M solution of methylamine in ethanol, 0.572 ml of acetic acid and 3.12 g of sodium triacetoxyborohydride are added, mixture stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate, the organic layers were dried and concentrated. The residue was purified using a silica gel chromatography column (chloroform: methanol = 49: 1 to 4: 1) to obtain 2.2 g of N- {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl) -N- methylamine, as shown below in table 136.

Industrial Applicability of the Invention

The compound of the present invention or a salt thereof has an excellent antagonistic effect on the tachykinin receptor. In addition, the compound of the present invention or its salt is excellent in terms of safety, absorption, brain transfer ability, metabolic stability, blood concentration and resistance, therefore, it has excellent pharmaceutical properties.

Table 136 Comparative Example No. Structural formula ms 38

210 (M ⁺ +1) 39

288 (M ⁺ +1)

Pharmacological experiments

In accordance with the method described in European Journal of Pharmacology, vol. 254, pp. 211-221 (1994), IM-9 cells (4 × 10 ⁶ cells / tube) were reacted with 0.3 nM [ ³ H] ( Sar ⁹ , Met ¹¹ (O ₂ )) of substance P (Kd value: 0.17 nM) and a test compound adjusted to 10 nM in 50 mM Tris-HCl (pH 7.4, 25 ° C) containing 150 mM NaCl , 3 mM MnCl ₂ , 40 μg / ml bacitracin, 4 μg / ml leipeptin, 4 μg / ml chymostatin, 4 μg / ml phosphoramidone and 0.02% bovine serum albumin, at room temperature for 60 minutes. The mixture was suction filtered on a GF / C glass filter pretreated with 0.3% polyethyleneimine and washed twice with 3 ml of ice-cold reaction buffer containing neither bovine serum albumin nor any protein kinase inhibitors, and radioisotope (imp. / min) on the filter was measured using a liquid scintillation counter. Specific binding was calculated by subtracting non-specific binding (L-703606 (2 μM) having antagonistic activity for the NK1 receptor) from total binding, and the level of inhibition of specific binding of the labeled ligand was calculated based on 10 nM test compound.

The results are presented in the following Tables A1 and A2.

Table A1 Example No. Inhibition Level (%) Example No. Inhibition Level (%) 58 (a) 73 276 69 89 61 277 67 92 89 278 58 134 61 284 75 143 83 285 83 152 68 286 84 153 81 287 90 154 61 288 93 156 59 289 90 157 73 290 95 160 78 291 94 161 69 292 92 163 58 303 90 180 66 305 90 186 72 306 90 189 75 308 91

201 70 314 92 210 63 315 92 213 70 316 90 215 92 318 94 265 89 337 92 266 94 349 90 269 91 357 90 270 88 358 82 272 71 359 91 274 68 364 93 Table A2 Example No. Inhibition Level (%) Example No. Inhibition Level (%) 371 98 463 92 407 76 467 90 428 94 470 94 445 92 473 90 452 89 475 91 453 92 477 91 455 62 480 91 461 92

Industrial Applicability of the Invention

The compound of the present invention or a salt thereof has an excellent antagonistic effect on the tachykinin receptor. In addition, the compound of the present invention or its salt is excellent in terms of safety, absorption, brain transfer ability, metabolic stability, blood concentration and resistance, therefore, it has excellent pharmaceutical properties.

Claims (18)

1. The piperidine compound represented by the formula [I]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula :

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group, a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroatom where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by —N (R ³ ) -, where R ³ represents a hydrogen atom or optionally substituted alkyl group, R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, with the proviso that excludes N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine, or pharmaceutically etc. acceptability salt. 2. The compound according to claim 1, where R ¹ represents an optionally substituted alkyl group. 3. The compound according to claim 1, where R ¹ represents an optionally substituted hydroxyl group. 4. The compound according to claim 1, where R ¹ represents a substituted thiol group. 5. The compound according to claim 1, where R ¹ represents a substituted carbonyl group. 6. The compound according to claim 1, where R ¹ represents a substituted sulfinyl group. 7. The compound according to claim 1, where R ¹ represents a substituted sulfonyl group. 8. The compound according to claim 1, where R ¹ represents a group represented by the formula:

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized. 9. A compound selected from the following (a) to (s): (a) (2R, 4S) -1- [N- (1- (8) - (3,5-bistrifluoromethylphenyl) ethyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxy-2-methylpropionylamino) piperidine, (b) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino) piperidine, (c) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, (d) (2R, 4S) -1- [N- {1- (8) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (3-hydroxy-3-methylbutyrylamino) piperidine, (e) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino) piperidine, (f) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl ) piperidine, (g) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl ) piperidine, (h) (2R, 4S) -1- {N (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -2-hydroxypropanesulfonyl) piperidine (i) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((S) -3-hydroxybutyrylamino ) piperidine, (j) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -3-hydroxybutyrylamino ) piperidine, (k) (2R, 4S) -4- (4-acetylpiperazinocarbonyl) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4- fluoro-2-methylphenyl) piperidine, (l) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothiomorpholinocarbonyloxy) piperidine, (m) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfonyl) piperidine, (n) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethanesulfonyl) piperidine, (o) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (4-hydroxypiperidinocarbonyl) piperidine, (p) (2R, 4S) -1- {N (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine, (q) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - ((R) -2-hydroxypropionyl ) piperidine, (r) (2R, 4S) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (2-hydroxyacetylamino) piperidine and (s) (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 - (1-methylethylthio) piperidine, or their pharmaceutically acceptable salts. 10. A method of obtaining a piperidine compound of the formula [I ']:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula :

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroatom where the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized; or R ¹¹ and R ¹² taken together with an adjacent nitrogen atom form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydro-pyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, a tetrazinyl group, a tetrazolyl group and a tetrazolyl group optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, where R ³ represents a hydrogen atom or an optionally substituted alkyl group, R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula [II]:

where ring A, R ¹ and R ² have the above meanings, with a compound of the formula [III]:

where ring B, R ³ and R ⁴ have the above meanings, in the presence of a urea bond forming agent, and, if desired, conversion to a pharmaceutically acceptable salt thereof. 11. A method of obtaining a piperidine compound of the formula [Ia]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by -N (R ³⁾ - wherein R ³ represents a hydrogen atom or an optionally substituted alkyl group and R ⁴ represents a hydrogen atom or an optional a substituted alkyl group, or a pharmaceutically acceptable salt thereof, comprising reducing a compound of formula [IV]:

where ring A, ring B, R ² , Z and R ⁴ are as defined above, and if desired, converted to a pharmaceutically acceptable salt thereof. 12. A method of obtaining a piperidine compound of the formula [I-b]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by —N (R ³ ) -, where R ³ represents a hydrogen atom or an optionally substituted alkyl group, R ⁴ represents a hydrogen atom or optionally substituted alkyl group, R ¹¹ and R ^{12 are the} same or different and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, wherein the heterocyclic group is optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, or R ¹¹ and R ^12, taken together with the adjacent nitrogen atom form a heterocyclic group selected from piperidino , Azatsiklogeptilnoy group, pyrrolidino group, imidazolidinyl group geksagidropirimidinilnoy group tiazolidilnoy group, morpholino group, triazolyl group, tetrazolyl group and purinyl group, wherein the heterocyclic group is optionally substituted and the nitrogen atom in the heterocyclic group is optionally oxidized, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula [IV]:

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings, with a compound of the formula [V]:

where R ¹¹ and R ¹² have the above meanings, X ¹ represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or a magnesium atom, and, if desired, conversion to a pharmaceutically acceptable salt thereof. 13. A method of obtaining a piperidine compound of the formula [I-c]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ¹³ represents an optionally substituted carboxyl group, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or atom halogen, Z represents an oxygen atom or a group represented by —N (R ³ ) -, where R ³ represents a hydrogen atom or optionally substituted a an alkyl group, R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula [IV]:

where ring A, ring B, R ² , Z, R ³ and R ⁴ have the above meanings, with a compound of the formula [VI]:

where X ² represents a leaving group and R ¹³ has the above meanings, reduction of the obtained compound of formula [VII]:

where ring A, ring B, R ¹³ , R ² , Z, R ³ and R ⁴ have the above meanings, and, if desired, conversion to a pharmaceutically acceptable salt thereof. 14. A method of producing a piperidine compound of the formula [I ″]:

where ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R ¹ represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group or a group represented by the formula :

where R ¹¹ and R ^{12 are the} same or different, and each represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as heteroatoms, wherein the heterocyclic group is optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, or R ¹¹ and R ^12, taken together with the adjacent nitrogen atom, form a heterocyclic group selected from piperidinogr ppy, azatsiklogeptilnoy group, pyrrolidino group, imidazolidinyl group geksagidropirimidinilnoy group tiazolidilnoy group, morpholino group, triazolyl group, tetrazolyl group and purinyl group, wherein the heterocyclic group is optionally substituted, and the nitrogen atom in the heterocyclic group is optionally oxidized, R ² represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, and R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula [II]:

where the ring A, R ¹ and R ² have the above meanings, with a compound of the formula [III ′]:

where ring B and R ⁴ have the above meanings, in the presence of a urea bond forming agent, and, if desired, converting it into a pharmaceutically acceptable salt. 15. A pharmaceutical composition having antagonistic activity against the NK1 tachykinin receptor, containing an effective amount of a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 16. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of a disease selected from inflammatory, allergic diseases, pain, migraine, neuralgia, itching, cough, diseases of the central nervous system, diseases of the digestive system, nausea, vomiting, disorders of the urinary system, diseases of the circulatory system and disorders of the immune system. 17. A method for the treatment and prevention of diseases selected from inflammatory, allergic diseases, pain, migraine, neuralgia, itching, cough, diseases of the central nervous system, diseases of the digestive system, nausea, vomiting, disorders of the urinary system, diseases of the circulatory system and disorders of the immune system, comprising administering to the mammal a clinically effective dose of a compound according to any one of claims 1 to 9. 18. The method according to 17, where the disease is a violation of the urinary system. The priority of May 29, 2002 according to the application JP 2002-155744 is established according to claims 1 and 9-18 of the amended claims; priority from 07/12/2002 according to the application US 60 / 395,343 established in all paragraphs of the amended claims; priority of 08.28.2002 according to the application JP 2002-248755 is established in all respects of the amended claims; priority from 09/11/2002 according to the application US 60 / 409,595 established in all paragraphs of the amended claims.