JP2003321460A - Azole compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an azole compound having the production and secretion- promoting activity of a neurotrophic factor and useful for the prevention and treatment of diabetic neuropathy. <P>SOLUTION: This azole compound is expressed by formula (1) [wherein, R<SP>1</SP>is H, a halogen atom, a heterocyclic group which is allowed to be substituted, a thiol group which is allowed to be substituted or an amino group which is allowed to be substituted; A is a cyclic amino group which is allowed to be substituted or -NR<SP>2</SP>-W-D (wherein, R<SP>2</SP>is H or an alkyl; W is a bond or a di-valent acyclic hydrocarbon group: and D is a cyclic group which is allowed to be substituted or an acyl group which is allowed to be substituted); B is a hydrocarbon group which is allowed to be substituted or a heterocyclic group which is allowed to be substituted; X is oxygen, sulfur or nitrogen which is allowed to be substituted; and Y is a bond or a di-valent acyclic hydrocarbon group] or is its salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD [0001] The present invention has a neurotrophic factor production / secretion promoting action and prevents diabetic neuropathy and the like.
It relates to therapeutically useful azole compounds.

[0002]

The following compounds have been reported as azole compounds. Formula (1)

[Chemical 2] [In the formula, R ¹ represents a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and A is B may be substituted with an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxyl group. It has been reported that a compound represented by an aromatic group and Y represents a divalent aliphatic hydrocarbon group] is useful as a prophylactic / therapeutic agent for diabetes (see Patent Document 1). Formula (2)

[Chemical 3] [In the formula, R ¹ represents a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and A is B may be substituted with an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxyl group. A compound represented by an aromatic group, X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and Y is a divalent hydrocarbon group or a heterocyclic group. It has been reported to be useful as an accelerator (see Patent Document 2). Formula (3)

[Chemical 4] [Wherein, R ¹ is an optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group; R ² is hydrogen or an optionally substituted hydrocarbon group; X is O, S or-;
NR ⁴ — (wherein R ⁴ represents hydrogen or an alkyl group which may be substituted); A is an aromatic hydrocarbon group or an aromatic heterocyclic group which may be substituted, respectively. R ³ is of the formula —OR ⁵ — (wherein R ⁵ represents hydrogen or an optionally substituted hydrocarbon group) or —N
R ⁶ R ⁷ (wherein, R ^6, R ⁷ are the same or different and each represents hydrogen or optionally substituted hydrocarbon group, R ^6,
R ⁷ represents a group represented by the formula (R ⁷ may form a ring together with an adjacent nitrogen atom)], and it is reported that the compound represented by the formula [7] is useful as a retinoid-related receptor function regulator (Patent Reference 3).

[0003]

[Patent Document 1] International Publication No. WO97 / 36882 Pamphlet

[Patent Document 2] International Publication No. WO01 / 14372 Pamphlet

[Patent Document 3] International Publication No. WO00 / 01679 Pamphlet

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an azole compound having an excellent neurotrophic factor production / secretion promoting action and low toxicity.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have found that the 5-position of the azole ring has the formula: -Y-CO-A [A is an optionally substituted cyclic amino group or -NR ² -WD ( R ² is a hydrogen atom or an alkyl group, W is a bond or a divalent acyclic hydrocarbon group, and D is an optionally substituted cyclic group,
Represents an optionally substituted amino group or an optionally substituted acyl group), and Y represents a bond or a divalent acyclic hydrocarbon group]. Formula (I) having the above characteristics

[Chemical 5] [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group,
An optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. , X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and A and Y have the same meanings as described above], based on their characteristic chemical structure The present invention has been completed based on this finding that it has a trophic factor production / secretion action.

That is, the present invention includes: 1) a compound represented by the formula (I) or a salt thereof (hereinafter sometimes abbreviated as compound (I)); 2) a complex in which R ¹ may be substituted. a Hajime Tamaki which is compound (I); a 4) a is -NR ² -W-D (R ² is a hydrogen atom or an alkyl group; 3) a compound is a good cyclic amino group which may be substituted (I) , W represents a bond or a divalent acyclic hydrocarbon group, and D represents a cyclic group which may be substituted, an amino group which may be substituted or an acyl group which may be substituted). (I); 5) The compound according to 4) above, wherein D is a cyclic group which may be substituted; 6) Compound (I) wherein B is an optionally substituted aryl group having 6 to 14 carbon atoms; 7) compounds wherein X is an oxygen atom (I); 8) Y is a C _1-4 alkylene compound ( ); 9) 3- [2- (1H- benzimidazol-1-yl)
-4- (4-chlorophenyl) -5-oxazolyl] -N
-[4- (Diethylphosphonomethyl) phenyl] propionamide; 3- [4- (4-chlorophenyl) -2- (4-morpholinyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) Phenyl] propionamide; 3- [4
-(4-Chlorophenyl) -2-phenyl-5-oxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl]
Propionamide; 3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] -N- {4-[(2-oxide-1,3,2-di Oxaphosphinan-2-yl) methyl] phenyl} propionamide; 4- [2- (1H-benzimidazole-
1-yl) -4- (4-chlorophenyl) -5-oxazolyl] -N-[(4-dimethylphosphonomethyl) phenyl]
Butanamide; 1- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} -4-piperidinol; 4-
{3- [2- (1H-benzimidazol-1yl) -4-
(4-Chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1-dioxide; 4- [2-
(1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] -N-[(4-diethylphosphonomethyl) phenyl] butanamide; or 4-
{3- [4- (4-chlorophenyl) -2- (1-methyl-
1H-indol-3-yl) -5-oxazolyl] propanoyl} thiomorpholine-1,1′-dioxide; 10) Compound (I) or a prodrug thereof; ) The above-mentioned 1 which is a prophylactic / therapeutic agent for diabetic neuropathy
0) The pharmaceutical according to 0); 12) The pharmaceutical according to 10), which is a pain ameliorating agent; 13) A neurotrophic factor production / secretion promoting agent containing the compound (I) or a prodrug thereof; Use of Compound (I) or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for: 15. A mammal, which is characterized by administering an effective amount of Compound (I) or a prodrug thereof to the mammal. 16) Use of compound (I) or a prodrug thereof for the manufacture of a pain ameliorating agent in a method for preventing or treating diabetic neuropathy; A method for improving pain in a mammal, which comprises administering Compound (I) or a prodrug thereof for producing a neurotrophic factor production / secretion promoter 19) A method for promoting the production or secretion of neurotrophic factor in a mammal, which comprises administering an effective amount of compound (I) or a prodrug thereof to the mammal;

The compound represented by the formula (I) is described in detail below. In the formula (I), examples of the “halogen atom” represented by R ¹ include fluorine, chlorine, bromine and iodine. Of these, fluorine and chlorine are preferred.
Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and an araliphatic hydrocarbon. Group, alicyclic aliphatic hydrocarbon group and the like.
Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, specifically, an alkyl group, an alkenyl group, an alkynyl group and the like.
Preferable examples of the alkyl group include alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethyl. Propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl,
Decyl etc. are mentioned. Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl and 2-methyl-1.
-Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2
-Pentenyl, 3-pentenyl, 4-pentenyl, 4-
Methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. Preferable examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-
Butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, etc. Is mentioned.

The alicyclic hydrocarbon group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, specifically, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like. Can be mentioned. Preferable examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.
2.2] octyl, bicyclo [3.2.1] octyl,
Bicyclo [3.2.2] nonyl, Bicyclo [3.3.
1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like. Preferable examples of the cycloalkenyl group include cycloalkenyl groups having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl and 3
-Cyclopenten-1-yl, 2-cyclohexene-1
-Yl, 3-cyclohexen-1-yl and the like. A preferred example of the cycloalkadienyl group is a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-
Cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-
Ile, etc. Examples of the aromatic hydrocarbon group include aryl groups having 6 to 14 carbon atoms. Preferable examples of the aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like. Of these, phenyl and naphthyl are preferable. The aryl group may be partially saturated, and examples of the partially saturated aryl group include dihydroindenyl, tetrahydronaphthyl and the like.

Examples of the araliphatic hydrocarbon group include araliphatic hydrocarbon groups having 7 to 14 carbon atoms, specifically, aralkyl group, arylalkenyl group, arylalkynyl group and the like. Preferable examples of the aralkyl group include an aralkyl group having a carbon number of 7 to 14, such as benzyl,
Examples thereof include phenethyl, naphthylmethyl, benzhydryl, phenylpropyl, phenylbutyl and diphenylethyl. Preferable examples of the arylalkenyl group include an arylalkenyl group having 8 to 13 carbon atoms, such as styryl. Preferable examples of the arylalkynyl group include arylalkynyl groups having 8 to 13 carbon atoms, such as phenylethynyl. Examples of the alicyclic aliphatic hydrocarbon group include an alicyclic aliphatic hydrocarbon group having 4 to 13 carbon atoms, specifically, a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkenylalkyl group, and the like. Preferable examples of the cycloalkylalkyl group include cycloalkylalkyl groups having 4 to 13 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl. Preferable examples of the cycloalkylalkenyl group include cycloalkylalkenyl groups having 5 to 13 carbon atoms, such as cyclopropylethenyl, cyclopentylethenyl, cyclohexylethenyl and the like. Preferred examples of the cycloalkenylalkyl group include:
Examples thereof include a cycloalkenylalkyl group having 4 to 13 carbon atoms, such as cyclopentenylmethyl, cyclopentenylethyl, cyclohexenylmethyl, cyclohexenylethyl and the like.

The "optionally substituted hydrocarbon group" represented by R ¹ may have 1 to 3 substituents at substitutable positions. As such a substituent, for example, a halogen atom, nitro, oxo, C _1-3 alkylenedioxy, an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, a substituted Examples thereof include an optionally substituted amino group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally substituted acyl group, and the like. Here, examples of the halogen atom include fluorine, chlorine, bromine and iodine. Of these, fluorine and chlorine are preferred. Examples of C _1-3 alkylenedioxy include methylenedioxy,
Examples thereof include ethylenedioxy. Examples of the "aromatic heterocyclic group" in the "optionally substituted aromatic heterocyclic group" include, as ring-constituting atoms, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms. And a 5- to 7-membered monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group contained therein. The condensed aromatic heterocyclic group includes, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. Examples thereof include a group condensed with a 5-membered ring. Suitable examples of the aromatic heterocyclic group include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl),
Pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl),
Pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),
Imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl,
Thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5
-Thiazolyl), isothiazolyl, oxadiazolyl (eg 1,2,4-oxadiazol-5-yl, 1,
3,4-oxadiazol-2-yl), thiadiazolyl (eg 1,3,4-thiadiazol-2-yl), triazolyl (eg 1,2,4-triazol-1-yl, 1,2,2) 4-triazol-3-yl, 1,2,3
-Triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl),
Tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), quinolyl (eg, 2-quinolyl, 3-
Quinolyl, 4-quinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl,
3-benzofuryl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, Benzimidazol-1-yl, benzimidazol-2-yl), indolyl (eg, indole-1-yl)
Yl, indol-3-yl), 1H-indazolyl (eg 1H-indazol-3-yl), 1H-pyrrolo [2,3-b] pyrazinyl (eg 1H-pyrrolo [2,3
-B] pyrazin-2-yl), 1H-pyrrolopyridinyl (eg, 1H-pyrrolo [2,3-b] pyridin-6-yl), 1H-imidazopyridinyl (eg, 1H-imidazo [4,5,5- b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl), 1H-imidazopyrazinyl (eg, 1H-imidazo [4,5-b] pyrazin-2-yl) , Triazinyl, isoquinolyl, benzoxazodiazolyl, benzothiadiazolyl, benztriazolyl and the like.

The "non-aromatic heterocyclic group" in the "optionally substituted non-aromatic heterocyclic group" is, for example, a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the carbon atom as a ring-constituting atom. A 5- to 7-membered monocyclic non-aromatic heterocyclic group or condensed non-aromatic heterocyclic group containing 1 to 4 atoms can be mentioned. Examples of the condensed non-aromatic heterocyclic group include these 5- to 7-membered monocyclic non-aromatic heterocyclic groups and 6-membered rings containing 1 to 2 nitrogen atoms,
Examples thereof include a group condensed with a benzene ring or a 5-membered ring containing one sulfur atom. Preferred examples of the non-aromatic heterocyclic group include pyrrolidinyl (eg, 1-pyrrolidinyl), piperidinyl (eg, piperidino), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino),
Piperazinyl (eg, 1-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimine-1-yl),
Oxazolidinyl (eg, oxazolidin-3-yl),
Thiazolidinyl (eg, thiazolidin-3-yl), imidazolidinyl (eg, imidazolidin-3-yl), imidazolinyl (eg, imidazolin-1-yl, imidazolin-2-yl), oxazolinyl (eg, oxazoline-yl)
2-yl), thiazolinyl (eg thiazolin-2-yl), oxazinyl (eg oxazin-2-yl), tetrahydrofuranyl, azepanyl, tetrahydropyridinyl (eg 1,2,3,6-tetrahydropyridine- 1
-Yl), dihydrobenzofuranyl, dioxolanyl,
Examples include dithiolanyl and tetrahydroisoquinolyl. The above aromatic heterocyclic group and non-aromatic heterocyclic group may have 1 to 3 substituents at substitutable positions. Such substituents include, for example, nitro,
Hydroxy, amino, oxo, halogen atom (eg, fluorine, chlorine, bromine, iodine), C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (Eg, methyl, ethyl), 1-3
Individual halogen atoms (eg, fluorine, chlorine, bromine, iodine)
And a C _1-6 alkoxy group (eg, methoxy, ethoxy), C _6-14 aryl (eg, phenyl) which may be substituted with

The "optionally substituted amino group" is, for example, 1 carbon atom which may have a substituent.
-10 alkyl group, C2-C10 alkenyl group,
A cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aralkyl having 7 to 14 carbon atoms, an acyl group having 1 to 15 carbon atoms or a heteroaryl group; Mention may be made of mono- or di-substituted amino groups. Here, "1 to 1 carbon atoms
0 alkyl group "," C2-C10 alkenyl group "," C3-C10 cycloalkyl group "," C3-C10 cycloalkenyl group "," C6-C14 "
"Aryl group" and "aralkyl having 7 to 14 carbon atoms"
Examples thereof include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ . As the "acyl group having 1 to 15 carbon atoms",
What is illustrated as an acyl group in the below-mentioned "acyl group which may be substituted" is mentioned. The acyl group is
Preferably formyl, C _1-10 alkyl-carbonyl,
C _1-6 alkoxy-carbonyl, C _6-14 aryl-carbonyl, C _7-13 aralkyl-carbonyl, aromatic heterocycle-carbonyl, 5- to 7-membered non-aromatic heterocycle-carbonyl, C _3-10 cycloalkyl- Carbonyl (eg, cyclopentanecarbonyl, cyclohexanecarbonyl); C _8-13 arylalkenyl-carbonyl (eg,
Styrylcarbonyl); C _8-13 arylalkynyl-
Carbonyl (eg, phenylethynylcarbonyl); C
_6-14 arylsulfonyl (eg, phenylsulfonyl);
Mono- or di-C _1-6 alkyl-carbamoyl
(Eg, methylcarbamoyl, tert-butylcarbamoyl); C _3-10 cycloalkyl-carbamoyl (eg,
Cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl); C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl); C
_7-14 aralkyl-carbamoyl (eg, benzylcarbamoyl, phenethylcarbamoyl, diphenylethylcarbamoyl); C _4-13 cycloalkylalkyl-carbamoyl (eg, cyclohexylmethylcarbamoyl); aromatic heterocyclic carbamoyl (eg, isoxazolylcarbamoyl, Benzothiazolylcarbamoyl); non-aromatic heterocyclic carbamoyl (eg, pyrrolidinylcarbamoyl); C _7-14 aralkyloxy-carbamoyl (eg, benzyloxycarbamoyl); Further, as the "acyl group having 1 to 15 carbon atoms", C _1-6
Alkoxy-carbamoyl (eg, methoxycarbamoyl), C _1-6 alkoxy-carbonylcarbamoyl
(Examples: methoxycarbonylcarbamoyl, ethoxycarbonylcarbamoyl) and the like.

Preferable examples of C _1-10 alkyl-carbonyl include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Preferable examples of C _1-6 alkoxy-carbonyl include (eg, tert-butoxycarbonyl) and the like. Suitable examples of C _6-14 aryl-carbonyl include benzoyl and the like. Preferable examples of C _7-13 aralkyl-carbonyl include benzylcarbonyl, phenethylcarbonyl and the like. Preferable examples of aromatic heterocycle-carbonyl include furylcarbonyl, pyrrolylcarbonyl, thienylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, 1H-indazolylcarbonyl, benzofuranylcarbonyl, quinolylcarbonyl and the like. Preferred examples of the 5- to 7-membered non-aromatic heterocycle-carbonyl include tetrahydrofurylcarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, hexamethyleneiminylcarbonyl, thiazolidinylcarbonyl and the like. To be Examples of the "heteroaryl group" include the aromatic heterocyclic groups exemplified as the substituents of the "optionally substituted heterocyclic group" for R ¹ . Of these, pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like are preferable.

These "alkyl groups having 1 to 10 carbon atoms",
"C2-C10 alkenyl group", "C3-C10
"Cycloalkyl group", "cycloalkenyl group having 3 to 10 carbon atoms", "aryl group having 6 to 14 carbon atoms", "aralkyl having 7 to 14 carbon atoms", "acyl group having 1 to 15 carbon atoms" and The "heteroaryl group" may have 1 to 2 substituents at substitutable positions, and examples of such a substituent include a halogen atom (eg, fluorine, chlorine,
Bromine, iodine); C optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine)
_1-6 alkyl group (eg, methyl, trifluoromethyl);
C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); hydroxy; nitro; C
_1-6 alkyl group (eg, methyl) amino group which may be mono- or di-substituted; C _1-6 alkylsulfonyl group (eg, methylsulfonyl); oxo; cyano; C
_7-13 aralkyl group (eg, benzyl); C _1-6 alkoxy-
Carbonylamino-C _1-6 alkyl group (eg, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl); mono- or di-C _1-10 alkylphosphono-
C _1-6 alkyl group (eg, dimethylphosphonomethyl, diethylphosphonomethyl); mono- or di-C _1-6 alkylamino-C _1-6 alkyl group (eg, dimethylaminomethyl) C _1-6 alkoxy —C _6-14 aryl group (eg, methoxyphenyl); C _1-6 alkyl-carbonyl-C
_6-14 aryl group (eg, acetylphenyl); oxo,
Heterocyclic groups optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl (eg, methyl, ethyl) and C _1-6 alkoxy (eg, methoxy, ethoxy) (eg,
Thienyl, furyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,
Indolyl, 1H-indazolyl, benzimidazolyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl); C _6-14 aryloxy group (eg, phenyloxy); C _7-13 aralkyloxy group (eg, benzyloxy); C _1-6 alkylthio group (eg methylthio); C _6-14 arylthio group optionally substituted by 1 to 3 halogen atoms (eg phenylthio); C _1-6 alkyl optionally substituted heterocycle Cyclic thio group (eg, pyrimidinylthio); C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl); Heterocyclic carbonyl group (eg, dihydroindolylcarbonyl); C _1-6 alkylsulfonyl group (eg , Methylsulfonyl); C _6-14 arylsulfonyl group (eg, phenylsulfonyl) ); Carbamoyl; C
_1-6 alkoxy-carboxamide group (eg, methoxycarboxamide, ethoxycarboxamide); sulfamoyl group optionally substituted by C _1-6 alkyl-carbonyl (eg, sulfamoyl, acetylsulfamoyl); and the like. Among these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine); 1 to
C _1-6 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 1 to 3 halogen atoms (eg, fluorine) C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with chlorine, chlorine, bromine, iodine); hydroxy; nitro; amino; C _1-6 alkylsulfonyl group (eg, methylsulfonyl) and the like are preferable. .

The substituted amino group is, for example, mono.
-Or di-C_1-10Alkylamino (eg, methylami)
No, dimethylamino, ethylamino, diethylamino,
Ethylmethylamino, propylamino, dibutylami
No); [C_1-6Substituted with alkoxy-carbonyl
May be] mono- or di-C_2-10Alkenylamino
(Eg, diallylamino); mono- or di-C_3-10Shiku
Lower alkylamino (eg, cyclohexylamino); [C
_1-6Heterocyclic thio optionally substituted with alkyl (eg,
Pyrimidinylthio), substituted with 1 to 3 halogen atoms
May be C_{6-1 Four}Arylthio, cyano, C_1-6A
Rukiruthio, halogen atom, heterocyclic carbonyl (eg, di-
1 to 3 selected from hydroindolylcarbonyl)
Optionally substituted with 4 substituents] mono- or di-
C_1-10Alkyl-carboxamides (eg acetylamido)
No, propionylamino); C_6-14Aryl-carboxy
Samide (eg, benzoylamino); C_6-14Arylami
No (eg, phenylamino); NC_1-10Alkyl-N-
C_6-14Arylamino (eg, N-methyl-N-phenyl
Amino); N-C_1-10Alkyl-NC_7-13Aralkyl
Amino (eg, N-methyl-N-benzylamino); mono
-Or di-C_1-6Alkoxy-carboxamide (eg, t
ert-butoxycarboxamide); [C_1-6Alkoxy,
C_6-14Aryloxy, heterocyclic group (e.g., triazolyl,
1 to 3 substituents selected from tetrazolyl)
May be substituted] mono- or di-C_6-14Aryl
-Carboxamides (eg phenylcarboxamide);
[C_1-6No 1 selected from alkoxy and halogen atoms
Optionally substituted with 3 substituents] mono- or
The-C_{7 −13}Aralkyl-carboxamide (eg, benz
Lucarboxamide, Phenethylcarboxamide, Pheny
Lupropylcarboxamide, phenylbutylcarboxa
(Mido); [halogen atom, C_1-61 selected from alkyl
To optionally substituted with 3 substituents]
Ring-carboxamide (e.g., furylcarboxamide,
Lorylcarboxamide, thienylcarboxamide, pyri
Dilcarboxamide, pyrimidinylcarboxamide, 1
H-indazolyl carboxamide, benzofuranyl carb
Voxamide, quinolylcarboxamide); [oxo, C
_1-6Alkoxy-carbonyl, C_1-6Alkoxy-C
_6-14Aryl (eg, methoxyphenyl), C_1-6Archi
Le-carbonyl-C_6-14Aryl (eg, acetylphene
Nil), carbamoyl, C_7-13Aralkyl (eg Ben
1) selected from a heterocyclic group (eg, piperidino)
It may be substituted with 3 substituents] 5 to 7
Membered non-aromatic heterocycle-carboxamide (e.g. tetrahydro
Furylcarboxamide, Thiomorpholinocarboxami
De, piperidinocarboxamide, piperazinocarboxa
Mid, hexamethyleneiminylcarboxamide, thiazo
Lysinylcarboxamide); [C_1-6Alkoxy-carbo
Xamide (eg, methoxycarboxamide, ethoxycarl
C optionally substituted with voxamide)_1-6In alkyl
May be substituted] C_3-10Cycloalkyl-
Ruboxamide (eg, cyclopentylcarboxamide,
Chlohexylcarboxamide); [Substituted with halogen atom
May have been done] C_8-13Arylalkenyl-cal
Voxamide (eg, styrylcarboxamide); C_8-13
Arylalkynyl-carboxamide (eg, phenylene
Tinylcarboxamide); Aromatic heterocycle (eg, thieni)
Le, frill, indolyl) -C_1-6Alkyl-carboxy
Samide; C_6-14Arylsulfonylamino (eg, phenyl
Sulfonylsulfonyl)); [hydroxy, C_1-6Arcoki
Shi, C_1-6Alkylthio, halogen atom, C_{1 -6}A
Lucoxy-carbonyl, C_1-6Alkoxy-carboxy
Samide, cyano, C_1-6Alkylsulfonyl, carba
Substituted with 1 to 3 substituents selected from moyl
May be present] Mono- or Di-C_1-6Alkyl-cal
Vamoylamino (eg, methylcarbamoylamino, tert-
Butylcarbamoylamino); [substituted by hydroxy
May be present] C_3-10Cycloalkyl-carbamoy
Luamino (eg, cyclopropylcarbamoylamino,
Clopentylcarbamoylamino, cyclohexylcar
(Vamoylamino); [position with 1 to 3 halogen atoms
C that may be replaced_1-6Alkyl, C_1-6Alkyl-
Sulfamoyl, which may be substituted with carbonyl, mo
No or di-C_1-6Alkylamino, mono-
Is di-C_1-10Alkylphosphono-C _1-6Alkyl
Group, halogen atom, C_6-14Arylsulfonyl (eg,
Phenylsulfonyl), C_7-13Aralkyloxy
(Eg benzyloxy), C_1-6Choose from alkoxy
Optionally substituted with 1 to 3 substituents] C
_{6-1 Four}Aryl-carbamoylamino (eg, phenyl
Carbamoylamino); [mono- or di-C_1-6A
1 to 3 selected from rualkylamino and halogen atoms
C optionally substituted with a substituent of_1-6Alkyl; halo
Gen atom; sulfamoyl; hydroxy; C_1-6Al
Substituted with 1 to 3 substituents selected from Koxy
May be present] C_7-14Aralkyl-carbamoylami
No (eg, benzylcarbamoylamino, phenethylcar)
Vamoylamino, diphenylethylcarbamoylami
No); C_1-6Alkoxy-carbonylcarbamoylurea
Mino (e.g., methoxycarbonylcarbamoylamino,
Toxycarbonylcarbamoylamino); C_4-13Cyclo
Alkylalkyl-carbamoylamino (eg cyclohexyl
Xylmethylcarbamoylamino); [oxo, C_1-6
Alkyl, hydroxy, C_1-6Selected from alkoxy
It may be substituted with 1 to 3 substituents] Heterocycle
(Eg thienyl, furyl, oxazolyl, isoxazoly
Le, imidazolyl, triazolyl, tetrazolyl, pyri
Jill, indolyl, 1H-indazolyl, benzimida
Zolyl, tetrahydrofuryl, pyrrolidinyl, piperidi
Nyl, morpholinyl, thiomorpholinyl) -C_{1-1 0}A
Rucyl-carbamoylamino (eg, methylcarbamoyl
Amino, ethylcarbamoylamino); [C_1-6Archi
Le and C_1-61 to 3 selected from alkoxy
Optionally substituted with a substituent] aromatic heterocyclic carbamo
Ilamino (eg, isoxazolylcarbamoylamino,
Benzothiazolylcarbamoylamino); [C_1-6Al
Optionally substituted with kill] non-aromatic heterocyclic carbamo
Ilamino (eg, pyrrolidinylcarbamoylamino);
C_7-14Aralkyloxy-carbamoylamino
(Eg, benzyloxycarbamoylamino);
You can

The "optionally substituted hydroxy group" is, for example, an optionally substituted "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", and "3 carbon atoms". -10 cycloalkyl group "," C3-C10 cycloalkenyl group "," C6-1 "
4 aryl group "," aralkyl having 7 to 14 carbon atoms ",
Examples thereof include a hydroxy group which may be substituted with an "acyl group having 1 to 15 carbon atoms" or a "heteroaryl group". Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "cycloalkenyl group having 3 to 10 carbon atoms", " Examples of the "aryl group having 6 to 14 carbon atoms" and "aralkyl having 7 to 14 carbon atoms" include those exemplified as the "hydrocarbon group" in the "optionally substituted hydrocarbon group" for R ^1. To be "C1-C1
Examples of the “acyl group of 5” include those exemplified as the substituents of the above-mentioned “optionally substituted amino group”. Examples of the "heteroaryl group" include the aromatic heterocyclic groups exemplified as the substituents of the "optionally substituted heterocyclic group" for R ¹ . Of these, pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like are preferable.

These "alkyl groups having 1 to 10 carbon atoms",
"C2-C10 alkenyl group", "C3-C10
"Cycloalkyl group", "cycloalkenyl group having 3 to 10 carbon atoms", "aryl group having 6 to 14 carbon atoms", "aralkyl having 7 to 14 carbon atoms", "acyl group having 1 to 15 carbon atoms" and The "heteroaryl group" may have 1 to 2 substituents at substitutable positions, and examples of such a substituent include a halogen atom (eg, fluorine, chlorine,
Bromine, iodine), C optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine)
_1-6 alkyl group (eg, methyl, trifluoromethyl),
C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), hydroxy, nitro, amino, C _1-6 alkyl A sulfonyl group (eg, methylsulfonyl) and the like can be mentioned.

The substituted hydroxy group is, for example, an optionally substituted alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group,
Examples thereof include an acyloxy group and a heteroaryloxy group. Preferable examples of the alkoxy group have 1 to 10 carbon atoms.
Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-
Examples include butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy and the like. Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy and 3-hexenyloxy. Preferable examples of the cycloalkyloxy group include cycloalkyloxy groups having 3 to 10 carbon atoms, such as cyclobutoxy, cyclopentyloxy and cyclohexyloxy. Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy.
Preferable examples of the aryloxy group include C6 to C14.
Aryloxy groups such as phenoxy and naphthyloxy. Preferable examples of the aralkyloxy group include an aralkyloxy group having a carbon number of 7 to 14, such as benzyloxy, phenethyloxy and naphthylmethyloxy. Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms such as C _1-6 alkyl-carbonyloxy (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy) and the like. Preferable examples of the heteroaryloxy group include a 5- to 7-membered monocyclic heteroaryloxy group such as 2-pyridyloxy, 3-pyridyloxy, 2-imidazolyloxy, 2-pyrimidinyloxy, 1,2,4. -Triazol-5-yloxy etc. are mentioned.

The above-mentioned alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group, acyloxy group and heteroaryloxy group have 1 to 2 substituents at substitutable positions. It may have a group, and examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). A C _1-6 alkyl group which may be substituted with (eg, methyl, trifluoromethyl), 1 to 3 halogen atoms (eg, fluorine, chlorine,
C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with bromine, iodine), hydroxy, nitro, amino, C _1-6 alkylsulfonyl group (eg, methylsulfonyl) and the like can be mentioned.

Examples of the thiol group which may be substituted include, for example, "C 1 to C 1 which may be substituted".
"10 alkyl group", "C2-C10 alkenyl group", "C3-C10 cycloalkyl group", "C3-C10 cycloalkenyl group", "C6-C14"
Aryl group "," aralkyl having 7 to 14 carbon atoms ",
Examples thereof include a thiol group which may be substituted with an "acyl group having 1 to 15 carbon atoms" or a "heteroaryl group". Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "cycloalkenyl group having 3 to 10 carbon atoms", ""Aryl group having 6 to 14 carbon atoms", "7 to 7 carbon atoms"
Examples of the “14 aralkyl”, “acyl group having 1 to 15 carbon atoms” and “heteroaryl group” include those exemplified in the above-mentioned “optionally substituted hydroxy group”. These may have 1 to 2 substituents at substitutable positions, and examples of such substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine), 1 to 3 substituents. Halogen atom (eg, fluorine, chlorine,
C _1-6 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with bromine, iodine), substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) Also a C _1-6 alkoxy group (eg, methoxy,
Ethoxy), hydroxy, nitro, amino, C _1-6 alkylsulfonyl group (e.g., methylsulfonyl), oxo,
Pyridyl and the like can be mentioned.

The substituted thiol group is, for example,
Optionally substituted alkylthio and alkenyl
Thio, cycloalkylthio, cycloalkenylthio, a
Reelthio, aralkylthio, acylthio, heteroant
Luthio and the like can be mentioned. Suitable examples of alkylthio group
Is an alkylthio group having 1 to 10 carbon atoms, for example,
Tylthio, ethylthio, propylthio, isopropylthio
O, butylthio, isobutylthio, sec.-butylthio,
t.-butylthio, pentylthio, isopentylthio, ne
Opentylthio, hexylthio, heptylthio, nonyl
Thio and the like. As a preferred example of the alkenylthio group
Is an alkenylthio group having 2 to 10 carbon atoms, for example, ari.
Allylthio, crotylthio, 2-pentenylthio
O, 3-hexenylthio and the like. Cycloal
Preferable examples of the cyruthio group include a cyclo group having 3 to 10 carbon atoms.
Lower alkylthio groups such as cyclobutylthio, cyclopepyl
Examples thereof include butylthio and cyclohexylthio. Shiku
Preferable examples of the alkenylthio group have 3 to 1 carbon atoms.
A cycloalkenylthio group of 0, for example 2-cyclopente
Nylthio, 2-cyclohexenylthio and the like can be mentioned.
It Preferred examples of the arylthio group include 6 to 1 carbon atoms.
4 arylthio groups, eg phenylthio, naphthylti
Oh, etc. As a preferred example of the aralkylthio group
Is an aralkylthio group having 7 to 14 carbon atoms, for example, benzyl.
Examples include ruthio, phenethylthio, and naphthylmethylthio.
To be Preferable examples of the acylthio group have 2 to 2 carbon atoms.
13 acylthio groups, eg C _1-6Alkyl-carboni
Ruthio group (eg, acetylthio, propionylthio, buty
Rilthio, isobutyrylthio) and the like. Hetero
A preferred example of the arylthio group is a 5- to 7-membered monovalent group.
Cyclic heteroarylthio groups, such as 2-pyridylthio,
3-pyridylthio, 2-imidazolylthio, 2-pyrimy
Dinylthio, 1,2,4-triazol-5-ylchi
O, 1,2,4-triazol-3-ylthio, etc.
To be The above-mentioned alkylthio group, alkenylthio group,
Cycloalkylthio group, cycloalkenylthio group, ant
Group, aralkylthio group, acylthio group and
1 to 2 teloarylthio groups at substitutable positions
May have a substituent of
Is, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine
Arsenic), 1-3 halogen atoms (eg, fluorine, chlorine,
C optionally substituted with bromine, iodine)_1-6Alkyl
(Eg, methyl, trifluoromethyl), 1-3 halo
Substituted with a gen atom (eg, fluorine, chlorine, bromine, iodine)
May be C_1-6Alkoxy (eg methoxy, eth
Xy), hydroxy, nitro, amino, C_1-6Alkyl
Sulfonyl (eg, methylsulfonyl), oxo, pyridi
And the like.

The acyl group in the "optionally substituted acyl group" is, for example, the formula: --COR ³ , --CO--.
_{^{OR 3, -SO 2 R 3,}} -SOR 3, -PO 3 R 3 R 4, -
CO-NR ^3a R ^4a , -CS-NR ^3a R ^4a [In the formula, R ³ and R ⁴ are the same or different and each represents a hydrogen atom,
It represents a hydrocarbon group or a heterocyclic group. Also, R ³ and R ⁴
May form a heterocycle with the adjacent oxo-substituted phosphorus atom and two oxygen atoms. R ^3a and R
^4a are the same or different and represent a hydrogen atom, a hydrocarbon group or a heterocyclic group, or R ^4a and R ^5a may form a nitrogen-containing heterocycle with an adjacent nitrogen atom]. Groups and the like. Examples of the “hydrocarbon group” represented by R ³ , R ⁴ , R ^3a or R ^4a include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ^1. To be The hydrocarbon group is preferably an alkyl group having 1 to 10 carbon atoms (preferably methyl, ethyl, propyl, butyl, tert.
-Butyl, pentyl, 1-ethylpropyl, 2,2-dimethylpropyl, isopentyl, hexyl); carbon number 2
-10 alkenyl groups (preferably 1-propenyl);
C2-C10 alkynyl group (preferably 2-propynyl); C3-C1 which may be condensed with a benzene ring
0 cycloalkyl group (preferably cyclopropyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl); cycloalkenyl group having 3 to 10 carbon atoms (preferably 2-cyclohexenyl); cycloalkane having 3 to 10 carbon atoms (preferably cyclopentane) ) A C6-14 aryl group which may be condensed with (preferably phenyl, dihydroindenyl, biphenylyl); C7-
14 aralkyl groups (preferably benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, benzhydryl, diphenylethyl); 8 to 8 carbon atoms
13 arylalkenyl groups (preferably styryl);
Arylalkynyl group having 8 to 13 carbon atoms (preferably phenylethynyl); cycloalkylalkyl group having 4 to 13 carbon atoms (preferably cyclohexylmethyl); cycloalkenylalkyl group having 4 to 13 carbon atoms (preferably cyclohexenylmethyl, Cyclohexenylethyl) and the like.

The "heterocyclic group" represented by R ³ , R ⁴ , R ^3a or R ^4a is an aromatic heterocyclic group exemplified as the substituent of the "optionally substituted hydrocarbon group" represented by R ^1. Examples include a cyclic group and a non-aromatic heterocyclic group. The heterocyclic group is preferably thiazolyl, oxazolyl,
Isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl, isoquinolyl,
Pyrrolidinyl, piperidinyl, piperazinyl, furyl,
Thienyl, pyrimidinyl, benzofuryl, 1H-indazolyl, morpholinyl, thiomorpholinyl, hexamethyleneiminyl, tetrahydroisoquinolyl, oxazolidinyl, thiazolidinyl and the like.

The heterocyclic ring formed by R ³ and R ⁴ together with the adjacent oxo-substituted phosphorus atom and two oxygen atoms includes, for example, an oxo-substituted phosphorus atom and two oxygen atoms other than carbon atoms as ring-constituting atoms. Further, a 4- to 7-membered heterocycle optionally containing 1 or 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, and the like can be mentioned. Specific examples of such a heterocycle include 2-oxide-1,3,2-dioxaphosphinane;
2-oxide-1,3,2-dioxaphosphorane and the like can be mentioned. The “nitrogen-containing heterocycle” formed by R ^3a and R ^4a together with the adjacent nitrogen atom includes, for example, at least one nitrogen atom other than carbon atom as a ring-constituting atom, and further includes an oxygen atom, a sulfur atom and a nitrogen atom. Optionally containing 1 or 2 heteroatoms 5
And a 7-membered nitrogen-containing heterocycle. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine,
Pyrazolidine, piperidine, piperazine, morpholine,
Examples thereof include thiomorpholine.

Preferred examples of "acyl group" include formyl
Carboxyl; Thiocarbamoyl;
C_1-10Alkyl-carbonyl (eg, acetyl, propyl
Onyl, butyryl, isobutyryl, valeryl, isovale
Lil, pivaloyl, hexanoyl, heptanoyl, oc
Tanoyle); C_2-10Alkenyl-carbonyl (eg,
Rotonyl); C_3-10Cycloalkyl-carbonyl
(Eg cyclobutanecarbonyl, cyclopentanecarbo
Nyl, cyclohexanecarbonyl, cycloheptanecal
Bonyl); C_3-10Cycloalkenyl-carbonyl
(Eg, 2-cyclohexenecarbonyl); C_6-14Ants
-Carbonyl (eg, benzoyl, 1-naphthoyl, 2
-Naphthoyl); C_7-14Aralkyl-carbonyl
(Eg benzylcarbonyl, phenethylcarbonylphen
Nylpropylcarbonyl, phenylbutylcarboni
Le); C_8-13Arylalkenyl-carbonyl (eg,
Styrylcarbonyl); C_8-13Arylalkynyl-
Carbonyl (eg, phenylethynylcarbonyl); aroma
Group heterocyclic carbonyls (eg, nicotinoyl, isonicotino
Yl, furyl carbonyl, thienyl carbonyl, pirimi
Dinylcarbonyl, benzofuranylcarbonyl, 1H-
Indazolylcarbonyl, quinolylcarbonyl);
Aromatic heterocyclic carbonyl (eg, pyrrolidinylcarbonyl,
Piperidinocarbonyl, morpholinocarbonyl, thiomo
Ruphorinocarbonyl, piperazinocarbonyl, thiazoli
Dinyl carbonyl, hexamethylene iminyl carbonyl
, Tetrahydroisoquinolylcarbonyl); C_1-6
Alkoxy-carbonyl (e.g., methoxycarbonyl, ether
Toxycarbonyl, Propoxycarbonyl, Butoxyca
Rubonyl, tert-butoxycarbonyl); C_6-14A
Reeloxy-carbonyl (eg, phenyloxycarbo)
Nyl, naphthyloxycarbonyl); C_7-14Aral
Kiroxy-carbonyl (eg, benzyloxycarbonyl
, Phenethyloxycarbonyl); mono- or di-
C_1-6Alkyl-carbamoyl (e.g., methylcarbamoyl
Yl, ethylcarbamoyl, dimethylcarbamoyl, di
Ethylcarbamoyl, ethylmethylcarbamoyl, pro
Pyrcarbamoyl, butylcarbamoyl, tert-butyl
Carbamoyl, pentylcarbamoyl, hexylcarba
Moyle); mono- or di-C_1-6Alkyl-thioca
Lubamoyl (eg, methylthiocarbamoyl, ethylthio
Carbamoyl); C_6-14Aryl-carbamoyl
(Eg, phenylcarbamoyl); C_3-10Cycloal
Kill-carbamoyl (eg, cyclopropylcarbamoy
, Cyclopentylcarbamoyl, cyclohexylcar
Vamoyl); C _7-14Aralkyl-carbamoyl
(Eg benzylcarbamoyl, phenethylcarbamoy
Diphenylethylcarbamoyl); C_4-13Cyclo
Alkylalkyl-carbamoyl (eg cyclohexyl
Methylcarbamoyl); aromatic heterocyclic carbamoyl
(Eg isoxazolylcarbamoyl, benzothiazolyl
Carbamoyl); non-aromatic heterocyclic carbamoyl (eg, pi
Loridinylcarbamoyl); C_1-10Alkyl sulfi
Nyl group (eg, methylsulfinyl, ethylsulfinyl
Le); C _1-10Alkylsulfonyl group (eg, methylsulfur
Sulfonyl, ethylsulfonyl); C _6-14Arylsul
Sulfonyl (eg, phenylsulfonyl); forming a ring
Good (mono- or di-C_1-10Alkyl) phospho
Group (eg, dimethylphosphono; diethylphosphono; diii
Sopropylphosphono; dibutylphosphono; 2-oxide
-1,3,2-dioxaphosphinanyl); mono- or
Di- (optionally substituted with 1 to 3 halogens
C_1-6Alkyl) -sulfamoyl (eg, methylsulfate
Famoyl, ethylsulfamoyl) and the like.
It

The acyl group may have 1 to 3 substituents at substitutable positions, and examples of such a substituent include 1 to 3 halogen atoms (eg, fluorine, chlorine). , C _1-6 alkyl (eg, methyl, ethyl) optionally substituted with bromine, iodine); optionally substituted with 1 to 3 halogen atoms (eg fluorine, chlorine, bromine, iodine) C _1-6 alkoxy (eg, methoxy, ethoxy);
Halogen atom (eg, fluorine, chlorine, bromine, iodine); nitro; hydroxy; amino optionally mono- or di-substituted with C _1-6 alkyl (eg, methyl, ethyl);
Cyano; mono- or di-C _1-10 alkylphosphono-C _1-6 alkyl group (eg, dimethylphosphonomethyl,
Diethylphosphonomethyl, dimethylphosphonoethyl);
Halogen atom (eg, fluorine, chlorine, bromine, iodine), C
Substituted with 1 to 3 substituents selected from _1-6 alkyl (eg methyl, ethyl), C _1-6 alkoxy (eg methoxy, ethoxy) and C _1-6 alkyl-carbonyl (eg acetyl) _Optionally C _6-14 aryl (eg,
Phenyl); C _7-13 aralkyl (eg, benzyl);
C _1-6 alkylthio (eg, methylthio) optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 1 to 3 halogen atoms (eg, fluorine, chlorine, C optionally substituted with bromine, iodine)
_6-14 aryloxy (eg, phenoxy); C _6-14 arylthio (eg, phenylthio) optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); C _{7- 13} aralkyloxy (eg, benzyloxy); heterocyclethio optionally substituted with C _1-6 alkyl (eg, methyl, ethyl) thio (eg, pyrimidinylthio); C _1-6 alkoxy-carbonyl (eg, methoxy) Carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl); C _6-14 arylsulfonyl (eg, phenylsulfonyl); carbamoyl; C _{1 −6}
Alkyl-carbonyl (eg, acetyl) optionally substituted sulfamoyl; Heterocyclic carbonyl (eg, dihydroindolylcarbonyl); C _1-6 alkoxy-carboxamide (eg, tert-butoxycarboxamide); C
_7-13 aralkyloxy-carboxamide (eg, benzyloxycarboxamide); oxo, C _1-6 alkyl (eg, methyl, ethyl) and C _1-6 alkoxy (eg,
A heterocyclic group which may be substituted with 1 to 3 substituents selected from methoxy and ethoxy (eg, thienyl, furyl, oxazolyl, isoxazolyl, imidazolyl,
Triazolyl, tetrazolyl, pyridyl, indolyl,
1H-indazolyl, benzimidazolyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl); and the like.

Preferable “optionally substituted acyl group”
Examples include formyl; carboxyl; carbamoy
Lu; Thiocarbamoyl; C_1-10Alkyl-carbonyl
(Eg acetyl, propionyl, butyryl, isobutyryl
Le, valeryl, isovaleryl, pivaloyl, hexanoy
Le, heptanoyl, octanoyl); C_2-10Archeni
Le-carbonyl (eg, crotonyl); C_3-10Cycloa
Rukyi-carbonyl (eg, cyclobutanecarbonyl, silane
Clopentanecarbonyl, cyclohexanecarbonyl,
Cycloheptanecarbonyl); C_3-10Cycloalkeni
Le-carbonyl (eg, 2-cyclohexenecarbonyl
Le); C_6-14Aryl-carbonyl (eg, benzoyl
Le, 1-naphthoyl, 2-naphthoyl); C_7-14Ara
Rukyi-carbonyl (eg, benzylcarbonyl, phenene
Tylcarbonyl Phenylpropylcarbonyl, Phenyl
Butylcarbonyl); C_8-13Aryl alkenyl
Rubonyl (eg, styrylcarbonyl); C_8-13Ally
Rualkynyl-carbonyl (eg, phenylethynylcarboxyl
Bonyl); aromatic heterocyclic carbonyl (eg, nicotinoi
Le, isonicotinoyl, furylcarbonyl, thienylca
Rubonyl, pyrimidinyl carbonyl, benzofuranyl cas
Lubonyl, 1H-indazolylcarbonyl, quinolylcarbox
Rubonyl); non-aromatic heterocyclic carbonyl (eg, pyrrolidi
Nylcarbonyl, piperidinocarbonyl, morpholinoca
Lubonyl, thiomorpholinocarbonyl, piperazinocar
Bonyl, thiazolidinyl carbonyl, hexamethylene
Minyl carbonyl, tetrahydroisoquinolyl carbonyl
Le); C_1-6Alkoxy-carbonyl (eg, methoxy
Carbonyl, ethoxycarbonyl, propoxycarboni
, Butoxycarbonyl, tert-butoxycarbonyl
); C_6-14Aryloxy-carbonyl (eg, phenol
Phenyloxycarbonyl, naphthyloxycarbonyl
Le); C_{7- 14}Aralkyloxy-carbonyl (eg,
Benzyloxycarbonyl, phenethyloxycarboni
Mono) or di- (halogen atom and C_1-6
1 to 3 units selected from alkoxy-carbonyl
C which may have a substituent_{1- 6}Alkyl) -carbamo
(E.g., methylcarbamoyl, ethylcarbamoyl,
Dimethylcarbamoyl, diethylcarbamoyl, ethyl
Methylcarbamoyl, propylcarbamoyl, triflu
Oroethylcarbamoyl, butylcarbamoyl, tert-
Butylcarbamoyl, Pentylcarbamoyl, Hexyl
Carbamoyl); mono- or di- (1 to 3 ha
C optionally substituted with a rogen_1-6Alkyl) -chi
Ocarbamoyl (eg, methylthiocarbamoyl, ethyl
Thiocarbamoyl); C_6-14Aryl-carbamoy
(Eg, phenylcarbamoyl); C _3-10Cycloa
Rukyl-carbamoyl (eg, cyclopropylcarbamoyl
, Cyclopentylcarbamoyl, cyclohexylcar
Vamoyl); C_7-14Aralkyl-carbamoyl
(Eg benzylcarbamoyl, phenethylcarbamoy
Diphenylethylcarbamoyl); C_4-13Cyclo
Alkylalkyl-carbamoyl (eg cyclohexyl
Methylcarbamoyl); aromatic heterocyclic carbamoyl
(Eg isoxazolylcarbamoyl, benzothiazolyl
Carbamoyl); non-aromatic heterocyclic carbamoyl (eg, pi
Loridinylcarbamoyl); C_1-10Alkyl sulfi
Nyl group (eg, methylsulfinyl, ethylsulfinyl
Le); C_1-10Alkylsulfonyl group (eg, methylsulfur
Sulfonyl, ethylsulfonyl); C_6-14Arylsul
Sulfonyl (eg, phenylsulfonyl); forming a ring
Good (mono- or di-C_1-10Alkyl) phospho
Group (eg, dimethylphosphono; diethylphosphono; diii
Sopropylphosphono; dibutylphosphono; 2-oxide
-1,3,2-dioxaphosphinanyl); mono- or
Di- (optionally substituted with 1 to 3 halogens
C_1-6Alkyl) -sulfamoyl (eg, methylsulfate
Famoyl, ethylsulfamoyl) and the like.
It In addition, as an “optionally substituted acyl group”
Is C_1-6Alkoxy-carbamoyl (eg, methoxy
Carbamoyl), C_1-6Alkoxy-carbonylcal
Vamoyl (eg, methoxycarbonylcarbamoyl, eth
Xycarbonylcarbamoyl), C_7-14Aralkillo
Xy-carbamoyl (eg, benzyloxycarbamoy
Le) and so on.

The "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by R ¹ is preferably an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, or 3 carbon atoms. 10 to 10 cycloalkyl groups, 7 to 1 carbon atoms
And an aralkyl group having 4 to 8 carbon atoms, an arylalkenyl group having 8 to 13 carbon atoms, and a cycloalkylalkyl group having 4 to 13 carbon atoms. The hydrocarbon group more preferably has 6 to 6 carbon atoms.
It is an aryl group of 14 and, among them, phenyl, naphthyl and the like are preferable. Substituents of the "optionally substituted hydrocarbon group" represented by R ^1, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) may be substituted by C _{1 -6} alkoxy group (eg, methoxy, ethoxy), halogen atom (eg, fluorine, chlorine, bromine, iodine), nitro, hydroxy, amino, C _1-3
Examples include alkylenedioxy (eg, methylenedioxy, ethylenedioxy) and the like. The number of substituents is, for example, 1 to 3
It is an individual.

[0029] As the "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ^1, include those exemplified as the "heterocyclic group" represented by R ^3.
The heterocyclic group is preferably an azolyl group which may be condensed with a benzene ring (for example, pyrrolyl, imidazolyl,
Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl) and the like. Among them, imidazolyl, benzimidazolyl, indolyl, 1H-indazolyl and the like are preferable, and imidazolyl and benzimidazolyl are particularly preferable.

R¹The heterocyclic group represented by
It may have 1 to 3 substituents. This
Examples of such a substituent include an optionally substituted fat.
Group hydrocarbon group, optionally substituted alicyclic hydrocarbon
Group, optionally substituted aromatic hydrocarbon group, substituted
Optionally substituted aromatic heterocyclic group, optionally substituted non-
Aromatic heterocyclic group, halogen atom, nitro, substituted
Optionally amino group, optionally substituted acyl group,
Optionally substituted hydroxy group, optionally substituted
Thiol group, optionally substituted acyl group, C
_1-3Examples include alkylenedioxy and oxo.
Here, "an optionally substituted aliphatic hydrocarbon group",
"Alicyclic hydrocarbon group which may be substituted" and "
"Fat" in "aromatic hydrocarbon group which may be replaced"
Group hydrocarbon group "," alicyclic hydrocarbon group "and" aromatic group "
As a "hydrocarbon group", R¹"Replaced
Examples of "hydrocarbon group" in "may be hydrocarbon group"
The ones shown are listed. Also, "may be replaced
Aromatic heterocyclic group "and" optionally substituted non-aromatic group "
"Aromatic heterocyclic group" and "non-aromatic heterocyclic group"
“Aromatic heterocyclic group” means R¹"Replaced
Examples of the substituent in the “hydrocarbon group which may be substituted”
There are some. In addition, "halogen atom"
Optionally substituted amino group ”,“ optionally substituted ”
Acyl group "," optionally substituted hydroxy "
Group "," optionally substituted thiol group "and" position ".
Optionally substituted acyl group "and" C _1-3Archi
As "rangeoxy", R¹"Replaced
Examples of the substituent in the "optional hydrocarbon group"
There are things.

In the above-mentioned "optionally substituted aliphatic hydrocarbon group", examples of the substituent include 1) hydroxy; 2) cyano; 3) halogen atom (eg, fluorine, chlorine, bromine, iodine); 4) Amidino; 5) Carboxyl; 6) Sulfo; 7) Azido; 8) Nitro; 9) Nitroso; 10) _C3-10 cycloalkyl; 11) _C6-14 aryl (eg, phenyl, naphthyl); 12) 5 to 6-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl); 13) 5 to 6-membered non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, Piperazinyl); 14) 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) optionally substituted C _1-6 alkoxy; 15) 1 to 3 halogen atoms (Eg, C _2-6 alkenyloxy optionally substituted with fluorine, chlorine, bromine, iodine); 16) C _3-10 cycloalkyloxy; 17) C _6-14 aryloxy (eg, phenyloxy, naphthyl) Oxy); 18) C _7-13 aralkyloxy; 19) thiol; 20) C _1-6 alkylthio optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); ) C _2-6 alkenylthio optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 22) C _3-10 cycloalkylthio; 23) C _6-14 arylthio ( examples, phenylthio, naphthylthio); 24) C _7-13 aralkylthio; 25) C _1-6 alkyl - carbonyl; _{26) C 1-6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, Puropokishika Boniru, butoxycarbonyl, tert- butoxycarbonyl); 27) may form a ring (mono - or di -C
_1-10 alkyl) phosphono group (eg, dimethylphosphono;
Diethylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl); 28) C optionally substituted with 1 to 3 halogens
Carbamoyl optionally mono- or di-substituted with _1-6 alkyl (eg, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl); 29) 1 to 3 halogens C optionally substituted with
Sulfamoyl optionally mono- or di-substituted with _1-6 alkyl (eg, sulfamoyl, methylsulfamoyl, ethylsulfamoyl); 30) thiocarbamoyl; 31) C _1-6 alkyl, C _1-6 Amino which may be mono- or di-substituted by a substituent selected from alkyl-carbonyl; and the like. The number of substituents is, for example, 1 to 3.

The above-mentioned "optionally substituted alicyclic hydrocarbon group", "optionally substituted aromatic hydrocarbon group", "optionally substituted aromatic heterocyclic group" and "substituted" In the “optionally non-aromatic heterocyclic group”,
Examples of the substituent include 1) hydroxy; 2) cyano; 3) halogen atom (eg, fluorine, chlorine, bromine, iodine); 4) amidino; 5) carboxyl; 6) sulfo; 7) azide; 8) nitro; 9) Nitroso; 10) C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 11) 1 to 3 halogen atoms (eg, fluorine) , _C2-6 alkenyl, optionally substituted with chlorine, bromine, iodine); 12) _C7-13 aralkyl; 13) _C3-10 cycloalkyl; 14) _C6-14 aryl (eg, phenyl, naphthyl). ); 15) 5- or 6-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl); 16) 5- or 6-membered non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, Piperidino, Piro Jiniru, piperazinyl); 17) 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, C _1-6 alkoxy optionally substituted by iodine); 18) 1 to 3 halogen atoms (e.g., C _2-6 alkenyloxy optionally substituted with fluorine, chlorine, bromine, iodine); 19) C _3-10 cycloalkyloxy; 20) C _6-14 aryloxy (eg, phenyloxy, naphthyloxy); 21) C _7-13 aralkyloxy; 22) thiol; 23) C _1-6 alkylthio optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 24) 1 C _2-6 alkenylthio optionally substituted with 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine); 25) C _3-10 cycloalkylthio; 26) C _6-14 arylthio (eg, phenylthio) , Naphthylthio); 27) C _7-13 aralkylthio; 28) C _1-6 alkyl-carbonyl; 29) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); 30 ) May form a ring (mono- or di-C
_1-10 alkyl) phosphono group (eg, dimethylphosphono;
Diethylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl); 31) C optionally substituted with 1 to 3 halogens
Carbamoyl optionally mono- or di-substituted with _1-6 alkyl (eg, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl); 32) 1 to 3 halogens C optionally substituted with
Sulfamoyl optionally mono- or di-substituted with _1-6 alkyl (eg, sulfamoyl, methylsulfamoyl, ethylsulfamoyl); 33) thiocarbamoyl; 34) C _1-6 alkyl, C _1-6 Amino which may be mono- or di-substituted by a substituent selected from alkyl-carbonyl; and the like. The number of substituents is, for example, 1 to 3.

The substituent in the "optionally substituted heterocyclic group" represented by R ¹ is preferably substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). Good C _1-6 alkyl (eg, methyl, ethyl), C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg, methoxy, ethoxy) ), A halogen atom (eg, fluorine, chlorine, bromine, iodine), nitro, hydroxy, amino, C _6-14 aryl (eg, phenyl), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy) ), A C _1-10 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl), hydroxy-C _1-6 alkyl (eg, hydroxymethyl) and the like. The number of substituents is, for example, 1 to 3.

The "optionally substituted hydroxy group" represented by R ^1, the "optionally substituted thiol group" and "optionally substituted amino group", R ¹
Examples of the substituent in the “optionally substituted hydrocarbon group” represented by

R ¹ is preferably an "optionally substituted heterocyclic group". The heterocyclic group is preferably an azolyl group which may be condensed with a benzene ring (eg, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl) and the like. Among them, imidazolyl, benzimidazolyl, indolyl, 1H-indazolyl and the like are preferable, and imidazolyl and benzimidazolyl are particularly preferable. R ¹ is more preferably C _1-6 alkyl (eg, methyl, ethyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), 1 to 3 C _1-6 alkoxy (eg, methoxy, ethoxy) optionally substituted with a halogen atom (eg, fluorine, chlorine, bromine, iodine), halogen atom (eg, fluorine, chlorine, bromine, iodine), nitro, hydroxy , Amino, C _6-14 aryl (eg, phenyl), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy), C _1-10 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl), 1 to 3 selected from hydroxy-C _1-6 alkyl (eg hydroxymethyl)
“Azolyl group optionally condensed with a benzene ring (eg, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
Thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl) "and the like. Among them, 1 to 3 halogen atoms (eg, fluorine,
Preference is given to imidazolyl or benzimidazolyl optionally substituted with a C _1-6 alkyl group (eg methyl, ethyl) optionally substituted with chlorine, bromine, iodine). R ¹ is particularly preferably benzimidazolyl.

A is an "optionally substituted cyclic amino group" or "-NR ² -WD (R ² is a hydrogen atom or an alkyl group, W is a bond or a divalent acyclic hydrocarbon group. Represents a cyclic group which may be substituted, an amino group which may be substituted or an acyl group which may be substituted). The "cyclic amino group" in the "optionally substituted cyclic amino group" includes, for example, at least one nitrogen atom other than carbon atom as a ring-constituting atom, and further selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a 5- to 8-membered nitrogen-containing heterocyclic group which may contain 1 or 2 hetero atoms. Preferable examples of the nitrogen-containing heterocyclic group include 1-pyrrolidinyl and 1-
Imidazolidinyl, 1-pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, 1-azocanyl, 3-
Examples thereof include thiazolidinyl and 3-oxazolidinyl. Among them, 1-piperidinyl, 1-piperazinyl, 4
-Morpholinyl, 4-thiomorpholinyl and the like are preferable.

The "cyclic amino group" has 1 at a substitutable position.
It may have 3 to 3 substituents. Examples of such a substituent include 1) oxo; 2) hydroxy; 3) cyano; 4) halogen atom (eg, fluorine, chlorine, bromine, iodine); 5) C _1-6 alkylenedioxy (eg, methylene). Dioxy,
Ethylenedioxy); 6) halogen atom (eg, fluorine, chlorine, bromine, iodine); hydroxy; cyano; C _1-6 alkoxy (eg,
Methoxy); mono C _1-6 alkyl - or di - amino optionally substituted (e.g., amino, methylamino, dimethylamino), C 5 not may be substituted with _{1 -6} alkyl 6-membered aromatic Group heterocyclic groups (eg, tetrazolyl);
5- to 6-membered non-aromatic heterocyclic group optionally substituted by C _1-6 alkyl (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidinyl, pyrrolidinyl, piperazinyl, dioxothiazolidinyl, dioxooxazolin Dinyl); carboxamide; optionally halogenated mono- or di-C _1-6 alkyl-carboxamide (eg, acetylamino, trifluoroacetylamino); mono- or di-C _1-6 alkoxy-carboxamide ( examples, tert- butoxy carboxamido) 1 to 3 substituents C _{1 -6} optionally it substituted with a substituent selected from
Alkyl group (eg, methyl, ethyl); 7) 1 to 3 selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally halogenated C _1-6 alkyl and C _1-6 alkoxy. C _6-14 aryl _optionally substituted with 4 substituents (eg phenyl); 8) C _1-6 optionally substituted with alkylenedioxy.
_7-13 Aralkyl group (eg, benzyl, benzhydryl); 9) 5 to 6 optionally substituted by C _1-6 alkyl group
Membered nitrogen-containing heterocyclic group (eg, pyridyl, piperidinyl, pyrimidinyl, pyrrolidinyl); 10) amino optionally mono- or di-substituted with C _1-6 alkyl (eg, amino, methylamino, dimethylamino); 11) C _1-6 alkyl-carbonyl (eg, acetyl); 12) C _1-6 alkyl-sulfonyl (eg, methylsulfonyl, ethylsulfonyl); 13) C _3-10 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl). 14) C _6-14 aryl-carbonyl (eg, benzoyl); 15) C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl, phenethylcarbonyl); 16) C _6-14 aryl-C _2-6 alkenyl-carbonyl
(Eg, styrylcarbonyl); 17) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); 18) optionally substituted with C _1-6 alkyl Good 5 to 6
Membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolylcarbonyl, thenoyl, pyridylcarbonyl); 19) 5 to 6 optionally substituted by C _1-6 alkyl
Membered non-aromatic heterocycle-carbonyl (eg, tetrahydrofuroyl); 20) carboxamide; 21) halogen atom (eg, fluorine, chlorine, bromine, iodine)
And C _1-6 to 1 selected from alkyl optionally substituted with 1-3 substituents mono - or di -C _{1 -6} alkyl - carboxamide (example, acetylamino, hexanoylamino, trifluoroacetylamino, N- acetyl -N- methylamino, pentafluoro propionylamino); 22) C _3-10 cycloalkyl - carboxamide (example, cyclohexylcarboxamide); 23) C _1-6 optionally substituted by alkylenedioxy C _{6 -14} aryl-carboxamide (eg, phenylcarboxamide); 24) C _7-13 aralkyl-carboxamide (eg, benzylcarboxamide, phenethylcarboxamide); 25) C _6-14 aryl-C _2-6 alkenyl-carboxamide (eg, styryl) 26) C _1-6 alkoxy-carboxamide (eg, tert-
Butoxycarboxamide); 27) 5 to 6 optionally substituted by C _1-6 alkyl
Membered aromatic heterocycle-carboxamide (eg, furylcarboxamide, pyrrolylcarboxamide, thienylcarboxamide, pyridylcarboxamide); 28) 5 to 6 optionally substituted by C _1-6 alkyl
Member non-aromatic heterocycle-carboxamide (eg, tetrahydrofurylcarboxamide); and the like.

The "optionally substituted cyclic amino group" for A is preferably 1) oxo; 2) hydroxy; 3) cyano; 4) halogen atom (eg, fluorine, chlorine, bromine, iodine). 5) C _1-6 alkylenedioxy (eg, methylenedioxy,
Ethylenedioxy); 6) halogen atom (eg, fluorine, chlorine, bromine, iodine); hydroxy; cyano; C _1-6 alkoxy (eg,
Methoxy); mono C _1-6 alkyl - or di - amino optionally substituted (e.g., amino, methylamino, dimethylamino), C 5 not may be substituted with _{1 -6} alkyl 6-membered aromatic Group heterocyclic groups (eg, tetrazolyl);
5- to 6-membered non-aromatic heterocyclic group optionally substituted by C _1-6 alkyl (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidinyl, pyrrolidinyl, piperazinyl, dioxothiazolidinyl, dioxooxazolin Dinyl); carboxamide; optionally halogenated mono- or di-C _1-6 alkyl-carboxamide (eg, acetylamino, trifluoroacetylamino); mono- or di-C _1-6 alkoxy-carboxamide ( examples, tert- butoxy carboxamido) 1 to 3 substituents C _{1 -6} optionally it substituted with a substituent selected from
Alkyl group (eg, methyl, ethyl); 7) 1 to 3 selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally halogenated C _1-6 alkyl and C _1-6 alkoxy. C _6-14 aryl _optionally substituted with 4 substituents (eg phenyl); 8) C _1-6 optionally substituted with alkylenedioxy.
_7-13 Aralkyl group (eg, benzyl, benzhydryl); 9) 5 to 6 optionally substituted by C _1-6 alkyl group
Membered nitrogen-containing heterocyclic group (eg, pyridyl, piperidinyl, pyrimidinyl, pyrrolidinyl); 10) amino optionally mono- or di-substituted with C _1-6 alkyl (eg, amino, methylamino, dimethylamino); 11) C _1-6 alkyl-carbonyl (eg, acetyl); 12) C _1-6 alkyl-sulfonyl (eg, methylsulfonyl, ethylsulfonyl); 13) C _3-10 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl). 14) C _6-14 aryl-carbonyl (eg, benzoyl); 15) C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl, phenethylcarbonyl); 16) C _6-14 aryl-C _2-6 alkenyl-carbonyl
(Eg, styrylcarbonyl); 17) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl); 18) optionally substituted with C _1-6 alkyl Good 5 to 6
Membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolylcarbonyl, thenoyl, pyridylcarbonyl); 19) 5 to 6 optionally substituted by C _1-6 alkyl
Membered non-aromatic heterocycle-carbonyl (eg, tetrahydrofuroyl); 20) carboxamide; 21) halogen atom (eg, fluorine, chlorine, bromine, iodine)
And C _1-6 to 1 selected from alkyl optionally substituted with 1-3 substituents mono - or di -C _{1 -6} alkyl - carboxamide (example, acetylamino, hexanoylamino, trifluoroacetylamino, N- acetyl -N- methylamino, pentafluoro propionylamino); 22) C _3-10 cycloalkyl - carboxamide (example, cyclohexylcarboxamide); 23) C _1-6 optionally substituted by alkylenedioxy C _{6 -14} aryl-carboxamide (eg, phenylcarboxamide); 24) C _7-13 aralkyl-carboxamide (eg, benzylcarboxamide, phenethylcarboxamide); 25) C _6-14 aryl-C _2-6 alkenyl-carboxamide (eg, styryl) 26) C _1-6 alkoxy-carboxamide (eg, tert-
Butoxycarboxamide); 27) 5 to 6 optionally substituted by C _1-6 alkyl
Membered aromatic heterocycle-carboxamide (eg, furylcarboxamide, pyrrolylcarboxamide, thienylcarboxamide, pyridylcarboxamide); 28) 5 to 6 optionally substituted by C _1-6 alkyl
Membered non-aromatic heterocycle-carboxamide (eg, tetrahydrofurylcarboxamide); 1-piperidinyl, 1-piperazinyl, 4-morpholinyl or 4-thiomorpholinyl, each of which may have 1 to 3 substituents selected from Is.

R²For example, the alkyl group represented by
If C_1-6Alkyl group (eg, methyl, ethyl, propyl,
Isopropyl). Among them, methyl is preferred
Good R²Is preferably a hydrogen atom. Indicated by W
"Divalent non-cyclic hydrocarbon group" is a non-cyclic divalent hydrocarbon
The group may be linear or branched, and
It may be saturated or unsaturated. "Bivalent
Examples of the “acyclic hydrocarbon group” include “divalent aliphatic carbon”.
“Hydrogen groups” are mentioned, among which 2 having 1 to 8 carbon atoms.
A valent aliphatic hydrocarbon group is preferred. "Divalent acyclic carbonization
As a suitable example of "hydrogen group", (1) C_1-8Alkylene (e.g., -CH₂−, − (CH₂)₂−, − (CH₂)
₃−, − (CH₂)_Four−, − (CH ₂)_Five−, − (CH₂)₆−, − (CH₂)₇
−, − (CH₂)₈−, −CH (CH₃) −, −C (CH₃)₂−, − (CH (CH
₃))₂−, − (CH₂)₂C (CH₃)₂−, − (CH₂)₃C (CH₃)₂-N
)); (2) C_2-8Alkenylene (eg, -CH = CH-, -CH₂-CH = CH
−, −C (CH₃)₂-CH = CH-, -CH₂-CH = CH-CH₂−, −C
H₂-CH₂-CH = CH-, -CH = CH-CH = CH-, -CH = CH-C
H₂-CH₂-CH₂-, Etc.) and the like. The “divalent acyclic hydrocarbon group” preferably has 1 carbon atom.
Is 4 divalent aliphatic hydrocarbon group, more preferred
Kuha C_1-4It is alkylene. Among them, -CH₂−, − (CH
₂)₂−, − (CH₂)₃−, − (CH₂)_Four-, Etc. are preferred, and
By the way, − (CH₂)₂−, − (CH₂)₃−, − (CH₂)_Four-Like
Good W is preferably a bond or having 1 to 4 carbon atoms.
Is a divalent aliphatic hydrocarbon group of
Joint or C_1-4It is alkylene. Among them, the bond,
-CH₂−, − (CH₂)₂−, − (CH₂)₃−, − (CH₂)_Four− Etc.
Preferably, inter alia, a bond,-(CH₂)₂−, − (CH₂)
₃−, − (CH₂)_Four-And the like are preferable.

The "cyclic group" in the "optionally substituted cyclic group" represented by D is, for example, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. Groups and the like. Here, examples of the “alicyclic hydrocarbon group” and the “aromatic hydrocarbon group” include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ^1. To be “Aromatic heterocyclic group” and “non-aromatic heterocyclic group” include R ¹
Examples of the substituent in the “optionally substituted hydrocarbon group” represented by The cyclic group is
Preferably an aryl group having 6 to 14 carbon atoms (preferably phenyl, biphenylyl), a cycloalkyl group having 3 to 10 carbon atoms (preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), 3 to carbon atoms 10 cycloalkenyl groups (preferably cyclohexenyl), 5- to 6-membered aromatic heterocyclic groups optionally condensed with a benzene ring (preferably furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, quinolyl ,
Isoquinolyl, benzothiazolyl, benzothiadiazolyl, isoxazolyl), a 5- to 6-membered non-aromatic heterocyclic group which may be condensed with a benzene ring (preferably pyrrolidinyl, tetrahydrofuranyl, thiazolinyl, oxazolinyl, thiazolidinyl, oxazolidinyl, dioxolanyl, piperidinyl , Piperazinyl, morpholino,
Thiomorpholino, dihydrobenzofuranyl) and the like. The cyclic group is more preferably an aryl group having 6 to 14 carbon atoms, and among them, phenyl is preferable.

The "cyclic group" represented by D is a substitutable position.
It may have 1 to 3 substituents. This
Examples of such a substituent include (1) oxo; (2) hydroxy; (3) Cyano; (4) Halogen atom (eg, fluorine, chlorine, bromine, iodine
Bare); (5) C_1-6Alkylenedioxy (eg methylene dioxy)
Ci, ethylenedioxy); (6) Carboxyl; (7) Halogen atom (eg, fluorine, chlorine, bromine, iodine
Hydroxyl; Cyano; C_1-6Alkoxy (eg,
Methoxy); C_1-6Alkyl mono- or di-substituted
Optional amino (eg, amino, methylamino, diamino
Methylamino); C _1-6May be substituted with alkyl
A 5- to 6-membered aromatic heterocyclic group (eg, tetrazolyl);
C_1-65- to 6-membered non-alkyl optionally substituted
Aromatic heterocyclic group (eg, tetrahydrofuryl, morpholyl
No, thiomorpholino, piperidinyl, pyrrolidinyl, pi
Perazinyl, dioxothiazolidinyl, dioxooxa
Zolidinyl); carboxyl group; C_1-6Alkoxy-
Carbonyl (eg, methoxycarbonyl, ethoxycarbo
Nyl, propoxycarbonyl, butoxycarbonyl, te
rt-butoxycarbonyl); may form a ring
(Mono- or Di-C_{1-1 0}Alkyl) phosphono group
(Eg, dimethylphosphono; diethylphosphono; diisop
Ropylphosphono; dibutylphosphono; 2-oxide-
1,3,2-dioxaphosphinanyl); carbamoyl;
Halogen atom, hydroxy and C_1-6Alkoxy-ca
Substituted with 1 to 3 substituents selected from
Optionally mono- or di-C_1-6Alkyl-cal
Vamoyl (eg, methylcarbamoyl, ethylcarbamoyl
, Dimethylcarbamoyl, diethylcarbamoyl, d
Tylmethylcarbamoyl, propylcarbamoyl, tri
Fluoroethylcarbamoyl, methoxycarbonylethy
Lucarbamoyl, 2-hydroxy-1-methoxycarboni
L-ethylcarbamoyl, 2-hydroxy-1-methoxy
Carbonyl-propylcarbamoyl); halogenated
May be C_1-6Alkyl and C_1-6Alkoxy
Substituted with 1 to 3 substituents selected from
Good mono- or di-C_{6 -14}Aryl-carbamoyl
(Eg phenylcarbamoyl, methoxyphenylcarba
Moyl, trifluoromethylphenylcarbamoyl);
C_1-6May be mono- or di-substituted with alkyl
Amino, optionally halogenated C_1-6Archi
Le, hydroxy and C_1-6Alkoxy-carbonyl
May be substituted with 1 to 3 substituents selected from
I Mono- or Di-C_7-13Aralkyl-carbamoyl
(Eg benzylcarbamoyl, phenethylcarbamoy
, Dimethylaminobenzylcarbamoyl, methoxyca
Lubonylphenethylcarbamoyl, trifluoromethyl
Benzylcarbamoyl); sulfamoyl; halogenated
Optionally mono- or di-C_1-6Alkyls
Rufamoyl (eg, methylsulfamoyl, ethylsulfate
Famoyl); with 1 to 3 substituents selected from
C that may be replaced_1-6Alkyl group (eg, methyl, ether
Chill, propyl, isopropyl, butyl, isobuty
Le); (8) C_3-10Cycloalkyl group (eg, cyclohexyl
Le); (9) C_6-14Aryl (eg, phenyl); (10) C_7-13Aralkyl (eg, benzyl); (11) 5- or 6-membered aromatic heterocyclic group (eg, thiadiazoli
Le); (12) 1-3 halogen atoms (eg, fluorine, chlorine, odor
C, which may be substituted with hydrogen, iodine)_1-6Alkoxy
Groups (eg, methoxy, ethoxy); (13) 1-3 halogen atoms (eg, fluorine, chlorine, odor
C, which may be substituted with hydrogen, iodine)_1-6Alkylchi
O (eg, methylthio); (14) C_6-14Aryloxy (eg, phenoxy); (15) C_1-6Mono- or di-substituted with alkyl
Optionally amino (eg, amino, methylamino, dimethyl
Amino, ethylamino, diethylamino, ethylmethyl
Amino, propylamino, dibutylamino); (16) C_1-10Mono- or di-substituted with alkyl
Optionally phosphono-C_1-6Alkylamino (eg
Suphonomethylamino, diethylphosphonomethylami
No); (17) Halogen atom (eg, fluorine, chlorine, bromine, iodine
Plain) and C_1-61 to 3 selected from alkyl
Mono- or di-C optionally substituted with a substituent
_1-6Alkyl-carboxamide (e.g., acetylamido)
No, hexanoylamino, trifluoroacetylami
No, N-acetyl-N-methylamino, pentafluoro
Propionylamino); (18) may form a ring (mono- or di-C
_1-10An alkyl) phosphono group (eg, dimethylphosphono;
Diethylphosphono; diisopropylphosphono; dibutyl
Phosphono; 2-oxide-1,3,2-dioxaphosphine
Nanil); (19) C_1-6Alkyl-carbonyl (eg, acetyl); (20) C_1-6Alkyl-sulfonyl (e.g., methylsulfur
Sulfonyl, ethylsulfonyl); (21) C_3-10Cycloalkyl-carbonyl (e.g. cyclo
Hexylcarbonyl); (22) C_6-14Aryl-carbonyl (e.g., benzoyl
); (23) C_7-13Aralkyl-carbonyl (eg, benzyl
Carbonyl, phenethylcarbonyl); (24) C_6-14Aryl-C_2-6Alkenyl-carboni
(Eg, styrylcarbonyl); (25) C_1-6Alkoxy-carbonyl (eg, methoxy
Carbonyl, tert-butoxycarbonyl); (26) C_1-65 to optionally substituted with alkyl
6-membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolyl
Lucarbonyl, pyridylcarbonyl); (27) C_1-65 to optionally substituted with alkyl
6-membered non-aromatic heterocycle-carbonyl (eg tetrahydro
Royle); (28) C_1-6Mono- or di-substituted with alkyl
Optional carbamoyl (eg, carbamoyl, dimethyl
Carbamoyl); (29) C_1-6Mono- or di-substituted with alkyl
You can use sulfamoyl (eg, sulfamoyl, dime
Tilsulfamoyl); and the like.

The "optionally substituted amino group" and "optionally substituted acyl group" represented by D are the substituents in the "optionally substituted hydrocarbon group" represented by R ^1. Examples of the above are listed.
Preferable examples of the "optionally substituted amino group" represented by D include 1) C _1-6 alkyl _optionally substituted with hydroxy,
C _6-14 aryl, amino optionally substituted mono- or di-substituted with a substituent selected from 5- or 6-membered aromatic heterocyclic group optionally substituted with nitro (eg pyridyl) (eg amino , Methylamino, dimethylamino, diisopropylamino, phenylamino, N-phenyl-N-
2) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
And C _1-6 to 1 selected from alkyl optionally substituted with 1-3 substituents mono - or di -C _1-6 alkyl - carboxamide (example, acetylamino, hexanoylamino, trifluoroacetylamino, N-acetyl-N-methylamino, pentafluoropropionylamino); 3) C _1-6 alkoxy-carboxamide optionally substituted with C _1-6 alkyl (eg, tert-butoxycarboxamide, N-tert-butoxycarbonyl) -N- methylamino); 4) C _1-6 alkyl optionally substituted by C _6-14 aryl - carboxamide (e.g., phenylcarboxamide); 5) C _1-6 alkyl optionally substituted with C _7-13 aralkyl-carboxamides (eg, benzylcarboxamide, phenethylcarboxamide); 6) substituted with C _1-6 alkyl 5 to 6-membered aromatic heterocycle-carboxamide (eg, furylcarboxamide, pyrrolylcarboxamide, thienylcarboxamide, pyridylcarboxamide); 7) 5 to 6-membered non-aromatic optionally substituted by C _1-6 alkyl Heterocycle-carboxamide (eg, tetrahydrofurylcarboxamide); and the like.

Preferable examples of the "optionally substituted acyl group" represented by D include (1) carboxyl; (2) C _1-6 alkyl-carbonyl (eg, acetyl); (3) C _{1 -6} alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl); (4) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl); (5) mono- or di-substituted with C _1-6 alkyl. Optionally carbamoyl (eg, carbamoyl, dimethylcarbamoyl); (6) sulfamoyl optionally mono- or di-substituted with C _1-6 alkyl (eg, sulfamoyl, dimethylsulfamoyl); (7) mono _-Or di- _C6-14 aryl-carbamoyl
(Eg, phenylcarbamoyl); (8) mono- or di-C _7-13 aralkyl-carbamoyl (eg, benzylcarbamoyl); (9) optionally form a ring (mono- or di-C
_1-10 alkyl) phosphono group (eg, dimethylphosphono;
Diethylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl); and the like.

D is preferably an optionally substituted ring
Group, more preferably (1) oxo; (2) hydroxy; (3) Cyano; (4) Halogen atom; (5) C_1-6Alkylenedioxy; (6) Carboxyl; (7) Halogen atom; hydroxy; cyano; C_1-6A
Lucoxy; C_1-6Mono- or di-substituted with alkyl
Optionally amino; C_1-6Substituted with alkyl
May be a 5- or 6-membered aromatic heterocyclic group (eg, tetrazoli
Le); C_1-65 to optionally substituted with alkyl
6-membered non-aromatic heterocyclic group (eg, tetrahydrofuryl, mol
Holino, thiomorpholino, piperidinyl, pyrrolidini
Le, piperazinyl, dioxothiazolidinyl, dioxo
Oxazolidinyl); carboxyl group; C _1-6Arco
Xy-carbonyl; may form a ring (also mono-
It is J-C_1-10Alkyl) phosphono group; carbamoy
Lu; halogen atom, hydroxy and C_1-6Alkoxy
-Substituted with 1 to 3 substituents selected from carbonyl
Optionally mono- or di-C_1-6Alkyl-
Carbamoyl; optionally halogenated C_1-6Al
Kill and C_1-61 to 3 selected from alkoxy
Mono- or di-C optionally substituted with 4 substituents
_6-14Aryl-carbamoyl; C_1-6Alkyl mono-
Or optionally di-substituted amino, halogenated
May be C_1-6Alkyl, hydroxy and C
_1-61 to 3 selected from alkoxy-carbonyl
Mono- or di-C optionally substituted with the substituents of
_7-13Aralkyl-carbamoyl; sulfamoyl; ha
Optionally monogenized or di-C_1-6A
1 to 3 units selected from Luquilsulfamoyl;
C optionally substituted with a substituent_1-6Alkyl group; (8) C_3-10Cycloalkyl group; (9) C_6-14Aryl; (10) C_7-13Aralkyl; (11) 5- or 6-membered aromatic heterocyclic group (eg, thiadiazoli
Le); (12) may be substituted with 1 to 3 halogen atoms
C_1-6An alkoxy group; (13) may be substituted with 1 to 3 halogen atoms
C_1-6Alkylthio; (14) C_6-14Aryloxy; (15) C_1-6Mono- or di-substituted with alkyl
May amino; (16) C_1-10Mono- or di-substituted with alkyl
Optionally phosphono-C_1-6Alkylamino; (17) Halogen atom and C_1-6Selected from alkyl
Mono or optionally substituted with 1 to 3 substituents
Or J-C_1-6Alkyl-carboxamide; (18) may form a ring (mono- or di-C
_1-10An alkyl) phosphono group; (19) C_1-6Alkyl-carbonyl; (20) C_1-6Alkyl-sulfonyl; (21) C_3-10Cycloalkyl-carbonyl; (22) C_6-14Aryl-carbonyl; (23) C_7-13Aralkyl-carbonyl; (24) C_6-14Aryl-C_2-6Alkenyl-carboni
Le; (25) C_1-6Alkoxy-carbonyl; (26) C_1-65 to optionally substituted with alkyl
6-membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolyl
Lucarbonyl, pyridylcarbonyl); (27) C_1-65 to optionally substituted with alkyl
6-membered non-aromatic heterocycle-carbonyl (eg tetrahydro
Royle); (28) C_1-6Mono- or di-substituted with alkyl
Carbamoyl which may be present; (29) C_1-6Mono- or di-substituted with alkyl
1 to 3 selected from the acceptable sulfamoyl
"C6-C6", each of which may be substituted with a substituent
14 aryl groups (preferably phenyl, biphenylyl
5) to 6) which may be condensed with a benzene ring
Membered aromatic heterocyclic groups (preferably furyl, thienyl, thia
Zolyl, imidazolyl, pyrazolyl, pyridyl, pyrazi
Nil, indolyl, quinolyl, isoquinolyl, benzothi
Azolyl, benzothiadiazolyl, isoxazoli
5) or "may not be condensed with benzene ring"
A 6-membered non-aromatic heterocyclic group (preferably pyrrolidinyl, te
Trahydrofuranyl, thiazolinyl, oxazolinyl,
Thiazolidinyl, oxazolidinyl, dioxolanyl,
Piperidinyl, piperazinyl, morpholino, thiomorpho
Reno, dihydrobenzofuranyl) ".

[0045] D is particularly preferably, it may also form a ring (mono - or di -C _1-10 alkyl) phosphono group (preferably, dimethylphosphono; diethylphosphono; diisopropylphosphono; Jibuchiruhosuho No; 2-
Oxide-1,3,2-dioxaphosphinanyl) optionally substituted C _1-6 alkyl group (preferably methyl, ethyl) having 6 to 14 carbon atoms and optionally substituted aryl group ( Preferred is phenyl).

Examples of the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by B include those exemplified as R ¹ . B is preferably an “optionally substituted hydrocarbon group”,
More preferably, it is an alkyl group having 1 to 10 carbon atoms (eg, methyl, isopropyl, t.-butyl) and an aryl group having 6 to 14 carbon atoms which may be substituted. Particularly, an optionally substituted aryl group having 6 to 14 carbon atoms is preferable. Preferable specific examples of B include C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg, methyl, ethyl, trifluoromethyl). , C optionally substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine)
_1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy), halogen atom (eg, fluorine, chlorine, bromine, iodine), nitro, formyl, C _1-3 alkylenedioxy (eg, methylenedioxy), aroma And an aryl group having 6 to 14 carbon atoms which may be substituted with 1 to 3 substituents selected from group heterocyclic groups (eg, benzofuryl) (preferably phenyl or biphenylyl, more preferably phenyl). Of these, an aryl group having 6 to 14 carbon atoms (preferably phenyl) which may be substituted with 1 to 3 halogen atoms (preferably chlorine or bromine) is preferable.

X represents an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom. Examples of the optionally substituted nitrogen atom represented by X include, for example, —NR ⁵ — (wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. Or an optionally substituted acyl group) and the like. here,
Represented by R ⁵ as "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", R ¹
Examples of the above are listed. The optionally substituted acyl group represented by R ^5, include those exemplified as the substituents of the "optionally substituted hydrocarbon group" represented by R ^1. R ⁵ is preferably a hydrogen atom, an optionally substituted hydrocarbon group or the like, more preferably a hydrogen atom, an optionally substituted alkyl group or the like, and particularly, a hydrogen atom, a C _1-4 alkyl group or the like. Is preferred. X is preferably an oxygen atom or a sulfur atom, and more preferably an oxygen atom.

"Divalent acyclic hydrocarbon group" represented by Y
Examples of the above include those exemplified as W. Y
Is preferably a divalent acyclic hydrocarbon group, more preferably
Or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms.
And particularly preferably C_1-4Alkylene (preferably --CH₂
−, − (CH₂)₂−, − (CH₂)₃−, − (CH₂)_Four-). Na
But,-(CH₂) ₂−, − (CH₂)₃−, − (CH₂)_Four-I like
Especially,-(CH₂)₂-And the like are preferable.

Suitable examples of the compound represented by the general formula (I) include the following compounds (A) to (F). Compound (A) R ¹ is C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms, C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms, a halogen atom, Nitro,
“Azolyl group optionally condensed with a benzene ring (eg, pyrrolyl), which may be substituted with 1 to 3 substituents selected from hydroxy, amino, C _6-14 aryl, and C _1-3 alkylenedioxy. , Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl) "; A may be substituted cyclic amino group; C _1-6 alkyl, C _1-6 alkoxy, halogen atom, nitro, formyl, and C _1-3 alkylenedioxy having 6 to 14 carbon atoms which may be substituted with 1 to 3 substituents. Aryl group (preferably phenyl); X is an oxygen atom or a sulfur atom; and Y is a divalent group having 1 to 4 carbon atoms. Aliphatic hydrocarbon group (preferably
A compound which is C _1-4 alkylene).

Compound (B) R ¹ is C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms, C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms, Halogen atom, nitro,
“Azolyl group optionally condensed with a benzene ring (eg, pyrrolyl), which may be substituted with 1 to 3 substituents selected from hydroxy, amino, C _6-14 aryl and C _1-3 alkylenedioxy. , Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl) "; A is -NR ² -WD
(R ² is a hydrogen atom or a C _1-6 alkyl group, W is a bond or C _1-4 alkylene, D is a cyclic group which may be substituted); B is substituted with 1 to 3 halogen atoms. Optionally C _1-6 alkyl, C _1-6 alkoxy, halogen atom,
An aryl group (preferably phenyl) having 6 to 14 carbon atoms which may be substituted with 1 to 3 substituents selected from nitro, formyl and C _1-3 alkylenedioxy;
A compound in which X is an oxygen atom or a sulfur atom; and Y is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms (preferably C _1-4 alkylene).

Compound (C) R¹Is (1) 1-3 halogen atoms (eg, fluorine, salt
C, which may be substituted with hydrogen, bromine, iodine)_1-6Al
Kill (eg, methyl, ethyl), 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine)
Good C_1-6Alkoxy (eg, methoxy, ethoxy),
Halogen atom (eg, fluorine, chlorine, bromine, iodine), Ni
Toro, hydroxy, amino, C_6-14Aryl (eg fe
Nil), C _1-3Alkylenedioxy (eg methylenedi
Oxy, ethylenedioxy), C_{1 −10}Alkyl sulfo
A nyl group (eg, methylsulfonyl, ethylsulfonyl),
Hydroxy-C_1-6Alkyl (eg hydroxymethyl)
Each substituted with 1 to 3 substituents selected from
May be, imidazolyl, benzimidazolyl, y
Ordryl or 1H-indazolyl; or (2) 1-3
Individual halogen atoms (eg, fluorine, chlorine, bromine, iodine)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, ethoxy), halogen atoms (eg, fluorine, chlorine,
Bromine, iodine), nitro, hydroxy, amino, C
_1-3Alkylenedioxy (eg, methylenedioxy, ether
1 to 3 substituents selected from
Alkyl having 1 to 10 carbon atoms, which may be substituted, respectively.
Kill group, aryl group having 6 to 14 carbon atoms, 3 to 10 carbon atoms
Cycloalkyl group, aralkyl group having 7 to 14 carbon atoms,
Arylalkenyl group having 8 to 13 carbon atoms, 4 to 1 carbon atoms
3 cycloalkylalkyl groups (preferably having 6 to 6 carbon atoms)
14 aryl groups); [R¹Preferably 1 to 3
C optionally substituted with a rogen atom_1-6With an alkyl group
Each optionally substituted imidazolyl or benzyl
Benzimidazolyl; more preferably benzimidazolyl
Le]; A 1) oxo; 2) hydroxy; 3) cyano; 4) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Bare); 5) C_1-6Alkylenedioxy (eg, methylenedioxy,
Ethylenedioxy); 6) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Hydroxyl; Cyano; C_1-6Alkoxy (eg, methoxy); C_1-6Alkyl
Optionally mono- or di-substituted with amino (eg,
Amino, methylamino, dimethylamino); C_{1 −6}Al
5- or 6-membered aromatic heterocycle optionally substituted with a kill
A group (eg, tetrazolyl); C_1-6Substituted with alkyl
A 5- to 6-membered non-aromatic heterocyclic group (eg, tetra
Hydrofuryl, morpholino, thiomorpholino, piperidi
Nyl, pyrrolidinyl, piperazinyl, dioxothiazoli
Dinyl, dioxooxazolidinyl); carboxami
De; optionally halogenated mono- or di-C
_1-6Alkyl-carboxamide (e.g., acetylamido)
No, trifluoroacetylamino); mono- or di-
C_1-6Alkoxy-carboxamide (e.g. tert-but
1 to 3 substitutions selected from xycarboxamide)
C optionally substituted with a group_{1 -6}Alkyl group (eg, methyl
Le, ethyl); 7) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Elementary), optionally halogenated C_1-6Alkyl and
And C_1-61 to 3 substitutions selected from alkoxy
C optionally substituted with a group_6-14Aryl (eg, pheny
Le); 8) C_1-6C optionally substituted with alkylenedioxy
_7-13Aralkyl groups (eg benzyl, benzhydryl); 9) C_1-65 to 6 which may be substituted with an alkyl group
Membered nitrogen-containing heterocyclic groups (eg pyridyl, piperidinyl, pyridyl
Midinyl, pyrrolidinyl); 10) C_1-6Mono- or di-substituted with alkyl
Good amino (eg, amino, methylamino, dimethylamino)
Mino); 11) C_1-6Alkyl-carbonyl (eg, acetyl); 12) C_1-6Alkyl-sulfonyl (e.g., methylsulfo
Nyl, ethylsulfonyl); 13) C_3-10Cycloalkyl-carbonyl (e.g. cyclohexyl
Xylcarbonyl); 14) C_6-14Aryl-carbonyl (eg, benzoyl); 15) C_7-13Aralkyl-carbonyl (e.g.
Lubonyl, phenethylcarbonyl); 16) C_6-14Aryl-C_2-6Alkenyl-carbonyl
(Eg, styrylcarbonyl); 17) C_1-6Alkoxy-carbonyl (e.g. methoxyca
Lubonyl, ethoxycarbonyl, propoxycarboni
, Butoxycarbonyl, tert-butoxycarbonyl
); 18) C_1-65 to 6 optionally substituted with alkyl
Membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolyl
Carbonyl, thenoyl, pyridylcarbonyl); 19) C_1-65 to 6 optionally substituted with alkyl
Membered non-aromatic heterocycle-carbonyl (e.g. tetrahydrofuro)
Ill); 20) carboxamide; 21) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
And C_1-61 to 3 substitutions selected from alkyl
Mono- or di-C optionally substituted with groups_{1 -6}A
Rutile-carboxamide (eg acetylamino, hexa
Noylamino, trifluoroacetylamino, N-acetate
Cyl-N-methylamino, pentafluoropropionyl
amino); 22) C_3-10Cycloalkyl-carboxamide (e.g.
Lohexylcarboxamide); 23) C_1-6Optionally substituted with alkylenedioxy
C_6-14Aryl-carboxamide (e.g., phenyl carboxamide
Xamide); 24) C_7-13Aralkyl-carboxamide (eg, benzyl
Carboxamide, phenethylcarboxamide); 25) C_6-14Aryl-C_2-6Alkenyl-carboxami
(Eg, styrylcarboxamide); 26) C_1-6Alkoxy-carboxamide (e.g., tert-
Butoxycarboxamide); 27) C_1-65 to 6 optionally substituted with alkyl
Membered aromatic heterocycle-carboxamide (e.g., furylcarboxyl
Samide, pyrrolylcarboxamide, thienylcarboxa
Amide, pyridylcarboxamide); 28) C_1-65 to 6 optionally substituted with alkyl
Membered non-aromatic heterocycle-carboxamide (e.g. tetrahydro
1 to 3 selected from furylcarboxamide);
1-piperidinini optionally having substituents
L, 1-piperazinyl, 4-morpholinyl or 4-thi
Omorpholinyl; B is (1) 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine)
Good C_1-6Alkyl (eg methyl, ethyl, triflu
Oromethyl), 1 to 3 halogen atoms (eg, fluorine,
C optionally substituted by chlorine, bromine, iodine)_1-6A
Lucoxy (eg methoxy, ethoxy, trifluorometho
Xy), halogen atom (eg, fluorine, chlorine, bromine, iodine)
Elementary), nitro, formyl, C _1-3Alkylenedioxy
(Eg, methylenedioxy), aromatic heterocyclic group (eg, benzene
Substituted with 1 to 3 substituents selected from
Optionally substituted aryl group having 6 to 14 carbon atoms (preferably
Is phenyl) or (2) an alkyl group having 1 to 10 carbon atoms
(Eg methyl, isopropyl, t.-butyl); [B is good
Preferably 1 to 3 halogen atoms (preferably chlorine, odor
Aryl having 6 to 14 carbon atoms which may be substituted with
Group (preferably phenyl)]; X is an oxygen atom or sulfur
Atom; and Y is a divalent aliphatic hydrocarbon having 1 to 4 carbon atoms
Elementary group (preferably C_1-4An alkylene).

Compound (D) R¹Is (1) 1-3 halogen atoms (eg, fluorine, salt
C, which may be substituted with hydrogen, bromine, iodine)_1-6Al
Kill (eg, methyl, ethyl), 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine)
Good C_1-6Alkoxy (eg, methoxy, ethoxy),
Halogen atom (eg, fluorine, chlorine, bromine, iodine), Ni
Toro, hydroxy, amino, C_6-14Aryl (eg fe
Nil), C _1-3Alkylenedioxy (eg methylenedi
Oxy, ethylenedioxy), C_{1 −10}Alkyl sulfo
A nyl group (eg, methylsulfonyl, ethylsulfonyl),
Hydroxy-C_1-6Alkyl (eg hydroxymethyl)
Each substituted with 1 to 3 substituents selected from
May be, imidazolyl, benzimidazolyl, y
Ordryl or 1H-indazolyl; or (2) 1-3
Individual halogen atoms (eg, fluorine, chlorine, bromine, iodine)
C optionally substituted with_1-6Alkoxy group (eg, met
Xy, ethoxy), halogen atoms (eg, fluorine, chlorine,
Bromine, iodine), nitro, hydroxy, amino, C
_1-3Alkylenedioxy (eg, methylenedioxy, ether
1 to 3 substituents selected from
Alkyl having 1 to 10 carbon atoms, which may be substituted, respectively.
Kill group, aryl group having 6 to 14 carbon atoms, 3 to 10 carbon atoms
Cycloalkyl group, aralkyl group having 7 to 14 carbon atoms,
Arylalkenyl group having 8 to 13 carbon atoms, 4 to 1 carbon atoms
3 cycloalkylalkyl groups (preferably having 6 to 6 carbon atoms)
14 aryl groups); [R¹Preferably 1 to 3
C optionally substituted with a rogen atom_1-6With an alkyl group
Each optionally substituted imidazolyl or benzyl
Benzimidazolyl; more preferably benzimidazolyl
]]; A is -NR²-WD; R²Is a hydrogen atom or C_1-6Alkyl group, W is a bond
Is C_1-4Alkylene, D (1) oxo; (2) hydroxy; (3) Cyano; (4) Halogen atom; (5) C_1-6Alkylenedioxy; (6) Carboxyl; (7) Halogen atom; hydroxy; cyano; C_1-6A
Lucoxy; C_1-6Mono- or di-substituted with alkyl
Optionally amino; C_1-6Substituted with alkyl
May be a 5- or 6-membered aromatic heterocyclic group (eg, tetrazoli
Le); C_1-65 to optionally substituted with alkyl
6-membered non-aromatic heterocyclic group (eg, tetrahydrofuryl, mol
Holino, thiomorpholino, piperidinyl, pyrrolidini
Le, piperazinyl, dioxothiazolidinyl, dioxo
Oxazolidinyl); carboxyl group; C _1-6Arco
Xy-carbonyl; may form a ring (also mono-
It is J-C_1-10Alkyl) phosphono group; carbamoy
Lu; halogen atom, hydroxy and C_1-6Alkoxy
-Substituted with 1 to 3 substituents selected from carbonyl
Optionally mono- or di-C_1-6Alkyl-
Carbamoyl; optionally halogenated C_1-6Al
Kill and C_1-61 to 3 selected from alkoxy
Mono- or di-C optionally substituted with 4 substituents
_6-14Aryl-carbamoyl; C_1-6Alkyl mono-
Or optionally di-substituted amino, halogenated
May be C_1-6Alkyl, hydroxy and C
_1-61 to 3 selected from alkoxy-carbonyl
Mono- or di-C optionally substituted with the substituents of
_7-13Aralkyl-carbamoyl; sulfamoyl; ha
Optionally monogenized or di-C_1-6A
1 to 3 units selected from Luquilsulfamoyl;
C optionally substituted with a substituent_1-6Alkyl group; (8) C_3-10Cycloalkyl group; (9) C_6-14Aryl; (10) C_7-13Aralkyl; (11) 5- or 6-membered aromatic heterocyclic group (eg, thiadiazoli
Le); (12) may be substituted with 1 to 3 halogen atoms
C_1-6An alkoxy group; (13) may be substituted with 1 to 3 halogen atoms
C_1-6Alkylthio; (14) C_6-14Aryloxy; (15) C_1-6Mono- or di-substituted with alkyl
May amino; (16) C_1-10Mono- or di-substituted with alkyl
Optionally phosphono-C_1-6Alkylamino; (17) Halogen atom and C_1-6Selected from alkyl
Mono or optionally substituted with 1 to 3 substituents
Or J-C_1-6Alkyl-carboxamide; (18) may form a ring (mono- or di-C
_1-10An alkyl) phosphono group; (19) C_1-6Alkyl-carbonyl; (20) C_1-6Alkyl-sulfonyl; (21) C_3-10Cycloalkyl-carbonyl; (22) C_6-14Aryl-carbonyl; (23) C_7-13Aralkyl-carbonyl; (24) C_6-14Aryl-C_2-6Alkenyl-carboni
Le; (25) C_1-6Alkoxy-carbonyl; (26) C_1-65 to optionally substituted with alkyl
6-membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolyl
Lucarbonyl, pyridylcarbonyl); (27) C_1-65 to optionally substituted with alkyl
6-membered non-aromatic heterocycle-carbonyl (eg tetrahydro
Royle); (28) C_1-6Mono- or di-substituted with alkyl
Carbamoyl which may be present; (29) C_1-6Mono- or di-substituted with alkyl
1 to 3 selected from the acceptable sulfamoyl
"C6-C6", each of which may be substituted with a substituent
14 aryl groups (preferably phenyl, biphenylyl
5) to 6) which may be condensed with a benzene ring
Membered aromatic heterocyclic groups (preferably furyl, thienyl, thia
Zolyl, imidazolyl, pyrazolyl, pyridyl, pyrazi
Nil, indolyl, quinolyl, isoquinolyl, benzothi
Azolyl, benzothiadiazolyl, isoxazoli
5) or "may not be condensed with benzene ring"
A 6-membered non-aromatic heterocyclic group (preferably pyrrolidinyl, te
Trahydrofuranyl, thiazolinyl, oxazolinyl,
Thiazolidinyl, oxazolidinyl, dioxolanyl,
Piperidinyl, piperazinyl, morpholino, thiomorpho
Lino, dihydrobenzofuranyl) "; [D is preferred
May form a ring (mono- or di-C
_1-10Alkyl) phosphono group (preferably dimethylpho
Suphono; Diethylphosphono; Diisopropylphosphono;
Dibutylphosphono; 2-oxide-1,3,2-dioxa
C optionally substituted with phosphinanyl)_1-6Archi
Even if it is substituted with a group (preferably methyl, ethyl)
A good aryl group having 6 to 14 carbon atoms (preferably phenyl group)
)]; B is (1) 1 to 3 halogen atoms (eg, fluorine)
C, which may be substituted with hydrogen, chlorine, bromine, iodine)
_1-6Alkyl (eg methyl, ethyl, trifluoromethyi
1 to 3 halogen atoms (eg, fluorine, chlorine, odor)
C, which may be substituted with hydrogen, iodine)_1-6Alkoxy
(Eg, methoxy, ethoxy, trifluoromethoxy),
Halogen atom (eg, fluorine, chlorine, bromine, iodine), Ni
Toro, Formyl, C _1-3Alkylenedioxy (eg, methyl
Dioxy), aromatic heterocyclic group (eg, benzofuryl)
Substituted with 1 to 3 substituents selected from
A good aryl group having 6 to 14 carbon atoms (preferably phenyl group)
Or (2) an alkyl group having 1 to 10 carbon atoms (eg,
Tyl, isopropyl, t.-butyl); [B is preferably
Position with 1 to 3 halogen atoms (preferably chlorine, bromine)
An optionally substituted aryl group having 6 to 14 carbon atoms (preferably
Phenyl)]; X is an oxygen atom or a sulfur atom;
Y is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms (preferred
More preferably C_1-4An alkylene).

Compound (E) R¹Is mono- or di-C_1-10Alkylamino (eg,
Cylamino, dimethylamino, ethylamino, diethyl
Amino, ethylmethylamino, propylamino, dibuty
Luamino); [C_1-6Alkoxy-carbonyl substituted
May be present] mono- or di-C_2-10Alkenylia
Mino (eg, diallylamino); mono- or di-C_3-10
Cycloalkylamino (eg, cyclohexylamino);
[C_1-6Heterocyclethio optionally substituted with alkyl
(Eg, pyrimidinylthio), with 1 to 3 halogen atoms
C which may be substituted_6-14Arylthio, cyano,
C_1-6Alkylthio, halogen atom, heterocyclic carbonyl
1 selected from (eg, dihydroindolylcarbonyl)
To 3 substituents] mono-or
Or J-C_1-10Alkyl-carboxamide (eg, acetone
Tylamino, propionylamino); C_6-14Aryl-
Carboxamide (eg, benzoylamino); C_{6- 14}Ants
Amino (eg, phenylamino); NC_1-10Archi
Ru-NC_6-14Arylamino (eg, N-methyl-N-
Phenylamino); N-C_1-10Alkyl-NC_7-13A
Ralalkylamino (eg, N-methyl-N-benzylami)
No); mono- or di-C_1-6Alkoxy-carboxa
Amide (eg, tert-butoxycarboxamide); [C_1-6
Alkoxy, C_6-14Aryloxy, heterocyclic groups (e.g.,
1 to 3 selected from lyazolyl and tetrazolyl)
Optionally substituted with a substituent of] mono- or di-C
_6-14Aryl-carboxamide (eg, phenylcarboxy
Samide); [C_1-6Choose from alkoxy and halogen atoms
Optionally substituted with 1 to 3 substituents]
No or di-C_7-13Aralkyl-carboxamide
(Eg benzylcarboxamide, phenethylcarboxa
Mid, phenylpropylcarboxamide, phenylbutyrate
Lecarboxamide); [halogen atom, C_1-6Alkyl?
May be substituted with 1 to 3 substituents selected from
I] Aromatic heterocycle-carboxamide (eg, furylcarbo
Xamide, pyrrolylcarboxamide, thienylcarboxy
Samide, pyridylcarboxamide, pyrimidinylcarbo
Xamide, 1H-indazolyl carboxamide, benzo
Furanylcarboxamide, quinolylcarboxamide);
[Oxo, C_1-6Alkoxy-carbonyl, C_1-6A
Lucoxy-C_6-14Aryl (eg, methoxypheny
Le), C_1-6Alkyl-carbonyl-C_6-14Aryl
(Eg acetylphenyl), carbamoyl, C_7-13A
Aralkyl (eg, benzyl), heterocyclic group (eg, piperidi
Substituted with 1 to 3 substituents selected from
May be] 5- to 7-membered non-aromatic heterocycle-carboxami
(E.g., tetrahydrofurylcarboxamide, thiomol
Holinocarboxamide, piperidinocarboxamide, piper
Perazino carboxamide, hexamethylene iminylcal
Voxamide, thiazolidinylcarboxamide); [C_1-6
Alkoxy-carboxamide (eg, methoxycarboxamide
Amide, ethoxycarboxamide)
I C_1-6Optionally substituted by alkyl] C_3-10
Cycloalkyl-carboxamide (eg, cyclopentyl
Carboxamide, cyclohexylcarboxamide);
[May be substituted with a halogen atom] C_8-13Ants
Alkenyl-carboxamide (eg, styrylcarbo
Xamide); C_8-13Arylalkynyl-carboxa
Mido (eg, phenylethynylcarboxamide); aromatic
Heterocycle (eg, thienyl, furyl, indolyl) -C_1-6
Alkyl-carboxamide; C_6-14Arylsulfonyl
Amino (eg, phenylsulfonylamino); [hydroxy
Shi, C_1-6Alkoxy, C_1-6Alkylthio, halogen
Atom, C_{1 -6}Alkoxy-carbonyl, C_1-6A
Lucoxy-carboxamide, cyano, C_1-6Alkyl
1 to 3 selected from sulfonyl and carbamoyl
Optionally substituted with a substituent] mono- or di-C
_1-6Alkyl-carbamoylamino (e.g.
Vamoylamino, tert-butylcarbamoylamino);
[Optionally substituted by hydroxy] C_3-10Shiku
Roalkyl-carbamoylamino (eg, cyclopropyl
Carbamoylamino, cyclopentylcarbamoylami
No, cyclohexylcarbamoylamino); [1 to
C optionally substituted with 3 halogen atoms_1-6Al
Kill, C_1-6Even if it is substituted with alkyl-carbonyl
Good sulfamoyl, mono- or di-C_1-6Archi
Luamino, mono- or di-C_1-10Alkyl phospho
No-C _1-6Alkyl group, halogen atom, C_6-14Ally
Rusulfonyl (eg, phenylsulfonyl), C_7-13
Aralkyloxy (eg, benzyloxy), C_1-6A
Substituted with 1 to 3 substituents selected from lucoxy
May be present] C_{6-1 Four}Aryl-carbamoylami
No (eg, phenylcarbamoylamino); [mono-also
Is di-C_1-6Selected from alkylamino and halogen atoms
C optionally substituted with 1 to 3 substituents
_1-6Alkyl; halogen atom; sulfamoyl; hydro
Kish; C_1-61 to 3 selected from alkoxy
It may be substituted with a substituent] C_7-14Aralkyl
-Carbamoylamino (eg, benzylcarbamoylami)
No, phenethylcarbamoylamino, diphenylethyl
Carbamoylamino); C_1-6Alkoxy-Carbonii
Rucarbamoylamino (eg, methoxycarbonylcarba
Moylamino, ethoxycarbonylcarbamoylami
No); C_4-13Cycloalkylalkyl-carbamoylurea
Mino (eg, cyclohexylmethylcarbamoylami)
No); [Oxo, C_1-6Alkyl, hydroxy, C_1-6A
Substituted with 1 to 3 substituents selected from lucoxy
Heterocycle (eg, thienyl, furyl, oxa)
Zolyl, isoxazolyl, imidazolyl, triazoly
Ru, tetrazolyl, pyridyl, indolyl, 1H-in
Dazolyl, benzimidazolyl, tetrahydrofuryl,
Pyrrolidinyl, piperidinyl, morpholinyl, thiomol
Folinyl) -C_{1-1 0}Alkyl-carbamoylamino
(Eg, methylcarbamoylamino, ethylcarbamoyl
Amino); [C_1-6Alkyl and C_1-6From alkoxy
May be substituted with 1 to 3 substituents selected
I] Aromatic heterocyclic carbamoylamino (eg, isoxazol
Rylcarbamoylamino, benzothiazolylcarbamoy
Luamino); [C_1-6May be substituted with alkyl
I] Non-aromatic heterocyclic carbamoylamino (eg, pyrrolidi
Nylcarbamoylamino); or C_7-14Aralchi
Luoxy-carbamoylamino (eg, benzyloxyca
Luvamoylamino); A is (1) -NR²-WD; R²Is a hydrogen atom or C_1-6Alkyl group, W is a bond
Is C_1-4Alkylene and D may form a ring (mono
-Or Di-C_1-10Alkyl) phosphono group (preferred
Ku, dimethylphosphono; diethylphosphono; diisop
Ropylphosphono; dibutylphosphono; 2-oxide-
Substituted with 1,3,2-dioxaphosphinanyl)
Good C_1-6Alkyl group (preferably methyl, ethyl)
An aryl group having 6 to 14 carbon atoms which may be substituted with
(Preferably phenyl); or (2) 1) oxo; 2) hydroxy; 3) cyano; 4) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Bare); 5) C_1-6Alkylenedioxy (eg, methylenedioxy,
Ethylenedioxy); 6) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Hydroxyl; Cyano; C_1-6Alkoxy (eg,
Methoxy); C_1-6Alkyl mono- or di-substituted
Optional amino (eg, amino, methylamino, diamino
Methylamino); C_{1 −6}May be substituted with alkyl
A 5- to 6-membered aromatic heterocyclic group (eg, tetrazolyl);
C_1-65- to 6-membered non-alkyl optionally substituted
Aromatic heterocyclic group (eg, tetrahydrofuryl, morpholyl
No, thiomorpholino, piperidinyl, pyrrolidinyl, pi
Perazinyl, dioxothiazolidinyl, dioxooxa
Zolidinyl); carboxamide; halogenated
Moyo Mono- or Di-C_1-6Alkyl-carboxa
Amide (eg, acetylamino, trifluoroacetylamido)
No); mono- or di-C_1-6Alkoxy-carboxy
Selected from samides (eg, tert-butoxycarboxamide)
C optionally substituted with 1 to 3 substituents_{1 -6}
An alkyl group (eg, methyl, ethyl); 7) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
Elementary), optionally halogenated C_1-6Alkyl and
And C_1-61 to 3 substitutions selected from alkoxy
C optionally substituted with a group_6-14Aryl (eg, pheny
Le); 8) C_1-6C optionally substituted with alkylenedioxy
_7-13Aralkyl groups (eg benzyl, benzhydryl); 9) C_1-65 to 6 which may be substituted with an alkyl group
Membered nitrogen-containing heterocyclic groups (eg pyridyl, piperidinyl, pyridyl
Midinyl, pyrrolidinyl); 10) C_1-6Mono- or di-substituted with alkyl
Good amino (eg, amino, methylamino, dimethylamino)
Mino); 11) C_1-6Alkyl-carbonyl (eg, acetyl); 12) C_1-6Alkyl-sulfonyl (e.g., methylsulfo
Nyl, ethylsulfonyl); 13) C_3-10Cycloalkyl-carbonyl (e.g. cyclohexyl
Xylcarbonyl); 14) C_6-14Aryl-carbonyl (eg, benzoyl); 15) C_7-13Aralkyl-carbonyl (e.g.
Lubonyl, phenethylcarbonyl); 16) C_6-14Aryl-C_2-6Alkenyl-carbonyl
(Eg, styrylcarbonyl); 17) C_1-6Alkoxy-carbonyl (e.g. methoxyca
Lubonyl, ethoxycarbonyl, propoxycarboni
, Butoxycarbonyl, tert-butoxycarbonyl
); 18) C_1-65 to 6 optionally substituted with alkyl
Membered aromatic heterocycle-carbonyl (eg, furoyl, pyrrolyl
Carbonyl, thenoyl, pyridylcarbonyl); 19) C_1-65 to 6 optionally substituted with alkyl
Membered non-aromatic heterocycle-carbonyl (e.g. tetrahydrofuro)
Ill); 20) carboxamide; 21) Halogen atom (eg, fluorine, chlorine, bromine, iodine)
And C_1-61 to 3 substitutions selected from alkyl
Mono- or di-C optionally substituted with groups_{1 -6}A
Rutile-carboxamide (eg acetylamino, hexa
Noylamino, trifluoroacetylamino, N-acetate
Cyl-N-methylamino, pentafluoropropionyl
amino); 22) C_3-10Cycloalkyl-carboxamide (e.g.
Lohexylcarboxamide); 23) C_1-6Optionally substituted with alkylenedioxy
C_6-14Aryl-carboxamide (e.g., phenyl carboxamide
Xamide); 24) C_7-13Aralkyl-carboxamide (eg, benzyl
Carboxamide, phenethylcarboxamide); 25) C_6-14Aryl-C_2-6Alkenyl-carboxami
(Eg, styrylcarboxamide); 26) C_1-6Alkoxy-carboxamide (e.g., tert-
Butoxycarboxamide); 27) C_1-65 to 6 optionally substituted with alkyl
Membered aromatic heterocycle-carboxamide (e.g., furylcarboxyl
Samide, pyrrolylcarboxamide, thienylcarboxa
Amide, pyridylcarboxamide); 28) C_1-65 to 6 optionally substituted with alkyl
Membered non-aromatic heterocycle-carboxamide (e.g. tetrahydro
1 to 3 selected from furylcarboxamide);
1-piperidinini optionally having substituents
L, 1-piperazinyl, 4-morpholinyl or 4-thi
Omorpholinyl; [A is preferably the above (1)]; B is (1) 1 to 3
Substitute with a logen atom (eg, fluorine, chlorine, bromine, iodine)
May be C_1-6Alkyl (eg, methyl, ethyl
, Trifluoromethyl), 1-3 halogen atoms
Substituted with (eg, fluorine, chlorine, bromine, iodine)
Good C_1-6Alkoxy (eg methoxy, ethoxy, tho
Lifluoromethoxy), halogen atom (eg, fluorine, salt
Element, bromine, iodine), nitro, formyl, C _1-3Archi
Dioxy (eg methylenedioxy), aromatic heterocycle
1 to 3 units selected from a group (eg, benzofuryl)
Aryl having 6 to 14 carbon atoms which may be substituted with a substituent
A group (preferably phenyl) or (2) having 1 to 10 carbon atoms
Alkyl groups (eg, methyl, isopropyl, t.-butyl
[B is preferably 1 to 3 halogen atoms (preferably
6 to 6 carbon atoms which may be substituted with chlorine, bromine)
14 aryl groups (preferably phenyl)]; X is oxygen
Atom or sulfur atom; and Y is divalent having 1 to 4 carbon atoms
Aliphatic hydrocarbon group (preferably C_1-4Alkylene)
Compound.

Compound (F) 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Diethylphosphonomethyl) phenyl] propionamide; 3- [4- (4-chlorophenyl) -2- (4-morpholinyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propion Amide; 3- [4- (4
-Chlorophenyl) -2-phenyl-5-oxazolyl]
-N- [4- (dimethylphosphonomethyl) phenyl] propionamide; 3- [2- (1H-benzimidazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] -N- {4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide; 4- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl]-
N-[(4-dimethylphosphonomethyl) phenyl] butanamide; 1- {3- [2- (1H-benzimidazol-1yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} -4- Piperidinol; 4- {3- [2- (1
H-benzimidazol-1yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1-dioxide; 4- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl)-
5-oxazolyl] -N-[(4-diethylphosphonomethyl) phenyl] butanamide; or 4- {3- [4- (4-
Chlorophenyl) -2- (1-methyl-1H-indol-3-yl) -5-oxazolyl] propanoyl} thiomorpholine-1,1′-dioxide.

As the salt of the compound represented by the formula (I),
A pharmacologically acceptable salt is preferable, and examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. Examples include salt. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt;
Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts; as well as aluminum salts and ammonium salts. Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline,
Examples thereof include salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like. Suitable examples of salts with acidic amino acids include aspartic acid,
Examples thereof include salts with glutamic acid and the like. Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized,
A compound that undergoes reduction, hydrolysis, etc. to convert to compound (I), and a compound that undergoes hydrolysis, etc. due to gastric acid etc. to convert to compound (I). As a prodrug of compound (I), an amino group of compound (I) is acylated,
Alkylated and phosphorylated compounds (eg, compound (I)
The amino group of eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,
3-dioxolen-4-yl) methoxycarbonylation,
Tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (eg, The hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,
Alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compound (I) having a carboxyl group esterified or amidated (eg, compound (I) having a carboxyl group ethyl esterified, phenyl esterified,
Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) Methylesterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds and the like); and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design 163.
The compound (I) may be changed under physiological conditions as described in pages 198 to 198. The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like. Furthermore, the compound (I) may be an anhydride or a hydrate.

Compound (I) and its prodrug (hereinafter sometimes simply abbreviated as the compound of the present invention) have low toxicity and can be used as they are or in a pharmaceutical composition by mixing with a pharmaceutically acceptable carrier or the like. As a result, it can be used as a neurotrophic factor production / secretion promoter for mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.). Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation , Solubilizing agents, suspending agents, tonicity agents,
It is used as a buffer and soothing agent. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used.

Preferable examples of excipients include lactose, sucrose,
D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, alumino metasilicate. Magnesium acid etc. are mentioned. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Suitable examples of binders include pregelatinized starch,
Sucrose, gelatin, gum arabic, methyl cellulose,
Examples thereof include carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose and the like. Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. And so on. Suitable examples of suspending agents include stearyl triethanolamine, sodium lauryl sulfate,
Surfactants such as laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; hydrophilic such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose Polymers: polysorbates, polyoxyethylene hydrogenated castor oil and the like. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbate and the like. Suitable examples of colorants include water-soluble food tar dyes (eg, food red Nos. 2 and 3, food yellow Nos. 4 and 5, food blue Nos. 1 and 2 and the like, water-insoluble lake dyes ( Examples thereof include aluminum salts of the above water-soluble food tar pigments), natural pigments (eg, β-carotene, chlorophyll, red iron oxide, etc.), etc. Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, and aspartame. , Stevia, etc.

Examples of the dosage form of the pharmaceutical composition include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, Oral agents such as emulsions and suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), external preparations (eg, transdermal preparations, ointments) Suppositories), suppositories (eg, rectal suppositories,
Vaginal suppositories, etc.), pellets, nasal agents, pulmonary agents (inhalants),
Parenteral agents such as eye drops can be mentioned, and these can be safely administered orally or parenterally. These preparations may be controlled-release preparations (eg, sustained-release microcapsules, etc.) such as immediate-release preparations or sustained-release preparations.
The pharmaceutical composition can be produced by a method conventionally used in the technical field of formulation, such as the method described in the Japanese Pharmacopoeia. Below, the concrete manufacturing method of a formulation is explained in full detail.
Although the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., it is, for example, about 0.1-1.
It is 00% by weight.

For example, an oral preparation includes an active ingredient as an active ingredient, an excipient (eg, lactose, sucrose, starch, D-mannitol, etc.), a disintegrant (eg, carboxymethylcellulose calcium), a binder (eg, pregelatinized starch). , Gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. are added for compression molding, and if necessary, taste masking, It is produced by coating with a coating base by a method known per se for the purpose of enteric property or sustainability.

Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained release film coating base and the like. Saccharose is used as the sugar coating base, and talc, precipitated calcium carbonate, gelatin,
You may use together 1 type (s) or 2 or more types selected from gum arabic, pullulan, a carnauba wax, etc. As the water-soluble film coating base, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
Cellulose polymers such as hydroxyethyl cellulose and methyl hydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co.], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan And so on. Examples of enteric film coating bases include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Rohm Pharma Co., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co.], methacrylic acid copolymer S [Eudragit S]
(Trade name), Rohm Pharma Co., Ltd., and the like; acrylic acid-based polymers; natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co.], ethyl acrylate / methyl methacrylate copolymer suspension. Suspended liquid [Eudragit NE
(Trade name), ROHM Pharma Co., Ltd., and the like. The coating base described above,
You may mix and use 2 or more types in an appropriate ratio. Further, at the time of coating, a light shielding agent such as titanium oxide, iron sesquioxide, etc. may be used.

Injectables are prepared by dispersing active ingredients (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol). ，
Chlorobutanol, phenol, etc., tonicity agent (eg,
Sodium chloride, glycerin, D-mannitol, D-
Soluble and suspended in an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution, etc.) or an oily solvent (eg, olive oil, sesame oil, cottonseed oil, vegetable oil such as corn oil, propylene glycol, etc.) together with sorbitol, glucose, etc. It is produced by turbidity or emulsification. At this time, if desired, additives such as solubilizing agents (eg, sodium salicylate, sodium acetate, etc.), stabilizers (eg, human serum albumin, etc.), soothing agents (eg, benzyl alcohol, etc.) may be used.

The compound of the present invention has an excellent neurotrophic factor production / secretion promoting action. Examples of the neurotrophic factor include neurotrophin, TGF-β superfamily, neurokine family, growth factor and the like. Neurotrophin is a nerve growth factor (nerve
Growth factor (NGF) gene family, which is a protein that plays an important role in differentiation and function maintenance of central and peripheral nervous system cells, synapse formation, regeneration upon damage, and repair. Specific examples of neurotrophins include:
NGF, BDNF (brain-derived neurotrophic factor, brain-derived neuron
trophic factor), NT-3 (neurotrophin-3, neur
otrophin-3), NT-4 / 5 (neurotrophin-4 / 5, neur
otrophin-4 / 5), NT-6 (Neurotrophin-6, neurot
rophin-6) and so on. Neurotrophins
Preferred are NGF, BDNF, NT-3 and the like. The TGF-β superfamily means a group of proteins known to exert various actions on various cells and tissues, which has a characteristic structure in which cysteine is arranged in a mature molecule. Specific examples include TGF-β1, TGF-β2, TGF-
β3, BMP (bone morphogenetic protein, Bone Morphogenetic Protein)
-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-
8A, BMP-8B, BMP-14 (GDF-5), GDNF (Glial cell line-derived neurotroph
ic factor), neurturin, artemin, persephin, GDF−
1, GDF-8, GDF (Growth / differentiat, Growth / differentiat
ion factor) −15, inhibit α, inhibit β, DAF (dauer
formation) 7 and the like. The TGF-β superfamily is preferably GDNF, GDF-15 and the like. Examples of the neurokine family include ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6).
Examples of growth factors include insulin-like growth factor 1 (ins
ulin growth factor-1: IGF-1), basic fibroblast growth factor, and the like. The neurotrophic factor is preferably neurotrophin,
The TGF-β superfamily and the like are more preferable, and NGF, BDNF, NT-3, GDNF, GDF-15 and the like are more preferable. Further, the compound of the present invention has an action of improving conduction velocity of motor nerve and sensory nerve, and an action of improving pain (eg, neuropathic pain).

The compounds of the present invention are, for example, neurodegenerative diseases (eg, Alzheimer-type senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis (AL
S), Down syndrome, etc.); peripheral neuropathy (eg, diabetic neuropathy, neuropathy due to cancer treatment, etc.); diabetic cardiomyopathy; peripheral nerve injury; spinal cord injury; multiple sclerosis; cerebral ischemic disease; epilepsy Depression; Inflammatory bowel disease (eg, inflammatory bowel disease); Chronic pain (eg, cancer pain); Problematic behavior associated with dementia (eg, loitering, aggressive behavior); Anxiety; Wound Numbness due to pain; pain; autonomic dysfunction (eg, diabetic autonomic neuropathy, subconscious hypoglycemia, gastroparesis, neurogenic diarrhea and constipation, erectile dysfunction, orthostatic hypotension, arrhythmia, heart failure, painless myocardial infarction, Dyshidrosis, neurogenic bladder, etc .; bladder dysfunction (eg, bladder reflex etc.); deafness; diabetic foot lesions; bone disease (eg, osteoporosis etc.); joint disease (eg, Charcot joint, deformity) Arthrosis,
Rheumatism, etc.); Hirschsprung disease (Hirschspru)
ng disease); neuropathic pain (eg, painful neuropathy, postherpetic neuralgia, back pain, trigeminal neuralgia, carpal tunnel syndrome,
It is useful as a prophylactic / therapeutic agent for phantom limb pain, spinal cord injury, multiple sclerosis, etc. In addition, the compound of the present invention is used for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), impaired glucose tolerance [IGT (Impaired Glucose Tolerance)],
Hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, etc.), hyperinsulinemia, obesity, bulimia nervosa, hypertension, cardiovascular disease (eg, atherosclerosis) It is also useful as a prophylactic / therapeutic drug for diseases such as arteriosclerosis); or for syndromes having some of these diseases (eg, syndrome X, visceral obesity syndrome, etc.). Furthermore, the compound of the present invention is also used for secondary prevention and suppression of progression of various diseases described above (eg, myocardial infarction, etc.) (eg, inhibition of progression from impaired glucose tolerance to diabetes). Furthermore, the compound of the present invention is a remedy for peripheral neuropathy or cerebral metabolic disorders; a healing promoter for skin damage due to metabolic or endocrine system diseases such as diabetes and trauma; a pancreatic regenerative drug (pancreatic function restoring drug); a renal regenerative drug ( It is also useful as a remedy for renal function); a drug for improving or suppressing pain (eg, neuropathic pain); a drug for preventing lower limb amputation; a drug for preventing sudden death.

The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, condition and the like, but when administered orally to an adult patient with peripheral neuropathy (eg diabetic neuropathy), it is usually 1 About 0.01-10
0 mg / kg body weight, preferably 0.05 to 30 mg / k
g body weight, more preferably 0.1 to 2 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

The compounds of the present invention are therapeutic agents for diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, antithrombotic agents, osteoporosis therapeutic agents. Agent, anti-dementia agent, erectile dysfunction improving agent, urinary incontinence / frequency treatment agent,
It can be used in combination with antiepileptic drugs, antidepressants, opioid agonists, nonsteroidal anti-inflammatory drugs, local anesthetics, vitamins and other drugs (hereinafter abbreviated as concomitant drugs). These concomitant drugs may be low molecular weight compounds, high molecular weight proteins, polypeptides, antibodies, or vaccines. The timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the administration subject at the same time or at a staggered time. Specific dosage forms include, for example,
1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, 2) administration of a single preparation obtained by separately formulating the compound of the present invention and a concomitant drug, by the same administration route Simultaneous administration, 3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug with a time lag in the same administration route, 4) Formulation of the compound of the present invention and a concomitant drug separately Administration of two types of pharmaceutical preparations obtained by the formulation, 5) administration of the two compounds obtained by separately formulating the compound of the present invention and a concomitant drug, and administration with different time lags by different administration routes (For example, administration of the compound of the present invention and concomitant drug in this order, or administration in the reverse order) and the like. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug is 0.01 to 10 parts by weight relative to 1 part by weight of the compound of the present invention.
0 parts by weight may be used.

As a therapeutic agent for diabetes, an insulin preparation (eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically synthesized using Escherichia coli or yeast; insulin zinc; protamine insulin) Zinc; fragments or derivatives of insulin (eg, INS-1 etc.), insulin sensitizers (eg, pioglitazone hydrochloride, rosiglitazone (maleic acid), GI-262570, reglixane (Reglixa)
ne) (JTT-501), netoglitazone
(MCC-555), YM-440, KRP-297, C
S-011, FK-614, the compound described in WO99 / 58510 (for example, (E) -4- [4- (5-methyl-
2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid), Ragaglitazar (NN-622), AR-H-0392.
42, BMS-298585, EML-16336, Tesaglitazar (AZ-242), Balaglitazone (NN-2344), ONO-5
816, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6
054, LY-510929, etc.), α-glucosidase inhibitors (eg,
Voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylurea agents (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, trazamide, acetohexamide, etc.) Gliclopyramide, glimepiride, glipizide, glybuzole, etc.), repaglinide,
Senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, etc.], GLP-1 receptor agonist [eg, GLP-1, NN-2211, AC-2993 (exendin
-4), BIM-51077, Aib (8,35) hGLP-1
(7,37) NH ₂ etc.], amylin agonist (eg pramlintide etc.), phosphotyrosine phosphatase inhibitor (eg vanadic acid etc.), dipeptidyl peptidase IV inhibitor (eg NVP-DPP-278, PT- 10
0, P32 / 98, etc.), β3 agonist (eg, CL-3
16243, SR-58611-A, UL-TG-30
7, SB-226552, AJ-9677, BMS-1
96085, AZ40140, etc., gluconeogenesis inhibitors (eg,
Glycogen phosphorylase inhibitor, glucose-6-
Phosphatase inhibitors, glucagon antagonists, etc.), SGL
T (sodium-glucose cotransporter) inhibitors (eg, T
-1095 etc.) and the like.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-1).
12, etc.), neurotrophic factors and their increasing drugs (eg, NG)
F, NT-3, BDNF, the neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4-
(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole, etc.), a nerve regeneration promoter (eg,
Y-128), PKC inhibitor (eg, LY-33353)
1), AGE inhibitors (eg, ALT946, pimagegedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (Eg,
Tiapride, mexiletine, etc.) and the like.

Antihyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin,
Atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt), squalene synthase inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- ( 3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-yl] acetyl] piperidine-4-acetic acid, etc.) or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like. Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.) or angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg Examples include manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like. As an antiobesity agent,
For example, central anti-obesity drugs (eg, dexfenfluramine,
Fenfluramine, phentermine, sibutramine, amphepramone, dexamphetamine, mazindol,
Phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (eg, orlistat, etc.), β
3 agonists (eg CL-316243, SR-586
11-A, UL-TG-307, SB-226552,
AJ-9677, BMS-196085, AZ4014
0, etc., peptide appetite suppressants (eg, leptin, CNT)
F (ciliary neurotrophic factor) and the like), cholecystokinin agonist (eg, lintotrypt, FPL-15849, etc.)
Etc.

Examples of the diuretics include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate), thiazide preparations (eg, ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, Penfluthizide, polythiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), Azosemide, isosorbide,
Ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Examples include plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Among them, 5-fluorouracil derivative such as furtulon or neofurtulon is preferable. Immunotherapeutic agents include, for example, microbial or bacterial components (eg, muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Example,
Interferon, interleukin (IL, etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like, among which IL-1, IL
-2, IL-12 and the like are preferable.

Examples of antithrombotic agents include heparin (eg,
Heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, aragatroban, etc.), thrombolytic drug (eg, urokinase, thisokinase) (tiso
kinase), alteplase, nateplase (n
ateplase), monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) ) Etc.) and the like. Examples of therapeutic agents for osteoporosis include alfacalcidol (alfacalcidol) and calcitriol (calcit).
riol), elcatonin, salmon calcitonin salmon, estriol
l), ipriflavone, disodium pamidronate, alendronate sodium hydrate, incadronate disodium and the like. Examples of anti-dementia agents include tacrine (ta
crine), donepezil (donepezil), rivastigmine (rivastigmine), galantamine (galantamine) and the like. Examples of erectile dysfunction improving agents include apomorphine and sildenafil citrate (sil
denafil citrate) and the like. Examples of therapeutic agents for urinary incontinence and frequent urination include flavoxate hydrochloride.
drochloride), oxybutynin hyd
rochloride), propiverine hydroc
hloride) and the like. Examples of the antiepileptic drug include gabapentin, carbamazepine and the like.
Examples of the antidepressant include amitriptyline, imipramine and the like. Examples of the opioid agonist include morphine and the like. Examples of the nonsteroidal anti-inflammatory drug include aspirin, acetaminophen, indomethacin and the like. Examples of local anesthetics include lidocaine and capsaicin. Examples of vitamins include vitamin B1 and vitamin B12.

Furthermore, drugs that have been shown to have an effect of improving cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, 5935-59]
39, 1989], progesterone derivatives (eg megesterol acetate) [Journal of Clinical Oncolog
y), Vol. 12, pp. 213-225, 1994], glucosteroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (both documents are the same as above), fat metabolism improving agents ( (Eg, eicosapentaenoic acid) [British Journal of Cancer, No. 68
Vol., 314-318, 1993], growth hormone,
IGF-1, or TN, a factor that induces cachexia
Antibodies against F-α, LIF, IL-6, oncostatin M and the like can also be used in combination with the compound of the present invention.

The concomitant drug is preferably an insulin preparation,
Insulin sensitizer, α-glucosidase inhibitor,
Biguanides, insulin secretagogues (preferably sulfonylureas), aldose reductase inhibitors, PK
C inhibitors, antiepileptic drugs, antidepressants, opioid agonists, non-steroidal anti-inflammatory drugs and the like.

The above concomitant drug may be used in combination of two or more kinds at an appropriate ratio. Preferred combinations when using two or more concomitant drugs include, for example, the following. 1) Insulin secretagogue (preferably sulfonylurea agent) and α-glucosidase inhibitor; 2) Insulin secretagogue (preferably sulfonylurea agent) and biguanide agent; 3) Insulin secretagogue (preferably sulfonylurea agent), biguanide agent And α-glucosidase inhibitor; 4) Insulin sensitizer and α-glucosidase inhibitor; 5) Insulin sensitizer and biguanide; 6) Insulin sensitizer, biguanide and α
-Glucosidase inhibitors.

When the compound of the present invention is used in combination with a concomitant drug, the doses of both components can be reduced within a safe range in consideration of the opposite effects of those components. In particular, the insulin sensitizer, insulin secretagogue (preferably sulfonylurea drug) and biguanide drug can be reduced in doses lower than usual doses. Therefore, the adverse effects that would be caused by these agents can be safely prevented.
In addition, the doses of therapeutic agents for diabetic complications, antihyperlipidemic agents, and antihypertensive agents can be reduced, and as a result, the adverse effects that may be caused by these agents can be effectively prevented.

The production method of the compound of the present invention will be described below. Compound (I) can be produced, for example, according to the following methods A to G or methods analogous thereto. [Method A]

[Chemical 6] [The symbols in the formulas have the same meanings as defined above] In this method, compound (I) is produced by subjecting compound (II) to an amidation reaction. This reaction is a method known per se, for example, a method in which compound (II) and compound (III) are directly condensed using a condensing agent, or compound (II)
It is carried out by a method of appropriately reacting the reactive derivative of the above with the compound (III). Examples of the condensing agent include carbodiimide-based condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide and its hydrochloride; phosphoric acid-based condensation reagents such as diethyl cyanophosphate and diphenylphosphoryl azide. Carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate and the like can be mentioned. Examples of the solvent used in the reaction using the condensing agent include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatics such as benzene and toluene. Hydrocarbons; ethers such as tetrahydrofuran, dioxane, diethyl ether; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio. The amount of the compound (III) used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 with respect to the compound (II).
It is a molar equivalent. The amount of the condensing agent used is usually 0.1 to 10 molar equivalents with respect to compound (II), preferably 0.3 to
It is 3 molar equivalents. When the carbodiimide-based condensation reagent is used as the condensing agent, a suitable condensation accelerator (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N- The reaction efficiency can be improved by using (hydroxyphthalimide, etc.). When the phosphoric acid type condensation reagent is used as the condensing agent, the reaction efficiency can be improved by adding an organic amine base such as triethylamine.
The amount of the above-mentioned condensation accelerator or organic amine base used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (II). The reaction temperature is usually
The temperature is -30 ° C to 100 ° C. The reaction time is usually 0.5
~ 60 hours.

In the method using the reactive derivative of the compound (II), examples of the reactive derivative of the compound (II) include acid anhydride, acid halide (acid chloride, acid bromide), imidazolide, and mixed acid anhydride. (For example, methyl carbonate, ethyl carbonate, an anhydride with isobutyl carbonate, etc.) and the like. For example, when using an acid anhydride or an acid halide, the reaction is usually performed in the presence of a base in a solvent that does not influence the reaction. Examples of the base include amines such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and 4-dimethylaminopyridine; lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, Examples thereof include alkali metal salts such as potassium carbonate and cesium carbonate. The amount of base used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (II). Examples of the solvent that does not influence the reaction include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as chloroform and dichloromethane; aromatics such as benzene and toluene. Hydrocarbons; ethers such as tetrahydrofuran, dioxane, diethyl ether; ethyl acetate, water and the like. These solvents may be mixed and used at an appropriate ratio. In addition,
When the above amides are used as the solvent that does not affect the reaction, the reaction can be performed in the absence of a base. The amount of the compound (III) used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 with respect to the compound (II).
It is a molar equivalent. The reaction temperature is usually -30 ° C to 100
℃. The reaction time is usually 0.5 to 20 hours.

When a mixed acid anhydride is used, compound (II) and a chlorocarbonic acid ester (eg, methyl chlorocarbonate,
Ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) in the presence of a base, and further reacted with compound (III). Examples of the base include amines such as triethylamine, aniline, N-methylmorpholine, N, N-dimethylaniline and 4-dimethylaminopyridine; sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, Examples thereof include alkali metal salts such as potassium carbonate and cesium carbonate. The amount of the base used is usually 0.1 to 10 with respect to the compound (II).
It is a molar equivalent, preferably 0.3 to 3 molar equivalents. The usage-amount of a compound (III) is 0.1-10 molar equivalent normally with respect to a compound (II), Preferably it is 0.3-3 molar equivalent. The reaction temperature is usually -30 ° C to 100 ° C. The reaction time is usually 0.5 to 20 hours. The compound (I) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography, a method using an ion exchange resin or a scavenger resin, and the like. Compound (II) used as a raw material in the above method A
Can be produced according to, for example, the method described in WO97 / 36882, WO01 / 14372 or the like, or a method analogous thereto. In addition, compound (III) can be produced according to a method known per se.

[Method B] (Substitution reaction)

[Chemical 7] [In the formula, L represents a leaving group, and other symbols have the same meanings as described above] Examples of the leaving group represented by L include a halogen atom (eg, fluorine, chlorine, bromine, iodine); an alkoxy group,
Examples thereof include oxygen functional groups such as phenoxy group; sulfur functional groups such as sulfanyl group, sulfinyl group, and sulfonyl group; amino group; acyl group. In this method, the compound (I
Compound (I) is produced by reacting a) with compound (IV). This reaction is carried out according to a conventional method, usually in the presence of a base, in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like. Alkaline earth metal salts; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Examples thereof include amines such as ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide. The amount of base used is preferably about 1 to about 5 molar equivalents relative to compound (Ia). Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone; chloroform and dichloromethane. And halogenated hydrocarbons; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about −
It is 50 to about 150 ° C, preferably about -10 to about 100 ° C. The reaction time is usually about 0.5 to about 20 hours. The compound (I) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography, a method using an ion exchange resin or a scavenger resin, and the like. The compound (Ia) used as a raw material in the above method B can be produced, for example, according to the above method A. In addition, compound (IV) can be produced according to a method known per se.

The compound (Ib) in which R ¹ in the formula (I) is an optionally substituted aryl group can also be produced by the following Method C. [Method C] (Suzuki coupling reaction)

[Chemical 8] [In the formula, La represents a halogen atom, R ^1a represents an ^optionally substituted aryl, and other symbols have the same meanings as described above.] As the halogen atom represented by La, fluorine, chlorine,
Examples include bromine and iodine. Examples of the "optionally substituted aryl group" for R ^1a include those in which the "hydrocarbon group" in the "optionally substituted hydrocarbon group" exemplified as R ¹ is an aryl group. To be Among them, 1 selected from C _1-6 alkyl and halogen atom
To phenyl which may be substituted with two or two substituents are preferable. Specific examples of the compound (V) include phenylboronic acid, tolylboronic acid, 4-fluorophenylboronic acid and the like. This method is based on the known Suzuki reaction (Journal of Organometallic Chemistry,
1999, 576, 147). That is, in this method, the compound (Iaa) and the compound (V) are reacted with each other using a palladium catalyst in the presence of a suitable base, if necessary, to give the compound (Iaa).
b) is produced. This reaction is carried out according to a conventional method, usually in the presence of a base, in a solvent that does not adversely influence the reaction.
Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like. Alkaline earth metal salts; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Examples thereof include amines such as ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide. The amount of the base used is preferably about 1 to about 5 molar equivalents relative to compound (Iaa). The amount of compound (V) used is
It is preferably about 1 to about 5 molar equivalents with respect to a). Examples of the solvent that does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone;
Halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide;
Examples thereof include sulfoxides such as dimethyl sulfoxide, water and the like. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50 to about 150.
C, preferably about -10 to about 100C. The reaction time is usually about 0.5 to about 20 hours. The compound (Ib) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography, a method using an ion exchange resin or a scavenger resin, and the like. The compound (I
aa) can be produced, for example, according to the above method A. In addition, compound (V) can be produced according to a method known per se.

The compound (Id) in which R ¹ in the formula (I) is an amino group which may be substituted with carbamoyl or thiocarbamoyl can also be produced by the following Method D. [Method D] (Reaction of aminoazole and isocyanate derivative)

[Chemical 9] [In the formula, X ₁ is an oxygen atom or a sulfur atom, R ^2a is a hydrogen atom or an optionally substituted alkyl group, and R ^{2b is}
Is an optionally substituted alkyl group or an optionally substituted aryl group, and other symbols have the same meanings as the above] As "an optionally substituted alkyl group" represented by R ^2a and R ^2b Examples of the "hydrocarbon group which may be substituted" exemplified as R ¹ include those in which the "hydrocarbon group" is an alkyl group. Of these, C _1-6 alkyl and the like are preferable. Examples of the “optionally substituted aryl group” represented by R ^2b include those in which the “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as R ¹ is an aryl group. To be Of these, phenyl and the like are preferable. Specific examples of the compound (VI) include phenyl isocyanate, isopropyl isocyanate, phenyl thioisocyanate and the like.
In this method, compound (Id) is produced by reacting compound (Ic) with compound (VI). This reaction is
The reaction is performed according to a conventional method, usually under neutral conditions, optionally in the presence of a suitable base, in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like. Alkaline earth metal salts; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Examples thereof include amines such as ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide. The amount of base used is preferably about 1 to about 5 molar equivalents relative to compound (Ic). The amount of the compound (VI) used is the compound (Ic)
On the other hand, it is preferably about 1 to about 5 molar equivalents. Examples of the solvent that does not adversely affect the reaction include benzene and
Aromatic hydrocarbons such as toluene and xylene; Ethers such as tetrahydrofuran, dioxane and diethyl ether; Ketones such as acetone and 2-butanone; Halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide etc. Amides; sulfoxides such as dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about −50 to about 150 ° C., preferably about −10 to about 100 ° C. The reaction time is usually about 0.5 to about 20 hours. The compound (Id) thus obtained is obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin or a scavenger resin, etc. It can be isolated and purified. Compound (Ic) used as a starting material in Method D can be produced, for example, according to Method A or Method B described above. In addition, compound (VI) can be produced according to a method known per se.

[Method E] (Reaction of aminoazole and acetal derivative)

[Chemical 10] [In the formula, R ^2c and R ^2d are the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, and R ⁶ is a C _1-6 alkyl group,
Other symbols have the same meanings as defined above] "an ^optionally substituted alkyl group" and "an optionally substituted aryl group" represented by R ^2c and R ^2d
Examples of R ^2b include those exemplified above as R ^2b . The C _1-6 alkyl group represented by R ⁶ is the above R ²
Examples of the above are listed. In this method, compound (If) is produced by reacting compound (Ie) with compound (VII). This reaction is carried out according to a conventional method, usually under neutral conditions, optionally in the presence of a suitable base, in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate; barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like. Alkaline earth metal salts; amines such as pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene; metal hydrogen such as potassium hydride and sodium hydride Compounds; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide, and the like. The amount of the base used depends on the compound (I
It is preferably about 1 to about 5 molar equivalents with respect to e). The amount of compound (VII) used is preferably about 1 to about 5 molar equivalents relative to compound (Ie). Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones such as acetone and 2-butanone; chloroform and dichloromethane. And halogenated hydrocarbons; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -50 to about 150 ° C, preferably about -1.
0 to about 100 ° C. The reaction time is usually about 0.5 to
It's about 20 hours. The compound (I
f) is a known separation and purification means such as concentration, concentration under reduced pressure,
Solvent extraction, crystallization, recrystallization, phase transfer, chromatography,
It can be isolated and purified by a method using an ion exchange resin or a scavenger resin. Compound (Ie) used as a starting material in Method E can be produced, for example, according to Method A or Method B described above. In addition, compound (VII) can be produced according to a method known per se.

[Method F] (Reaction of aminoazole and carboxylic acid derivative)

[Chemical 11] [The symbols in the formulas have the same meanings as above] In this method, compound (Ig) is produced by reacting compound (Ic) with compound (VIII). This method
It can be carried out in the same manner as in the above method A. The compound (Ig) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography, a method using an ion exchange resin or a scavenger resin, and the like. Compound (Ic) used as a raw material in Method F
Can be produced according to the above-mentioned Method A or Method B. In addition, compound (VIII) can be produced according to a method known per se.

Among the compounds (Ia) used as the starting material in the above Method B, the compound (Iaa) whose leaving group represented by L is a halogen atom and the compound (Iaa) used as the starting material in the Method C are, for example, It can be manufactured according to the following Method G. [Method G] Zandmeier reaction of aminoazole

[Chemical 12] [Symbols in the Formulas Have the Same Meaning as Above] This reaction is carried out, for example, according to the known Sandmeyer reaction. That is, the compound (Ie) is subjected to a diazotization reaction, and the resulting diazonium salt is reacted with a monovalent or divalent copper salt and hydrochloric acid or hydrobromic acid in a solvent that does not adversely influence the reaction. Thereby, compound (Iaa) can be produced. The diazotization reaction is
It is carried out according to a known method using a diazotizing agent.
Examples of the diazotizing agent include nitrites such as nitrous acid and sodium nitrite; and nitrosyl halides such as nitrosyl chloride. The amount of diazotizing agent used is usually about 1 to 5 molar equivalents relative to compound (Ie). Examples of the monovalent or divalent copper salt include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (II) chloride, and copper bromide (I).
I), copper (II) iodide and the like. The amount of copper salt used is usually about 1 to 5 molar equivalents relative to compound (Ie). Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; aromatic amines such as quinoline and pyridine; acetone, dimethyl sulfoxide, phosphoric acid, acetic acid, and water. And so on.
These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually about -20 to 200 ° C, preferably about 0.
~ 150 ° C. The reaction time is usually about 0.5 to 20 hours.

This reaction can also be carried out by reacting compound (Ie) with alkyl nitrite in the presence of a monovalent or divalent copper salt in a solvent that does not affect the reaction. . Examples of the monovalent or divalent copper salt include the same ones as described above. The amount of copper salt used is
It is usually about 1 to 5 molar equivalents relative to compound (Ie). Examples of the solvent that does not influence the reaction include ethers such as tetrahydrofuran and dioxane; acetonitrile, acetone, dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio. Examples of the alkyl nitrite include t-butyl nitrite and isoamyl nitrite. The amount of alkyl nitrite used is usually about 1 to the compound (Ie).
It is 5 molar equivalents. The reaction temperature is usually about -20 to 200.
C., preferably about 0 to 150.degree. The reaction time is usually about 0.5 to 20 hours. The compound (Iaa) thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin or a scavenger resin. It can be isolated and purified.

In each of the above reactions, when the starting compound has amino, carboxy, hydroxy, or carbonyl as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. After the reaction, the target compound can be obtained by removing the protective group if necessary. Examples of the amino-protecting group include formyl, C _1-6 alkyl-carbonyl (eg,
Acetyl, propionyl, etc.), C _1-6 alkoxy-
Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), benzoyl, C _7-13 aralkyl-carbonyl (eg, benzylcarbonyl), C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, 9) -Fluorenylmethoxycarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-
Butyldiethylsilyl etc.), C _2-6 alkenyl (eg 1-allyl etc.) and the like. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine,
Bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), nitro, etc. Examples of the carboxy protecting group include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),
C _7-13 aralkyl (eg, benzyl etc.), phenyl, trityl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.), C _2-6 alkenyl (eg. , 1-allyl etc.) and the like. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_It may be substituted with _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro and the like.

Examples of the hydroxy protecting group include, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C _7-13 aralkyl (eg, benzyl, etc.), formyl, C _1-6 alkyl-carbonyl (eg. ,
Acetyl, propionyl, etc.), benzoyl, C _7-1
3 aralkyl - carbonyl (e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert- butyldiethylsilyl, etc.),
C _2-6 alkenyl (eg, 1-allyl etc.) and the like can be mentioned. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.), C
_It may be substituted with _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro and the like. Examples of the carbonyl protecting group include a cyclic acetal (eg, 1,3-dioxane etc.), an acyclic acetal (eg, di-C _1-6 alkyl acetal etc.) and the like. In addition, methods for removing these protecting groups are known per se, for example, Protective Groups in Organic Synthesis (Protective Groups in O
rganic Synthesis), published by John Wiley and Sons (198
It may be performed according to the method described in 0). For example,
Acid, base, ultraviolet light, hydrazine, phenylhydrazine,
Sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide,
Trimethylsilyl bromide, etc.)
A reduction method or the like is used.

In each of the above reactions, when the starting compound can form a salt, the compound may be used as a salt. As such salts, those exemplified as the salts of the compound represented by the formula (I) are used. When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I), and are each synthesized by a known synthesis method or separation method. Can be obtained as a single item. For example, when the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I). The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the racemate of the final product according to a conventional method. As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used. 1) Fractional recrystallization method racemate and optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
Phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, and this is separated by a fractional recrystallization method, and if desired, a free optical isomer is obtained through a neutralization step. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separating optical isomers (chiral column) for separation. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation,
Optical isomers by developing water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as single or mixed solutions To separate. In the case of gas chromatography, for example, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences Inc.). 3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this mixture is subjected to usual separation means (eg, fractional recrystallization, chromatography method, etc.) to obtain a single substance. Then, a method of obtaining an optical isomer by cleaving the optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, when the compound (I) has hydroxy or 1,2 amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid],
(−)-Menthoxyacetic acid and the like) and the like are subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound and the optically active amine or alcohol reagent are subjected to a condensation reaction to obtain an amide or ester diastereomer, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

[0089]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Reference Examples, Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.

EXAMPLES In the following reference examples and examples,
Unless otherwise specified,% means weight percent. In addition, room temperature refers to a temperature of 1 to 30 ° C. Reference Example 1 Ethyl 2-chloro-4-isopropyl-5-thiazolecarboxylate (30.0 g) was dissolved in 200 mL of toluene, and a 70% toluene solution of sodium dihydridobis (2-methoxyethoxy) aluminate (59.1 g) was added. 0
Dropwise at ° C. Reaction mixture with sodium potassium tartrate
A 10% aqueous solution of tetrahydrate (100 mL) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oil (23.2 g). This oil was converted to tetrahydrofuran (1
50 ml), manganese dioxide (60 g) was added, and the mixture was stirred at room temperature for 12 hours. Manganese dioxide was removed by filtration, the organic layer was concentrated, and the residue was purified by silica gel column chromatography. From the elution part of hexane-ethyl acetate (9: 1, volume ratio), 2-chloro-4-isopropyl-5-thiazolecarbaldehyde (12.0
g, 54%) as a yellow oil. NMR (CDCl ₃ ) δ: 1.39 (6H, t, d, J = 7Hz), 3.45-3.65 (1H, m), 1
0.06 (1H, s).

Compounds of Reference Examples 2 to 4 were synthesized in the same manner as in Reference Example 1 except that an ethyl 2-chloro-5-thiazolecarboxylate derivative having a different 4-position substituent was used as a starting material. Reference Example 2 4-tert-butyl-2-chloro-5-thiazolecarbaldehyde yield: 69%. Yellow oil. NMR (CDCl ₃ ) δ: 1.52 (9H,
s), 10.31 (1H, s). Reference Example 3 2-Chloro-4-phenyl-5-thiazolecarbaldehyde yield 70%. Pale yellow solid Reference Example 4 2-chloro-4-methyl-5-thiazolecarbaldehyde yield 82%. Yellow oil. NMR (CDCl ₃ ) δ: 2.31 (3H, s), 1
0.31 (1H, s).

Reference Example 5 2-Chloro-4-isopropyl-5-thiazolecarbaldehyde (2.0 g), ethyl diethylphosphonoacetate (2.47 g), sodium hydride (0.44 g),
A mixture of N, N-dimethylformamide (10 mL) was stirred at room temperature for 1 hour. Benzimidazole (1.54 g) and sodium hydride (0.44 g) were added to the reaction mixture.
Was added, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into water, the precipitated crystals were filtered, and washed with water. Recrystallized from acetone-hexane to give (2E) -3- [2- (1H-
Benzimidazol-1-yl) -4-isopropyl-
5-Thiazolyl] ethyl propenoate (3.01 g, 84
%) Was obtained as pale yellow prism crystals. Melting point 229-2
30 ° C.

The compounds of Reference Examples 6 to 8 were synthesized in the same manner as in Reference Example 5. Reference Example 6 Ethyl (2E) -3- [2- (1H-benzimidazol-1-yl) -4-tert-butyl-5-thiazolyl] propenoate Yield: 84%. Pale yellow prism, melting point 129-130
C (recrystallized from acetone-hexane). Reference Example 7 (2E) -3- [2- (1H-benzimidazol-1-yl) -4-phenyl-5-thiazolyl] propenoate ethyl yield: 84%. Amorphous solid-state NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7Hz), 4.27 (2H, q, J = 7H
z), 6.25 (1H, d, J = 15Hz), 7.4-7.6 (6H, m), 7.7-7.9 (2H,
m), 7.95 (1H, d, J = 15Hz), 8.1-8.2 (1H, m), 8.63 (1H, s). Reference Example 8 (2E) -3- [2- (1H-benzimidazole-1- Yyl) -4-methyl-5-thiazolyl] ethyl propenoate Yield: 81%. Pale yellow prism, melting point 109-112
C (recrystallized from acetone-hexane).

Reference Example 9 Ethyl (2E) -3- [2- (1H-benzimidazol-1-yl) -4-isopropyl-5-thiazolyl] propenoate (1.50 g), 5% palladium-carbon (1 .0
g), tetrahydrofuran (20 mL) ethanol (2
(0 mL) of the mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 14 hours. The catalyst is filtered off and the organic layer is concentrated,
3- [2- (1H-benzimidazol-1-yl) -4
Ethyl -isopropyl-5-thiazolyl] propionate (1.50 g, 99%) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7Hz), 1.34 (6H, d, J = 7Hz),
2.66 (2H, t, J = 7Hz), 3.1-3.2 (1H, m), 3.14 (2H, t, J = 7Hz),
4.18 (2H, q, J = 7Hz), 7.35-7.5 (2H, m), 7.8-7.9 (1H, m),
8.05-8.15 (1H, m), 8.46 (1H, s).

The compounds of Reference Examples 10 and 11 were synthesized in the same manner as in Reference Example 9. Reference Example 10 3- [2- (1H-benzimidazol-1-yl) -4
Ethyl -tert-butyl-5-thiazolyl] propionate Yield: 99%. Yellow oil. NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7Hz), 1.48 (9H, s), 2.71 (2
H, t, J = 7Hz), 3.32 (2H, t, J = 7Hz), 4.19 (2H, q, J = 7Hz), 7.
3-7.5 (2H, m), 7.8-7.9 (1H, m), 8.05-8.15 (1H, m), 8.43 (1
H, s). Reference Example 11 3- [2- (1H-benzimidazol-1-yl) -4
-Phenyl-5-thiazolyl] ethyl propionate yield: 88%. Pale yellow prism, melting point 81-82 ° C
(Recrystallized from acetone-hexane).

Reference Example 12 Methyl 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionate (1.50 g), dihydroxyphenylborane (650 mg), sodium hydrogen carbonate (1.68 g), Tetrakis (triphenylphosphine) palladium (250 mg), toluene (50 m
A mixture of L), ethanol (25 mL), and water (25 mL) was stirred under an argon atmosphere with heating under reflux for 12 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography. Methyl 3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] propionate (1.50 g, 88%) was obtained as a yellow oil from the elution with hexane-ethyl acetate (6: 1, volume ratio). NMR (CDCl ₃ ) δ: 2.82 (2H, t, J = 7.5Hz), 3.29 (2H, t, J = 7.5H)
z), 3.70 (3H, s), 7.3-7.5 (5H, m), 7.69 (2H, d, J = 8.5Hz),
8.0-8.1 (2H, m).

In the same manner as in Reference Example 12, Reference Examples 13 to 1
Compound 5 was synthesized. Reference Example 13 4- [4- (4-chlorophenyl) -2-phenyl-5-
Ethyl oxazolyl] butanoate yield: 90%. Yellow oil NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7Hz), 2.0-2.3 (2H, m), 2.43
(2H, t, J = 7Hz), 3.00 (2H, t, J = 7Hz), 4.12 (2H, q, J = 7HZ),
7.3-7.5 (5H, m), 7.66 (2H, d, J = 8.5Hz), 8.0-8.1 (2H, m). Reference Example 14 Methyl 3- [4- (3,4-dichlorophenyl) -2-phenyl-5-oxazolyl] propionate Yield: 69%. Yellow oil NMR (CDCl ₃ ) δ: 2.83 (2H, t, J = 7Hz), 3.29 (2H, t, J = 7Hz),
3.71 (3H, s), 7.4-7.7 (5H, m), 7.91 (1H, d, J = 2Hz), 8.0-
8.1 (2H, m). Reference Example 15 6- [4- (4-chlorophenyl) -2-phenyl-5-
Methyl oxazolyl] hexanoate Yield: 90%. Yellow oil NMR (CDCl ₃ ) δ: 1.4-1.6 (2H, m), 1.6-1.9 (4H, m), 2.33 (2
H, t, J = 7Hz), 2.93 (2H, t, J = 7Hz), 3.66 (3H, s), 7.4-7.5
(5H, m), 7.65 (2H, d, J = 8.5Hz), 8.0-8.1 (2H, m).

Reference Example 16 Ethyl 5- [2-chloro-4-chlorophenyl-5-oxazolyl] pentanoate (6.30 g), potassium carbonate (5.08 g), benzimidazole (4.34 g),
A mixture of N, N-dimethylformamide (50 mL) was stirred at 120 ° C. for 1 hour. Pour the reaction mixture into water,
The precipitated crystals are collected by filtration, washed with water and dried to give 5- [2-
Ethyl (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] pentanoate (7.20 g, 90% yield) was obtained. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7Hz), 1.7-2.0 (4H, m), 2.39
(2H, t, J = 7Hz), 3.00 (2H, t, J = 7Hz), 4.14 (2H, q, J = 7Hz),
7.4-7.5 (4H, m), 7.67 (2H, d, J = 8.5Hz), 7.88 (1H, d, J = 7.5
Hz), 8.26 (1H, d, J = 7.5Hz), 8.59 (1H, s).

In the same manner as in Reference Example 16, Reference Examples 17 to 2
Compound 1 was synthesized. Reference Example 17 3- [2- (1H-benzimidazol-1-yl) -4
Methyl-(3,4-dichlorophenyl) -5-oxazolyl] propionate Yield: 62%. Pale yellow prism, melting point 81-82 ° C
(Recrystallized from acetone-isopropyl ether). Reference Example 18 Ethyl 4- [4- (4-chlorophenyl) -2- (5,6-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] butanoate Yield: 90%. Pale yellow prism, melting point 119-120
C (recrystallized from acetone-hexane). Reference Example 19 Methyl 3- [4- (4-chlorophenyl) -2- (5,6-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] propionate Yield: 88%. Pale yellow prism, melting point 151-152
C (recrystallized from acetone-ethyl acetate). Reference Example 20 4- [2- (1H-benzimidazol-1-yl) -4
Ethyl-(4-chlorophenyl) -5-thiazolyl] butanoate Yield: 55%. Pale yellow solid. NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7Hz), 2.0-2.2 (2H, m), 2.42
(2H, t, J = 7Hz), 3.05 (2H, t, J = 7Hz), 4.13 (2H, q, J = 7Hz),
7.4-7.5 (4H, m), 7.64 (2H, d, J = 8.5Hz), 7.85-7.9 (1H, m),
8.05-8.1 (1H, m), 8.54 (1H, s). Reference Example 21 3- [2- (1H-benzimidazol-1-yl) -4
Ethyl-(4-chlorophenyl) -5-thiazolyl] propionate Yield: 33%. Pale yellow prism, melting point 121-122
C (recrystallized from acetone-ethyl acetate).

Reference Example 22 Ethyl 2- [2-chloro-4-chlorophenyl-5-oxazolyl] -2-oxoacetate (5.0 g), benzimidazole (2.26 g), sodium hydride (0.7 g).
A mixture of 6 g) and N, N-dimethylformamide (50 mL) was stirred at 0 ° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 2- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl)-. 5-Oxazolyl] -2-oxoethyl acetate (4.57 g, 7
3%) crystals were obtained. Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prism crystals. Melting point 143
~ 144 ° C. Reference Example 23 2- [2- (1H-benzimidazol-1-yl) -4
Ethyl-(4-chlorophenyl) -5-oxazolyl] -2-oxoacetate (3.50 g) was dissolved in a mixed solvent of tetrahydrofuran (60 mL) -ethanol (20 mL), and sodium borohydride (100 mg) was added at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. Pour the reaction mixture into water,
The precipitated solid was collected by filtration and dried. The obtained solid was added to thionyl chloride (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, poured into 10% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was washed with water,
It was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in acetic acid (50 mL), zinc powder (10 g) was added, and the mixture was stirred for 30 minutes while heating under reflux. The insoluble matter was removed by filtration, the filtrate was concentrated, poured into a 10% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and 2- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) was extracted from the eluate of acetone-hexane (1: 2, volume ratio).
-5-Oxazolyl] ethyl acetate (2.07 g, 61
%) Crystals were obtained. Recrystallization from acetone-isopropyl ether gave colorless needle crystals. Melting point 152-153
° C. Reference Example 24 (2E) -3- [2- (1H-benzimidazol-1-yl) -4-isopropyl-5-thiazolyl] propenoic acid ethyl ester (1.00 g), 2N normal sodium hydroxide aqueous solution (5 mL), A mixture of tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, and dried (2E) -3- [2- (1H-benzimidazole-
Crystals of 1-yl) -4-isopropyl-5-thiazolyl] propenoic acid (0.90 g, 98%) were obtained. Recrystallization from acetone-hexane gave pale yellow prism crystals. Melting point 262-264 [deg.] C.

In the same manner as in Reference Example 24, the compounds of Reference Examples 25 to 38 were synthesized by alkaline hydrolysis of the corresponding ester. Reference Example 25 (2E) -3- [2- (1H-benzimidazol-1-yl) -4-tert-butyl-5-thiazolyl] propenoic acid Yield: 93%. Pale yellow prism, melting point 256-257
C (recrystallized from acetone-hexane). Reference Example 26 (2E) -3- [2- (1H-benzimidazol-1-yl) -4-phenyl-5-thiazolyl] propenoic acid Yield: 89%. Light yellow prism crystal, decomposed at a melting point of 285 ° C (recrystallized from acetone-hexane). Reference Example 27 (2E) -3- [2- (1H-benzimidazol-1-yl) -4-methyl-5-thiazolyl] propenoic acid Yield: 81%. Pale yellow prism, melting point 247-251
C (recrystallized from acetone-hexane). Reference Example 28 3- [2- (1H-benzimidazol-1-yl) -4
-Isopropyl-5-thiazolyl] propionic acid yield: 88%. Pale yellow prism, melting point 187-188
C (recrystallized from acetone-hexane). Reference Example 29 3- [2- (1H-benzimidazol-1-yl) -4
-Tert-Butyl-5-thiazolyl] propionic acid yield: 85%. Pale yellow prism, melting point 193-194
C (recrystallized from acetone-hexane). Reference Example 30 3- [2- (1H-benzimidazol-1-yl) -4
-Methyl-5-thiazolyl] propionic acid yield: 82%. Pale yellow prism, melting point 175-179
C (recrystallized from acetone-hexane). Reference Example 31 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] propionic acid yield: 85%. Pale yellow prism, melting point 300 ° C or higher (recrystallized from acetone-hexane). Reference Example 32 4- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] butanoic acid yield: 71%. Pale yellow prism, melting point 199-200
C (recrystallized from acetone-hexane). Reference Example 33 2- [2- (1H-benzimidazol-1-yl) -4
Yield of-(4-chlorophenyl) -5-oxazolyl] acetic acid: 82%. Colorless needle crystals, melting point 256-257 ° C (recrystallized from methanol-ethyl acetate). Reference Example 34 3- [4- (4-chlorophenyl) -2- (5,6-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] propionic acid yield: 80%. Colorless needle crystals, melting point 238-240 ° C (recrystallized from ethanol-hexane). Reference Example 35 4- [4- (4-chlorophenyl) -2- (5,6-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] butanoic acid Yield: 97%. Colorless needle crystals, melting point 205-206 ° C (recrystallized from tetrahydrofuran-hexane). Reference Example 36 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] butanoic acid yield: 87%. Colorless prism crystals, melting point 158-159 ° C (recrystallized from ethyl acetate-hexane). Reference Example 37 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] propionic acid yield: 80%. Colorless prism, melting point 166-167 ° C
(Recrystallized from ethyl acetate-hexane). Reference Example 38 5- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-oxazolyl] pentanoic acid yield: 93%. Pale yellow solid. NMR (CDCl ₃ ) δ: 1.7-2.0 (4H, m), 2.46 (2H, t, J = 7Hz), 3.01
(2H, t, J = 7Hz), 7.2-7.3 (4H, m), 7.68 (2H, d, J = 8.5Hz),
7.87 (1H, d, J = 7.5Hz), 8.27 (1H, d, J = 7.5Hz), 8.63 (1H,
s).

Reference Example 39 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] butanoic acid (2.03 g), potassium carbonate (2.76 g), benzimidazole (1.18 g),
A mixture of N, N-dimethylformamide (30 mL) was stirred at 120 ° C for 4 hours. Pour the reaction mixture into water,
The precipitated crystals are collected by filtration, washed with water and dried to give 4- [2-
(1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] butanoic acid (2.22
g, yield 82%). Recrystallization from tetrahydrofuran-ethanol gave colorless needle crystals. Melting point 199-2
00 ° C. Reference Example 40 6- [2- (1H-Benzimidazol-1-yl) -4- (4-chlorophenyl) -5 was prepared in the same manner as in Reference Example 39.
-Oxazolyl] hexanoic acid was prepared. Yield: 86
%. Pale yellow prism crystals, melting point 158-159 ° C (recrystallized from acetone-isopropyl ether). Reference Example 41 2-Bromo-4'-chloropropiophenone (45.0
A mixture of g), thiobenzamide (24.7 g), sodium acetate (14.8 g) and ethanol (400 mL) was stirred with heating under reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 4- (4-chlorophenyl) -5-methyl-2-phenylthiazole (3
(5.1 g, 68%) crystals were obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 90-9
1 ° C. Reference Example 42 4- (4-chlorophenyl) -5-methyl-2-phenylthiazole (35.1 g), N-bromosuccinimide (24.0 g), azobisisobutyronitrile (4.1
A mixture of 1 g) and carbon tetrachloride (400 mL) was stirred with heating under reflux for 3 hours. The precipitated solid was removed by filtration, the organic layer was concentrated, and the residue was purified by silica gel column chromatography. Hexane-ethyl acetate (1
(9: 1, volume ratio) From the elution part, 5- (bromomethyl) -4-
(4-chlorophenyl) -2-phenylthiazole (3
0.8 g, 69%) crystals were obtained. Recrystallization from ethyl acetate gave colorless prism crystals. Melting point 108-109 [deg.] C. Reference Example 43 A solution of ethyl malonate (17.5 g) in N, N-dimethylformamide (50 mL) was added with sodium hydride (4.3).
8 g) was added at 0 ° C. and the mixture was stirred for 30 minutes, and then a solution of 5- (bromomethyl) -4- (4-chlorophenyl) -2-phenylthiazole (8.0 g) in N, N-dimethylformamide (200 mL) was added to 0. Added at ° C. After stirring at 0 ° C for 2 hours, the mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. This oil was added to ethanol (14
0 mL) and dissolve in 10% aqueous sodium hydroxide solution (1
40 mL) was added, and the mixture was stirred at 60 ° C for 2 hr. The reaction mixture was poured into water and washed with diethyl ether, the aqueous layer was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a yellow powder. Add this powder to pyridine (140m
L), and stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated, diluted with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3- [4- (4-chlorophenyl) -2-phenyl-
5-thiazolyl] propionic acid (5.71 g, 75%)
Was obtained as a yellow powder. Recrystallization from ethyl acetate-hexane gave colorless prism crystals, melting point 142-143 ° C.

Reference Example 44 Methyl 3- {2-chloro-4- [4- (trifluoromethyl)] phenyl-5-oxazolyl} propionate (1.
33 g), potassium carbonate (1.38 g), benzimidazole (1.18 g), N-methylpyrrolidone (10 m
The mixture of L) was stirred at 120 ° C. for 1 hour. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from ethyl acetate-hexane to give 3-
{2- (1H-benzimidazol-1-yl) -4-
Methyl [4- (trifluoromethyl) phenyl] -5-oxazolyl} propionate (1.15 g, yield 70%) was obtained as pale yellow prism crystals. Melting point 129-130 [deg.] C. Reference Example 45 3- {2- (1H-benzimidazol-1-yl) -4
A mixture of methyl [-(4- (trifluoromethyl) phenyl] -5-oxazolyl} propionate (1.00 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) at room temperature for 1 hour. Stir it. The reaction mixture was poured into dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from tetrahydrofuran-ethanol to give 3- {2- (1H-
Benzimidazol-1-yl) -4- [4- (trifluoromethyl) phenyl] -5-oxazolyl} propionic acid (1.00 g, yield 83%) was obtained as pale yellow prism crystals. Melting point 224-226 [deg.] C. Reference Example 46 To a mixture of 2- (ethylsulfanyl) ethylamine (0.94 g) and tetrahydrofuran (10 mL), ditert-butyl dicarbonate (2.14 g) was added dropwise while stirring under ice cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated,
It was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography. 2- (ethylsulfanyl) ethylcarbamic acid was extracted from ethyl acetate-hexane (1: 4, volume ratio) eluate. tert-Butyl was obtained as a colorless oil. (1.83 g, yield 100%). NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.5Hz), 1.45 (9H, s),
2.55 (2H, q, J = 7.5Hz), 2.66 (2H, t, J = 6.5Hz),
3.24-3.36 (2H, m), 4.94 (1H, brs).

Reference Example 47 2- (Ethylsulfanyl) ethylcarbamic acid tert-
Butyl (1.83g) and tetrahydrofuran (15mL)
M-Chloroperbenzoic acid (4.84 g) was added to the above mixture with stirring under ice cooling. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give tert-butyl 2- (ethylsulfonyl) ethylcarbamate as a colorless oil. (2.07 g, 98% yield). NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 8Hz), 1.45 (9H, s),
3.04 (2H, q, J = 8Hz), 3.19 (2H, t, J = 6.5Hz), 3.58
-3.70 (2H, m), 5.22 (1H, brs). Reference Example 48 2- (ethylsulfonyl) ethylcarbamic acid tert-
To a mixture of butyl (1.5 g) and ethyl acetate (15 mL), 4N hydrochloric acid / ethyl acetate solution (4 mL) was added dropwise while stirring under ice cooling. After stirring at room temperature for 4 hours, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 2- (ethylsulfonyl) ethylamine hydrochloride crystals.
(0.76 g, 69% yield). Recrystallization from ethanol gave colorless prism crystals. Melting point 103 to 104 ° C. Reference Example 49 Ditert-butyl dicarbonate (8.16 g) was added dropwise to a mixture of 2- (methylsulfanyl) ethylamine (3.01 g) and tetrahydrofuran (30 mL) under ice cooling while stirring. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated,
It was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography. From the elution part of ethyl acetate-hexane (1: 4, volume ratio), 2- (methylsulfanyl) ethylcarbamic acid tert- Butyl was obtained as a colorless oil. (5.62g, 89%). NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.11 (3H, s), 2.62 (2H,
t, J = 6.5Hz), 3.33 (2H, q, J = 6.5Hz), 4.94 (1H, br
s).

Reference Example 50 2- (Methylsulfanyl) ethylcarbamic acid tert-
M-Chloroperbenzoic acid (5.67 g) was added to a mixture of butyl (2.0 g) and tetrahydrofuran (20 mL) while stirring under ice cooling. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain crystals of tert-butyl 2- (methylsulfonyl) ethylcarbamate. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. (1.78 g, yield 76%). Melting point 85-
86 ° C. Reference Example 51 2- (methylsulfonyl) ethylcarbamic acid tert-
To a mixture of butyl (1.5 g) and ethyl acetate (10 mL), 4N hydrochloric acid / ethyl acetate solution (3 mL) was added dropwise while stirring under ice cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 2- (methylsulfonyl) ethylamine hydrochloride crystals.
(1.04 g, yield 97%). Recrystallization from ethanol gave colorless prism crystals. Mp 169-170 ° C Reference Example 52 2- (methylsulfanyl) ethylcarbamic acid tert-
Lithium aluminum hydride (1.39 g) was added to a mixture of butyl (3.5 g) and tetrahydrofuran (20 mL) while stirring under ice cooling, and the mixture was heated under reflux for 2 hours. After cooling the reaction mixture, sodium sulfate decahydrate (5 g) was added, and the solid was filtered off. The filtrate was concentrated, diluted with tetrahydrofuran, and ditert-butyl dicarbonate was added dropwise with stirring under ice cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography. From ethyl acetate-hexane (1: 4, volume ratio) eluate, N-methyl-
Tert-Butyl N- [2- (methylsulfanyl) ethyl] carbamate was obtained as a colorless oil. (0.82 g, yield 22%). NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.14 (3H, s), 2.56-2.68
(2H, m), 2.89 (3H, s), 3.34-3.46 (2H, m).

Reference Example 53 To a mixture of tert-butyl N-methyl-N- [2- (methylsulfanyl) ethyl] carbamate (0.8 g) and tetrahydrofuran (10 mL) was added m-chloroperbenzoic acid (2.11 g). It was added while stirring under ice cooling. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate to give N-methyl-N- [2- (methylsulfonyl)).
Ethyl] tert-butyl carbamate was obtained as a colorless oil. (0.83 g, yield 89%). NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.93 (3H, s), 2.94 (3H,
s), 3.20-3.36 (2H, m), 3.64-3.74 (2H, m). Reference Example 54 tert-butyl N-methyl-N- [2- (methylsulfonyl) ethyl] carbamate (0.81 g) and acetic acid. To a mixture of ethyl (10 mL), 4N hydrochloric acid / ethyl acetate solution (2 mL) was added dropwise while stirring under ice cooling. After stirring at room temperature overnight, the precipitated crystals were collected by filtration and washed with ethyl acetate to give N-methyl-N- [2- (methylsulfonyl) ethyl] amine hydrochloride as crystals. (0.38
g, 64% yield). Recrystallization from ethanol gave colorless prism crystals. Melting point 259 to 260 ° C. Reference Example 55 Tetrahydrothiopyran-4-one (5.0 g), hydroxylamine hydrochloride (15 g) and ethanol (400 mL)
Sodium acetate (29.3 g) was added to the mixture of and the mixture was stirred at room temperature overnight. The reaction liquid was cooled to 0 ° C., and the precipitated crystals were collected by filtration and washed with water at 0 ° C. to obtain tetrahydrothiopyran-4-one oxime crystals. Recrystallization from petroleum ether gave white prism crystals. (2.36 g, yield 66
%). Melting point 85-86 [deg.] C.

Reference Example 56 To a mixture of lithium aluminum hydride (5.42 g) and tetrahydrofuran (400 mL), a solution of tetrahydrothiopyran-4-one oxime (3.75 g) in tetrahydrofuran (30 mL) was added with stirring under ice cooling, and the mixture was heated. Stir overnight under reflux. After cooling the reaction mixture, 2
A normal sodium hydroxide aqueous solution was added, and the precipitated solid was filtered off. The filtrate is concentrated to half its volume and diluted with dicarbonate.
tert-Butyl (7.5 g) was added dropwise with stirring under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated,
It was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain crystals of tert-butyl (tetrahydrothiopyran-4-yl) carbamate. (4.68 g, 75% yield). Recrystallization from ethyl acetate-hexane gave white prism crystals. Melting point 141-142
° C.

Reference Example 57 (Tetrahydrothiopyran-4-yl) carbamic acid te
rt-Butyl (2.0g) and tetrahydrofuran (20m
To the mixture of L), m-chloroperbenzoic acid (5.0 g) was added with stirring under ice cooling. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (1,
1-dioxide tetrahydro-2H-thiopyran-4-
Ill) crystals of tert-butyl carbamate were obtained. (1.63
g, 71% yield). Recrystallization from diisopropyl ether-hexane gave white prism crystals. Melting point 207-20
8 ° C. Reference Example 58 To a mixture of tert-butyl (1,1-dioxidetetrahydrothiopyran-4-yl) carbamate (1.5 g) and ethyl acetate (10 mL), 4N hydrochloric acid / ethyl acetate solution (3 mL) was ice-cooled. It was dripped while stirring under. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give (1,1-dioxidetetrahydrothiopyran-4-yl) amine hydrochloride crystals. (0.78g,
Yield 95%). Recrystallization from ethanol gave colorless prism crystals. Melting point 288-289 ° C. Reference Example 59 4-hydroxypiperidine-1-carboxylic acid tert-butyl (1
Methanesulfonyl chloride (5.98 g) and triethylamine (5.53 g) were sequentially added to a mixture of 0 g) and tetrahydrafuran (100 mL mL) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crystals of tert-butyl 4- (methylsulfonyl) piperidine-1-carboxylate. Recrystallization from ethyl acetate-hexane gave white prism crystals. (13.2 g, yield 95
%). Melting point 94-95 [deg.] C.

Reference Example 60 4- (Methylsulfonyl) piperidine-1-carboxylic acid te
A mixture of rt-butyl (12.5 g), methyl mercaptan sodium salt (3.31 g), tetra-n-butylammonium iodide (1.66 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 72 hours. The insoluble matter was filtered using Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl 4- (methylthio) piperidine-1-carboxylate was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). (6.89 g, yield 67%). NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.40-1.60 (2H, m), 1.82-
2.00 (2H, m), 2.10 (3H, s), 2.60-2.80 (1H, m), 2.80-3.
00 (2H, m), 3.92-4.08 (2H, m). Reference Example 61 4- (Methylthio) piperidine-1-carboxylic acid tert-butyl (3.0 g) and tetrahydrofuran (30 mL) were mixed with m-chloroperoxide. Benzoic acid (7.03 g) was added with stirring under ice cooling. The reaction mixture was stirred at room temperature for 6 hr, diluted with ethyl acetate, and washed successively with 2N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate to obtain crystals of tert-butyl 4- (methylsulfonyl) piperidine-1-carboxylate.
(2.00 g, 59% yield). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 107-108 [deg.] C. Reference Example 62 4- (methylsulfonyl) piperidine-1-carboxylic acid te
To a mixture of rt-butyl (1.5 g) and ethyl acetate (10 mL), 4N hydrochloric acid / ethyl acetate solution (2.5 mL) was added dropwise while stirring under ice cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 4- (methylsulfonyl) piperidine hydrochloride crystals.
(1.08 g, yield 95%). Recrystallization from ethanol gave colorless prism crystals. Melting point 271-272 ° C

Reference Example 63 Sodium azide (4.31 g) was added to a mixed solution of tetrahydrothiopyran-4-one (5.14 g) and concentrated hydrochloric acid (20 mL) under ice cooling. After stirring the reaction mixture at room temperature for 4 hours,
Sodium carbonate was added, diluted with ice water, and extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1,4-thiazepan-5-one crystals. (3.62 g, yield 62%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 120-121 ° C. Reference Example 64 To a mixture of lithium aluminum hydride (2.31 g) and tetrahydrofuran (100 mL), a solution of 1,4-thiazepan-5-one (4.0 g) in tetrahydrofuran (30 mL) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 30 hours. Stirred. 2N sodium hydroxide was added to the reaction mixture until aluminum hydroxide was precipitated, and the solid was filtered off. The filtrate was concentrated until the liquid volume was halved, and ditert-butyl dicarbonate (7.32 g) was added dropwise with stirring under ice cooling. 2 at room temperature
After stirring for an hour, the reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl 1,4-thiazepan-4-carboxylate was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). (6.00 g, 91% yield). NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.92-2.10 (2H, m), 2.60-
2.76 (4H, m), 3.50-3.68 (4H, m). Reference Example 65 tert-Butyl 1,4-thiazepan-4-carboxylate (3.0
g) and tetrahydrofuran (20 mL) in a mixture of m
-Chloroperbenzoic acid (7.48 g) was added with stirring under ice cooling. The reaction mixture was stirred at room temperature for 1 hr, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crystals of tert-butyl 1,1-dioxide-1,4-thiazepan-4-carboxylate. (1.19 g, yield 35
%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 120-121 ° C.

Reference Example 66 1,1-Dioxide-1,4-thiazepan-4-carboxylate tert-butyl (1.0 g) and ethyl acetate (10 mL)
4N hydrochloric acid / ethyl acetate solution (2.5 mL) was added dropwise to the mixture under stirring with ice cooling. After stirring at room temperature for 16 hours, the precipitated crystals were collected by filtration, washed with ethyl acetate,
Crystals of 1,1-dioxide-1,4-thiazepane hydrochloride were obtained. (0.61 g, 81% yield). Recrystallization from ethanol gave colorless prism crystals. Melting point 196-200 [deg.] C. Reference Example 67 4-Iodoaniline (10 g) in tetrahydrofuran (20
Ditert-butyl dicarbonate (11 g) was added to the solution (0 mL) and the reaction mixture was heated under reflux for 16 hours. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography, and tert-butyl 4-iodophenylcarbamate crystals were obtained from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. (10.7 g, 73% yield). Melting point 148-149 [deg.] C. Reference Example 68 To a mixed solution of 4-nitrobenzaldehyde (8.56 g) and ethyl phosphite (7.81 g) was added triethylamine (1.5 m).
L) was gradually added. The reaction solution was stirred for 1 hour, diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography. From the elution part of ethyl acetate-hexane (1: 1, volume ratio), diethyl α-hydroxy-4-nitrobenzylphosphonate was added. Was obtained. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. (4.62 g, 28% yield). Melting point 94-95
° C.

Reference Example 69 10 parts of a mixed solution of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.42 g) and methanol (30 mL) was used.
% Palladium-carbon (0.14 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere at atmospheric pressure. Radium-carbon was removed from the reaction mixture by filtration, the filtrate was concentrated,
A solid of diethyl 4-amino-α-hydroxybenzylphosphonate was obtained. (1.02 g, yield 80%). NMR (CDCl ₃ ) δ: 1.18-1.34 (6H, m), 2.98 (1H, brs), 3.
72 (2H, brs), 3.82-4.16 (4H, m), 4.87 (1H, d, J = 10H
z), 6.68 (2H, d, J = 8.5Hz), 7.20-7.34 (2H, m). Reference Example 70 Mixture of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.0 g) and chloroform (10 mL) In liquid
Diethylaminosulfur trifluoride (1.4m
L) was added and the reaction was warmed to room temperature. Saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. After concentrating the extract, the residue was purified using preparative HPLC to give 4-
[(Diethylphosphono) (fluoro) methyl] nitrobenzene (0.1 g, 10% yield) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.22-1.42 (6H, m), 4.00-4.34 (4H, m),
5.86 (1H, dd, J = 45,9Hz), 7.64 (2H, d, J = 7Hz), 8.
28 (2H, d, J = 9Hz). Reference Example 71 4-Nitrobenzaldehyde (2.0 g), trimethyl orthoformate (2 mL), p-toluenesulfonic acid (20 m
A mixed solution of g) and methanol (20 mL) was heated under reflux for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. Triethyl phosphite (2.12 g) and dichloromethane (30 mL) were added to the residue, boron trifluoride diethyl ether complex (5.2 mL) was gradually added at -20 ° C under an argon atmosphere, and the mixture was stirred overnight at room temperature. . Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and diethyl α-methoxy-4-nitrobenzylphosphonate (3.8 g, yield 95%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. NMR (CDCl ₃ ) δ: 1.20-1.30 (6H, m), 3.45 (3H, s), 4.02
-4.20 (4H, m), 4.63 (1H, d, J = 17Hz), 7.58-7.66 (2H,
m), 8.24 (2H, d, J = 8.8 Hz).

Reference Example 72 10% Palladium-carbon (0.5 g) was added to a mixed solution of diethyl α-methoxy-4-nitrobenzylphosphonate (3.7 g) and methanol (50 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure. I stirred it all night. Palladium-carbon was removed by filtration, and the filtrate was concentrated to give crystals of diethyl 4-amino-α-methoxybenzylphosphonate. Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. (2.0 g, yield 60%). Melting point 100-101
° C. Reference Example 73 Acetic acid (18 mL) was added at room temperature to a mixed solution of 1- (3-chlorophenyl) -2-hydroxyethanone (21.8 g), potassium cyanate (20.8 g) and 2-propanol (100 mL). The reaction solution was stirred for 30 minutes, water was added, and the precipitated crystals were collected by filtration and recrystallized from methanol-diisopropyl ether to give 4- (3-chlorophenyl) oxazol-2 (3H) -one (6.7 g, yield). 41% solids were obtained. NMR (CDCl ₃ ) δ: 7.15 (1H, s), 7.22-7.42 (4H, m), 10.54
(1H, brs). Reference Example 74 4- (3-chlorophenyl) oxazol-2 (3H) -one (3.31 g) and acetonitrile (15 mL) were added to a solution of 0.
Concentrated sulfuric acid (5.01 g) was gradually added at ° C. 0 ℃ in the reaction solution
Then, methyl acrylate (3.05 mL) was added and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 3- [4- (3-chlorophenyl) -2-oxo- was obtained from the elution part of ethyl acetate-hexane (1: 1, volume ratio).
Methyl 2,3-dihydro-5-oxazolyl] propionate (3.0 g, 63%) was obtained as an oil. NMR (CDCl ₃ ) δ: 2.71 (2H, t, J = 7.5Hz), 2.98 (2H, t,
J = 7.5Hz), 3.61 (3H, s), 7.24-7.50 (4H, m).

In the same manner as in Reference Example 74, Reference Examples 75 to 7
Compound 7 was synthesized. Reference Example 75 3- [2-oxo-4-phenyl-2,3-dihydro-
Methyl 5-oxazolyl] propionate Yield: 71%. Colorless prism crystal melting point 166-167 ° C. (Recrystallized from isopropyl ether-hexane) Reference Example 76 3- [2-oxo-4- (4-methoxyphenyl)-
Methyl 2,3-dihydro-5-oxazolyl] propionate Yield: 5.7 g (Yield: 42%) pale yellow solid NMR (CDCl ₃ ) δ: 2.68 (2H, t, J = 7Hz), 2.96 (2H, t, J
= 7Hz), 3.68 (3H, s), 3.84 (3H, s), 7.34-7.42 (2H,
m), 8.08-8.16 (2H, m). Reference Example 77 3- [2-oxo-4- (4-fluorophenyl)-
Methyl 2,3-dihydro-5-oxazolyl] propionate Yield: 5.9 g (yield: 65%) Solid-state NMR (CDCl ₃ ) δ: 2.70 (2H, t, J = 7Hz), 2.97 (2H, t, J
= 7Hz), 3.68 (3H, s), 7.10-7.20 (2H, m), 7.40-7.50 (2
H, m).

Reference Example 78 3- [4- (3-chlorophenyl) -2-oxo-2,3
Methyl -dihydro-5-oxazolyl] propionate (3.0 g) and phosphorus oxychloride (4 mL) were gradually added with pyridine (0.86 mL) at room temperature and stirred at 90 ° C for 3 hours. After cooling the reaction solution, acetonitrile was added, poured into water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- [2-chloro-4- (3-chlorophenyl) -5-oxazolyl] propionate (2.3% was obtained from the elution part of ethyl acetate-hexane (4: 1, volume ratio). g, 72%) as an oil. NMR (CDCl ₃ ) δ: 2.76 (2H, t, J = 7.5Hz), 3.21 (2H, t,
J = 7.5Hz), 3.70 (3H, s), 7.30-7.40 (2H, m), 7.48-7.
54 (1H, m), 7.66 (1H, s).

In the same manner as in Reference Example 78, Reference Examples 79 to 8
Compound 1 was synthesized. Reference Example 79 Methyl 3- [2-chloro-4-phenyl-5-oxazolyl] propionate Yield: 63%. Oil NMR (CDCl ₃ ) δ: 2.74 (2H, t, J = 7.5Hz), 3.22 (2H, t,
J = 7.5Hz), 3.69 (3H, s), 7.28-7.48 (3H, m), 7.58-7.
66 (2H, m). Reference Example 80 3- [2-chloro-4- (4-methoxyphenyl) -5-
Methyl oxazolyl] propionate Yield: 12%. Oil NMR (CDCl ₃ ) δ: 2.73 (2H, t, J = 7 Hz), 3.18 (2H, t, J
= 7Hz), 3.69 (3H, s), 3.84 (3H, s), 6.90-7.00 (2H,
m), 7.50-7.60 (2H, m). Reference Example 81 3- [2-chloro-4- (4-fluorophenyl) -5-
Methyl oxazolyl] propionate Yield: 72%. Oil NMR (CDCl ₃ ) δ: 2.76 (2H, t, J = 7.5Hz), 3.21 (2H, t,
J = 7.5Hz), 3.70 (3H, s), 7.30-7.40 (2H, m), 7.48-7.
54 (1H, m), 7.66 (1H, s).

Reference Example 82 Methyl 3- [2-chloro-4- (3-chlorophenyl) -5-oxazolyl] propionate (2.31 g), 1H-benzimidazole (1.82 g), potassium carbonate (3.19 g)
And a mixture of N, N-dimethylformamide (12 mL) was stirred at 120 ° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 3- [2- (1H-benzimidazol-1-yl)-was obtained from the elution part of ethyl acetate-hexane (1: 1, volume ratio).
A solid of methyl 4- (3-chlorophenyl) -5-oxazolyl] propionate (1.85 g, 63%) was obtained. NMR (CDCl ₃ ) δ: 2.86 (2H, t, J = 7Hz), 3.36 (2H, t, J
= 7Hz), 3.73 (3H, s), 7.38-7.56 (4H, m), 7.60-7.66 (1
H, m), 7.76-7.82 (1H, m), 7.86-7.90 (1H, m), 8.20-8.
26 (1H, m), 8.57 (1H, s).

Reference Examples 83 to 8 were carried out in the same manner as Reference Example 82.
Compound 5 was synthesized. Reference Example 83 3- [2- (1H-benzimidazol-1-yl)-
Methyl 4-phenyl-5-oxazolyl] propionate Yield: 72%. Solid-state NMR (CDCl ₃ ) δ: 2.85 (2H, t, J = 7.5Hz), 3.36 (2H, t,
J = 7.5Hz), 3.72 (3H, s), 7.38-7.52 (5H, m), 7.76 (2
H, d, J = 7Hz), 7.88 (1H, d, J = 7Hz), 8.26 (1H, d,
J = 7Hz), 8.58 (1H, s). Reference Example 84 3- [2- (1H-benzimidazol-1-yl)-
Methyl 4- (4-methoxyphenyl) -5-oxazolyl] propionate Yield: 61%. Solid-state NMR (CDCl ₃ ) δ: 2.83 (2H, t, J = 7.5Hz), 3.33 (2H, t,
J = 7.5Hz), 3.72 (3H, s), 3.87 (3H, s), 7.02 (2H, d,
J = 9Hz), 7.38-7.50 (2H, m), 7.68 (2H, d, J = 9Hz),
7.87 (1H, d, J = 8Hz), 8.24 (1H, d, J = 8Hz), 8.57 (1
H, s). Reference Example 85 3- [2- (1H-benzimidazol-1-yl)-
Methyl 4- (4-fluorophenyl) -5-oxazolyl] propionate Yield: 70%. Solid-state NMR (CDCl ₃ ) δ: 2.85 (2H, t, J = 8Hz), 3.33 (2H, t, J
= 8Hz), 3.72 (3H, s), 7.14-7.22 (2H, m), 7.38-7.50 (2
H, m), 7.70-7.80 (2H, m), 7.84-7.90 (1H, m), 8.20-8.
26 (1H, m), 8.57 (1H, s).

Reference Example 86 Methyl 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolylpropionate (1.5 g), 4-tert
Sodium hydride (60% in oil, 0.24 g) was added to a mixed solution of -butylphenol (0.9 g) and N, N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 2 hours and at 70 ° C for another 30 minutes. . The reaction solution was diluted with methanol (20 mL), and 2N aqueous sodium hydroxide solution (5
(mL) and stirred at room temperature for 30 minutes. The reaction solution was diluted with water, acidified with 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3- [2- (4-te
rt-Butylphenoxy) -4- (4-chlorophenyl)-
Crystals of 5-oxazolyl] propionic acid (1.6 g, yield 80%) were obtained. Recrystallization from ethanol gave colorless prism crystals. Melting point 166-167 [deg.] C. Reference Example 87 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionic acid (1.43 g), cyclohexylmercaptan (0.6 g) and N, N-dimethylformamide (20 mL) were mixed with 100 Stir at 1.5 ° C. for 1.5 hours. The reaction solution was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline,
After drying over anhydrous magnesium sulfate, it was concentrated to give 3- [4- (4
-Chlorophenyl) -2- (cyclohexylsulfanyl) -5-oxazolyl] propionic acid (0.95 g, yield 52
%) Crystals were obtained. Recrystallization from methanol gave colorless prism crystals. Melting point 136-137 [deg.] C. Reference Example 88 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionic acid (1.43 g), 1-methylpiperazine (2.5 g) and isopropyl alcohol (20 m
The mixed solution of L) was heated under reflux for 10 hours. The reaction solution was concentrated, diluted with water, acidified with 2N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 3-
[4- (4-chlorophenyl) -2- (4-methyl-1-)
Piperazinyl) -5-oxazolyl] propionic acid (1.37
g, yield 70%) to obtain colorless prism crystals. Melting point 157-
160 ° C.

Reference Example 89 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionic acid (1.43 g), 2-mercapto-4-methylpyrimidine hydrochloride (1.05 g), potassium carbonate ( A mixed solution of 2.76 g) and N, N-dimethylformamide (20 mL) was stirred at 110 ° C. for 10 hours under a nitrogen atmosphere. The reaction solution was diluted with water, acidified with 2N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3- [4- (4-chlorophenyl) -2-
[(4-methylpyrimidin-2-yl) sulfanyl] -5
A colorless prism crystal of -oxazolepropionic acid (1.65 g, yield 88%) was obtained. Melting point 174-175 [deg.] C. Reference Example 90 Methyl 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionate (3.0 g), imidazole (0.82 g) and N, N-dimethylformamide (20
Sodium hydride (60% in oil, 0.5 g) was added to the mixed solution (mL), and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, 3- [4- (4-chlorophenyl) -2- (1H-imidazol-1-yl).
Methyl-5-oxazolyl] propionate (1.6 g, yield
80%) crystals were obtained. Recrystallization from methanol gave colorless prism crystals. Melting point 95-96 [deg.] C. Reference Example 91 Methyl 3- [4- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -5-oxazolyl] propionate (1.6 g) and paraformaldehyde (37% aqueous solution, 4 mL) were sealed. The mixture was stirred at 100 ° C. for 16 hours. The reaction solution was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography, chloroform-ethyl acetate-methanol (8: 1: 4, volume ratio). From the elution part, 3- {4-
(4-chlorophenyl) -2- [2- (hydroxymethyl)
-1H-imidazol-1-yl] -5-oxazolyl}
Methyl propionate was obtained. To this ester form, 2N aqueous sodium hydroxide solution (2 mL) and methanol (4 mL
mL) was added, and the mixture was stirred at 80 ° C for 10 min. The reaction solution was diluted with water, acidified with a 2N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and recrystallized from methanol-chloroform.
Colorless prism crystals of 3- {4- (4-chlorophenyl) -2- [2- (hydroxymethyl) -1H-imidazol-1-yl] -5-oxazolyl} propionic acid (0.65 g, yield 38%) were obtained. Obtained. Melting point 171-173 [deg.] C.

Reference Example 92 Sodium methoxide (1.1 g) was added to a solution of 1-propylmercaptan (0.54 mL) in methanol (20 mL), and then 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl. ] Methyl propionate (1.5g)
Was added, and the mixture was stirred for 30 minutes while heating under reflux. The reaction solution was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and hexane-acetone (9: 1,
(Volume ratio) From the elution part, 3- [4- (4-chlorophenyl)
Methyl -2- (1-propylsulfanyl) -5-oxazolyl] propionate was obtained. A 2N aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) were added to this ester compound, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water and acidified with 2N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and recrystallized from isopropyl ether to give 3- [4- (4-chlorophenyl) -2- (1- Colorless prism crystals of propylsulfanyl) -5-oxazolyl] propionic acid (1.0 g, yield 63%) were obtained. Melting point 1
28-129 ° C. Reference Example 93 2- (methylsulfanyl) -1H-imidazole (1.09
g), 3- [2-chloro-4- (4-chlorophenyl)-
Sodium hydride (60% in oil, 0.4 g) was added to a mixture of methyl 5-oxazolepropionate (2.4 g) and N, N-dimethylformamide (24 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline,
After dried over anhydrous magnesium sulfate, concentrated to give 3- {4-
Crystals of methyl (4-chlorophenyl) -2- [2- (methylsulfanyl) -1H-imidazol-1-yl] -5-oxazolyl} propionate (1.9 g, 63% yield) were obtained. Recrystallization from methanol gave light brown prism crystals. Melting point 88-89 [deg.] C. Reference Example 94 3- {4- (4-chlorophenyl) -2- [2- (methylsulfanyl) -1H-imidazol-1-yl] -5-
To a solution of methyl oxazolyl} propionate (2.0 g) in dichloromethane (40 mL) was added m-chloroperbenzoic acid (70% purity, 2.6 g) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hr, washed successively with aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated to 3
Methyl-{4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl] -5-oxazolyl} propionate (1.65 g, 76% yield)
Was obtained. Recrystallization from methanol gave colorless prism crystals. Melting point 112-113 [deg.] C.

Reference Example 95 3- {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl] -5-
Oxazolyl} methyl propionate (1.4 g) 1,4-
A 2N aqueous sodium hydroxide solution (3.5 mL) was added to the dioxane (7 mL) solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water and acidified with 2N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3-
Colorless prism crystals of {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl] -5-oxazolyl} propionic acid (1.22 g, yield 90%) were obtained. . Melting point 166-167 [deg.] C. Reference Example 96 A mixture of 1- (chloroacetyl) -5,6,7,8-tetrahydronaphthalene (12.0 g) and acetamide (34 g) was stirred at 135 ° C for 3.5 hours. The reaction mixture was poured into water, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 9, volume ratio). 2-methyl-4- (5,6,7,8-
Tetrahydronaphthalen-2-yl) oxazole (9.
57 g, yield 78%) was obtained. Recrystallization from hexane-ethyl acetate gave colorless prism crystals. Melting point 53-54
° C. Reference Example 97 A solution of 2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) oxazole (9.0 g) in dichloromethane (90 mL) was charged with a solution of bromine (2.2 mL) in dichloromethane (5 mL) at room temperature. It was dripped at. Reaction at room temperature 3
After stirring for 0 minutes, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. After drying the organic layer over anhydrous magnesium sulfate,
Concentrate to 5-bromo-2-methyl-4- (5,6,7,
Crystals of 8-tetrahydronaphthalen-2-yl) oxazole (11.7 g, yield 95%) were obtained. Recrystallization from ethanol gave colorless plate crystals. Melting point 97-98 [deg.] C.

Reference Example 98 5-Bromo-2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) oxazole (11.0
To a mixed solution of g) and tetrahydrofuran (100 mL), 1.6N n-butyllithium hexane solution (24 mL) was added dropwise at -78 ° C under a nitrogen atmosphere. Reaction at -78 ° C
After stirring for 10 minutes, carbon dioxide gas was blown into the reaction solution for 30 minutes. The reaction solution was poured into water and washed with ether.
The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and then concentrated to [2
-Methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] carboxylic acid (7.4
g, yield 76%). Recrystallization from ethyl acetate gave colorless crystals. Melting point 183-185 [deg.] C. Reference Example 99 [2-Methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] carboxylic acid (6.0 g) in methanol (120 mL) was added concentrated sulfuric acid (6.0
mL) was added, and the mixture was stirred with heating under reflux for 18 hr. After concentrating the reaction solution, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to [2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl). Crystals of methyl-5-oxazolyl] carboxylate (4.75 g, 76% yield) were obtained. Recrystallization from ethanol gave colorless crystals. Melting point 96-97 [deg.] C. Reference Example 100 [2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] carboxylate in a diethyl ether (90 mL) solution of methyl (4.5 g) 0.
Lithium aluminum hydride (0.63 g) was added at ° C.
The reaction solution was stirred at room temperature for 30 minutes, water (3.2 mL) was added, and the precipitated solid was removed by filtration. The filtrate was concentrated, and the obtained solid was washed with isopropyl ether to give [2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] methanol (3.63
g, yield 90%). Recrystallization from ethanol gave colorless crystals. Melting point 132-133 [deg.] C.

Reference Example 101 [2-Methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] methanol (3.3 g) in a solution (40 mL) of thionyl chloride at 0 ° C. (1.5
mL) was added. The reaction mixture was stirred at room temperature for 15 minutes and then concentrated. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. Sodium hydride (60% in oil, 0.6 g) was added to a mixed solution of ethyl 2-chloroacetoacetate (2.68 g) and N, N-dimethylformamide (40 mL) at 0 ° C, and the mixture was stirred for 5 min. To this reaction solution, at room temperature, N, N
-Dimethylformamide (10 mL) solution was added, and the mixture was stirred at room temperature for 2.5 hr. Water was poured into the reaction solution, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was diluted with ethanol (30 mL), 2N aqueous sodium hydroxide solution (16 mL) was added at 0 ° C, and the mixture was stirred for 20 min. Water was added to the reaction solution and washed with diethyl ether. 2 water layers
The mixture was acidified with a normal hydrochloric acid aqueous solution and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2-chloro-3- [2
-Methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5-oxazolyl] propionic acid (3.93 g, yield 91%) was obtained as colorless prism crystals. Melting point 141-142 [deg.] C. Reference Example 102 2-chloro-3- [2-methyl-4- (5,6,7,8)
90% in a solution of tetrahydronaphthalen-2-yl) -5-oxazolyl] propionic acid (3.2 g) in acetic acid (30 mL).
Zinc powder (3.25 g) was added at 90 ° C, and the mixture was stirred at 90 ° C for 15 min. The insoluble material was removed by filtration, and the filtrate was concentrated. Water was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3- [2-methyl-4- (5,6,7,8-tetrahydronaphthalen-2-yl) -5- Oxazolyl]
Propionic acid (2.25 g, yield 79%) was obtained as colorless prism crystals. Melting point 135-136 [deg.] C. Reference Example 103 2,4-dibromo-1-phenylbutan-1-one (3
0.6g) and acetamide (47.2g) at 130 ° C
Then stir for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 2- (2-methyl-4-phenyl-5-oxazolyl) ethyl acetate (16.6) was eluted from an acetone-hexane (1: 4, volume ratio) eluate.
g, yield 68%) was obtained as an oil. This oil (16.6
To a solution of g) in methanol (40 mL) was added 2N aqueous sodium hydroxide solution (40 mL). The mixture was stirred at room temperature for 30 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and then concentrated. Dissolve the residue (10.5 g) in chloroform (100 mL),
N, N-dimethylformamide (4 mL) was added, and the temperature was 0 ° C.
Thionyl chloride (11.4 mL) was added dropwise. The reaction solution was stirred for 30 minutes while heating under reflux, and then concentrated. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. Water organic layer,
It was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 5- (2-chloroethyl) -2-methyl-4.
-Phenyloxazole (11.0 g, 97% yield) was obtained as an oil. This oil (9.8 g) was added to acetone (150 m
L), add sodium iodide (12.3 g),
Heated to reflux for hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 5-
(2-Iodoethyl) -2-methyl-4-phenyloxazole (11.5 g, yield 83%) was obtained as an oil. This oil (11.5 g) was dissolved in dimethyl sulfoxide (20 mL), and the solution was added dropwise to a solution of sodium cyanide (2.16 g) in dimethyl sulfoxide (80 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated saline,
The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 3- (2
-Methyl-4-phenyl-5-oxazolyl) propionitrile (3.3 g, 42% yield) was obtained as an oil. Benzaldehyde (7.5 g) and zinc chloride (0.78 g) were added to this oil (3.0 g), and the mixture was stirred at 170 ° C for 5 hr.
After cooling the reaction solution, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 3- [4-phenyl-2- (2-phenyl-2-hexane) was eluted from diethyl ether-hexane (3: 7, volume ratio).
Crystals of ((E) -2-phenylethenyl) -5-oxazolyl] propionitrile (1.45 g, yield 34%) were obtained. Recrystallization from methanol gave light brown crystals. Melting point 117
~ 118 ° C.

Reference Example 104 3- [4-phenyl-2-((E) -2-phenylethenyl) -5-oxazolyl] propionitrile (1.3 g) in ethanol (18 mL) was dissolved in 2N sodium hydroxide. An aqueous solution (9 mL) was added, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was cooled, water was added, and the mixture was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate,
Concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 3- [4-phenyl-2-((E) -2-phenylethenyl) -5-oxazolyl] propionic acid (0.9 g,
A colorless prism crystal having a yield of 65% was obtained. Melting point 138-13
9 ° C. Reference Example 105 4-phenyl-2,5-dimethyloxazole (6.21
g), N-bromosuccinimide (5.34g), azobisisobutyronitrile (0.25g), carbon tetrachloride (90mL)
The mixture was stirred with heating under reflux for 15 minutes. The reaction mixture was cooled, washed successively with water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 5-bromomethyl-4-phenyl-2-
Methyloxazole (6.73 g, yield 78%) was obtained as colorless crystals. Melting point 75-76 [deg.] C. Reference Example 106 To a solution of diethyl 2-methylmalonate (3.13 g) in N, N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.6 g) at 0 ° C, and the mixture was stirred for 5 minutes. A solution of 5-bromomethyl-4-phenyl-2-methyloxazole (3.78 g) in N, N-dimethylformamide (20 mL) was added to the reaction solution. The reaction mixture was stirred for 30 minutes, ice water was added, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is ethanol (15 mL)
The mixture was diluted with, and 2N aqueous sodium hydroxide solution (10 mL) was added at 0 ° C., and the mixture was further stirred for 1.5 hr. Water was added to the reaction solution and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was converted to pyridine (30
mL) and stirred with heating under reflux for 4 hours.
The reaction solution was concentrated, dissolved in ethanol (15 mL), 2N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction solution and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the precipitated crystals were collected by filtration and recrystallized from isopropyl ether to give 2-methyl-3- (4-phenyl-). 2-methyl-5
Crystals of -oxazolyl) propionic acid (2.25 g, 61% yield) were obtained. Melting point 109-110 [deg.] C.

Reference Example 107 A 1.6N n-butyllithium hexane solution (12.5 mL) was added dropwise to a solution of diisopropylamine (2.02 g) in tetrahydrofuran (20 mL) at 0 ° C. After stirring the reaction solution for 10 minutes, a solution of isobutyric acid (0.88 g) in tetrahydrofuran (5 mL) was added. After stirring the reaction solution for another 30 minutes, 5-bromomethyl-4- (4-chlorophenyl) -2 was added.
A solution of -methyloxazole (2.52g) in tetrahydrofuran (15mL) was added. The reaction mixture was stirred for 1 hr, water was added, the mixture was concentrated, and the residue was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
Dissolve the residue in 10% hydrochloric acid methanol solution (30 mL),
The mixture was stirred with heating under reflux for 1.5 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with diethyl ether.
The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with diethyl ether-hexane (3: 7, volume ratio). This oily substance was dissolved in ethanol (5 mL), 2N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 80 ° C. for 15 min. The reaction mixture was acidified with 2N aqueous hydrochloric acid solution and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The precipitated crystals were collected by filtration and recrystallized from isopropyl ether to give 2,2-dimethyl-3- (2-methyl-4-phenyl-5-oxazolyl) propionic acid (1.0 g, yield 39
%) Crystals were obtained. Melting point 129-130 [deg.] C. Reference Example 108 1- (4-chlorophenyl) propan-1-one (6.5
g) in dichloromethane (60 mL) solution with bromine (2.0 m
A solution of L) in dichloromethane (5 mL) was added at room temperature.
The reaction mixture was concentrated, 1-methylcyclohexanecarboxamide (5.44 g) was added to the residue, and the mixture was stirred at 130 ° C for 3 hr. Water was added to the reaction solution, and the mixture was extracted with diethyl ether.
The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography (developing solvent: acetone-hexane (1: 9, volume ratio)). Iodine (7.0
g), N-bromosuccinimide (4.3 g), azobisisobutyronitrile (0.2 g) and carbon tetrachloride (70 m)
L) was added and the mixture was heated under reflux for 30 minutes. The solid was filtered off and the filtrate was concentrated to give an oil. Ethyl 2-chloroacetoacetate (1.65 g) and N, N-dimethylformamide (20
Sodium hydride (60% in
Oil, 0.4 g) was added and stirred for 10 minutes. The above-mentioned oily substance was added to the reaction liquid, and the mixture was further stirred for 1 hr. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), 2N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction solution and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with diethyl ether. Water organic layer,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Dilute the residue with acetic acid (10 mL), 90 ° C
Then, zinc powder (0.68 g) was added, and the mixture was stirred at 90 ° C for 15 minutes.
The insoluble material was removed by filtration, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: acetone-hexane (1: 4, volume ratio)) to give 3- [4- (4-chlorophenyl) -2- (1-methylcyclohexyl) -5-oxazolyl. ] Propionic acid (0.
Crystals of 65 g, yield 5%) were obtained. Recrystallization from diisopropyl ether gave colorless prism crystals. Melting point 138-
139 ° C.

Reference Example 109 Methyl 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionate (1.50 g), 1H-
Indazole (1.18 g), potassium carbonate (1.38
A mixture of g) and N, N-dimethylformamide (20 mL) was stirred at 120 ° C for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were collected by filtration, dried, dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (20 mL), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. Acidify the reaction mixture with 1N aqueous hydrochloric acid,
It was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were collected by filtration with isopropyl ether and dried to give 3- [4- (4-chlorophenyl) -2- (1H-indazol-1-yl) -5-oxazolyl] propionic acid (824 mg,
Yield 45%) was obtained as pale yellow prism crystals. Melting point 20
4-205 ° C. Reference Example 110 3,4- (methylenedioxy) benzoic acid (3.24 g),
Oxalyl chloride (2.97 g), N, N-dimethylformamide (0.1 mL), tetrahydrofuran (80 m)
The mixture of L) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in pyridine (50 mL). To this solution was added a solution of methyl 5- (4-chlorophenyl) -4-hydroxy-5-oxopentanoate (5.0 g) in pyridine (25 mL) at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous hydrochloric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate,
Concentrated to give a yellow oil. This oil was converted to acetic acid (100
mL), ammonium acetate (7.52 g) was added, and the mixture was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography, and 3- [4- (4-chlorophenyl) -2- [3,4- (methylenedioxy) phenyl]-was obtained from the elution with hexane-ethyl acetate (4: 1). 5
Methyl -oxazolyl] propionate (1.59 g, 2
1%) colorless powder was obtained. Recrystallization from methanol gave colorless prism crystals. Melting point 123-124 [deg.] C.

Similar to Reference Example 110, Reference Example 111
~ 122 compounds were synthesized. Reference Example 111 Methyl 3- [4- (4-chlorophenyl) -2- (1-naphthyl) -5-oxazolyl] propionate Yield: 44%. Colorless prism crystals. Melting point 76-77 [deg.] C.
(Recrystallized from isopropyl ether-hexane) Reference Example 112 3- [4- (4-chlorophenyl) -2- (1-methyl-
Methyl 1H-indol-2-yl) -5-oxazolyl] propionate Yield: 36%. Oil NMR (CDCl ₃ ) δ: 2.42-2.80 (4H, m), 3.70 (3H, s), 4.02
(3H, s), 6.11 (1H, dd, J = 9, 4Hz), 7.10-7.20 (1H,
m), 7.32-7.40 (2H, m), 7.42-7.54 (3H, m), 7.66-7.72
(1H, m), 8.02-8.10 (2H, m). Reference Example 113 3- [4- (4-chlorophenyl) -2- (1-methyl-
Methyl 1H-indol-3-yl) -5-oxazolyl] propionate Yield: 36%. Colorless prism crystals. Melting point 132-133 [deg.] C. (Recrystallized from isopropyl ether-hexane) Reference Example 114 3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] propionate methyl yield: 7%. Colorless prism crystals. Melting point 180-181 [deg.] C. (Recrystallization from isopropyl ether-hexane) Reference Example 115 Methyl 3- [4- (4-chlorophenyl) -2- (2,3-dichlorophenyl) -5-oxazolyl] propionate Yield: 23%. Colorless prism crystals. Melting point 92-93 [deg.] C. (Recrystallized from isopropyl ether-hexane)

Reference Example 116 Methyl 3- [4- (4-chlorophenyl) -2-cyclohexyl-5-oxazolyl] propionate Yield: 65%. Yellow oil. NMR (CDCl ₃ ) δ: 1.25-1.85 (8H, m), 2.05-2.1 (2H, m), 2.71
(2H, t, J = 8Hz), 3.17 (2H, t, J = 8Hz), 3.68 (3Hs), 7.37 (2
H, d, J = 8.5Hz), 7.59 (2H, d, J = 8.5Hz). Reference Example 117 3- [2-benzyl-4- (4-chlorophenyl) -5-
Methyl oxazolyl] propionate yield: 41%. Yellow oil. NMR (CDCl ₃ ) δ: 2.68 (2H, t, J = 8Hz), 3.15 (2H, t, J = 8Hz),
3.62 (3H, s), 4.11 (2H, s), 7.25-7.35 (5H, m), 7.37 (2H.d,
J = 8.5Hz), 7.59 (2H, d, J = 8.5Hz). Reference Example 118 Methyl 3- [4- (4-chlorophenyl) -2- (4-fluorophenyl) -5-oxazolyl] propionate : 51%. Colorless prism crystals, melting point 97-98 ° C (recrystallized from ethyl acetate-hexane). Reference Example 119 3- [4- (4-chlorophenyl) -2- (2-naphthyl)
Methyl-5-oxazolyl] propionate Yield: 47%. Colorless prism, melting point 120-121 ° C
(Recrystallized from ethyl acetate-hexane). Reference Example 120 3- [4- (4-chlorophenyl) -2- (2-thienyl)
Methyl-5-oxazolyl] propionate Yield: 37%. Colorless prism crystals, melting point 66-67 ° C (recrystallized from hexane). Reference Example 121 Methyl 3- [4- (4-chlorophenyl) -2- (4-methoxyphenyl) -5-oxazolyl] propionate Yield: 53%. Colorless prism crystals, melting point 83-84 ° C (recrystallized from methanol). Reference Example 122 Methyl 3- [4- (4-chlorophenyl) -2- (1-propyl) -5-oxazolyl] propionate Yield: 62%. Yellow oil. NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.5Hz), 1.75-1.85 (2H, m),
2.72 (2H, t, J = 8Hz), 2.73 (2H, t, J = 7.5Hz), 3.18 (2H, t, J =
8Hz), 3.68 (3H, s), 7.38 (2H.d, J = 8.5Hz), 7.59 (2H, d, J =
8.5Hz).

Reference Example 123 Methyl 3- [4- (4-chlorophenyl) -2- [3,4- (methylenedioxy) phenyl] -5-oxazolyl] propionate (1.29 g) Potassium hydroxide (0. 44
A mixture of g), methanol (20 mL) and tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to 3-
A colorless powder of [4- (4-chlorophenyl) -2- [3,4- (methylenedioxy) phenyl] -5-oxazolyl] propionic acid (1.22 g, 98%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 199-200 ° C.

Reference Example 124 was prepared in the same manner as Reference Example 123.
~ 143 compounds were synthesized. Reference Example 124 3- [2- (1H-benzimidazol-1-yl) -4
-Phenyl-5-thiazolyl] ethyl propionate yield: 88%. Pale yellow prism, melting point 81-82 ° C
(Recrystallized from acetone-hexane). Reference Example 125 3- [4- (3,4-dichlorophenyl) -2-phenyl-5-oxazolyl] propionic acid yield: 98%. Pale yellow prism, melting point 197-198
C (recrystallized from acetone-hexane). Reference Example 126 6- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] hexanoic acid yield: 79%. Colorless prism crystals, melting point 123-124 ° C (recrystallized from ethanol-hexane). Reference Example 127 3- [2- (1H-benzimidazol-1-yl) -4
-(3,4-Dichlorophenyl) -5-oxazolyl] propionic acid yield: 91%. Colorless prism, melting point 233-234 ° C
(Recrystallized from acetone-hexane).

Reference Example 128 3- [4- (4-chlorophenyl) -2-cyclohexyl-5-oxazolyl] propionic acid Yield: 98%. Colorless prism, melting point 150-151 ° C
(Recrystallized from ethyl acetate-hexane). Reference Example 129 3- [2-benzyl-4- (4-chlorophenyl) -5-
Oxazolyl] propionic acid yield: 98%. Colorless prism, melting point 175-176 ° C
(Recrystallized from ethyl acetate). Reference Example 130 3- [4- (4-chlorophenyl) -2- (4-fluorophenyl) -5-oxazolyl] propionic acid yield: 93%. Colorless prism, melting point 162-163 ° C
(Recrystallized from ethyl acetate-hexane). Example 131 3- [4- (4-chlorophenyl) -2- (2-naphthyl)
-5-Oxazolyl] propionic acid yield: 97%. Colorless prism, melting point 167-168 ° C
(Recrystallized from ethyl acetate-hexane). Reference Example 132 3- [4- (4-chlorophenyl) -2- (2-thienyl)
-5-Oxazolyl] propionic acid yield: 94%. Colorless prism, melting point 160-161 ° C
(Recrystallized from ethyl acetate-hexane). Reference Example 133 3- [4- (4-chlorophenyl) -2- (4-methoxyphenyl) -5-oxazolylpropionic acid yield: 93%. Colorless prism, melting point 152-153 ° C
(Recrystallized from ethanol).

Reference Example 134 3- [4- (4-chlorophenyl) -2- (1-propyl) -5-oxazolepropionic acid Yield: 84%. Colorless prism, melting point 150-151 ° C
(Recrystallized from ethanol). Reference Example 135 3- [4- (4-chlorophenyl) -2- (1-naphthyl) -5-oxazolyl] propionic acid yield: 89%. Colorless prism crystal melting point 154-155 ° C. (Recrystallized from isopropyl ether-hexane) Reference Example 136 3- [4- (4-chlorophenyl) -2- (1-methyl-
1H-indol-2-yl) -5-oxazolyl] propionic acid yield: 91%, colorless prism mp 195-196 ° C. (Recrystallized from ethyl acetate-hexane) Reference Example 137 3- [4- (4-chlorophenyl) -2- (1-methyl-
1H-indol-3-yl) -5-oxazolyl] propionic acid yield: 98%. Colorless prism crystal melting point 209-210 ° C. (Recrystallization from isopropyl ether-hexane) Reference Example 138 3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] propionic acid yield: 80%, colorless prism crystals Melting point 214-216 [deg.] C. (Recrystallization from isopropyl ether-hexane) Reference Example 139 3- [4- (4-chlorophenyl) -2- (2,3-dichlorophenyl) -5-oxazolyl] propionic acid yield: 90%. Colorless prism crystal melting point 166-167 ° C. (Recrystallized from isopropyl ether-hexane) Reference Example 140 2- (1H-benzimidazol-1-yl) -4-
(3-Chlorophenyl) -5-oxazolepropionic acid yield: 71%. Light yellow solid NMR (CDCl ₃ ) δ: 2.91 (2H, t, J = 7.5Hz), 3.37 (2H, t,
J = 7.5Hz), 7.32-7.52 (4H, m), 7.60-7.64 (1H, m), 7.
79 (1H, s), 7.87 (1H, d, J = 8Hz), 8.27 (1H, d, J = 8.
5Hz), 8.62 (1H, s).

Reference Example 141 3- [2- (1H-benzimidazol-1-yl)-
4-Phenyl-5-oxazolyl] propionic acid yield: 91%. Solid-state NMR (CDCl ₃ ) δ: 2.89 (2H, t, J = 7.5Hz), 3.38 (2H, t,
J = 7.5Hz), 7.34-7.56 (5H, m), 7.76 (2H, d, J = 8H
z), 7.86 (1H, d, J = 7.5Hz), 8.28 (1H, d, J = 7.5H
z), 8.64 (1H, s). Reference Example 142 3- [2- (1H-benzimidazol-1-yl)-
4- (4-Methoxyphenyl) -5-oxazolyl] propionic acid yield: 81%, pale yellow solid NMR (CDCl ₃ ) δ: 2.88 (2H, t, J = 7Hz), 3.35 (2H, t, J
= 7Hz), 3.87 (3H, s), 7.02 (2H, d, J = 9Hz), 7.34-7.
52 (2H, m), 7.69 (2H, d, J = 9Hz), 7.86 (1H, d, J = 8H
z), 8.27 (1H, d, J = 8Hz), 8.62 (1H, s). Reference Example 143 3- [2- (1H-benzimidazol-1-yl)-
4- (4-Fluorophenyl) -5-oxazolyl] propionic acid yield: 70%. Light yellow solid NMR (CDCl ₃ ) δ: 2.89 (2H, t, J = 7Hz), 3.35 (2H, t, J
= 7Hz), 7.10-7.24 (2H, m), 7.36-7.52 (2H, m), 7.68-7.
80 (2H, m), 7.86 (1H, d, J = 7Hz), 8.26 (1H, d, J =
7.5Hz), 8.63 (1H, s).

Reference Example 144 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionic acid (1.0 g), 1-phenylpiperazine (2.27 g), potassium carbonate (2.42)
A mixture of g) and N, N-dimethylformamide (20 mL) was stirred at 100 ° C for 3 hours. The reaction mixture was poured into aqueous ammonium chloride solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography, ethyl acetate-chloroform-methanol (10: 10: 1,
(Volume ratio) From the elution part, 3- [4- (4-chlorophenyl)
A powder of 2- (4-phenyl-1-piperazinyl) -5-oxazolyl] propionic acid (0.76 g, yield 53%) was obtained. Recrystallization from ethyl acetate gave colorless prism crystals. Melting point 177-178 [deg.] C.

In the same manner as in Reference Example 144, Reference Example 145
And 146 compounds were synthesized. Reference Example 145 3- [4- (4-chlorophenyl) -2- (2-pyrimidinylsulfanyl) -5-oxazolyl] propionic acid yield: 76%. Colorless prism, melting point 198-199 ° C
(Recrystallized from ethyl acetate). Reference Example 146 3- [2- (N-benzylamino) -4- (4-chlorophenyl) -5-oxazolyl] propionic acid Yield: 86%. Colorless prism, melting point 178-179 ° C
(Recrystallized from ethyl acetate-hexane).

Reference Example 147 4- (4-chlorophenyl) -2-phenyloxazole (14.43 g), phosphorus oxychloride (12.97 g),
A mixture of N, N-dimethylformamide (100 mL) was stirred at 90 ° C for 1.5 hours. The reaction mixture was poured into ice water, the precipitated solid was collected by filtration, washed successively with aqueous sodium hydrogen carbonate solution and water, dried, and the obtained crystals were recrystallized from acetone-hexane to give 4- (4- Chlorophenyl) -2-phenyl-5-oxazolecarbaldehyde (7.90 g, 49%) was obtained as yellow prism crystals. NMR (CDCl ₃ ) δ: 7.45-7.65 (5H, m), 8.10 (2H, d, J = 8.5Hz),
8.2-8.25 (2H, m), 10.03 (1H, s). This compound (3.95g), malonic acid (2.90g),
A mixture of piperidine (0.36 g) and pyridine (80 mL) was stirred at 100 ° C for 8 hours. The reaction mixture was poured into ice water, acidified with a 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated (2E) -3- [4-
(4-Chlorophenyl) -2-phenyl-5-oxazolyl] propenoic acid (4.36 g, 96%) was obtained as a yellow powder. Recrystallization from ethyl acetate gave yellow prism crystals. Melting point 255-257 [deg.] C. Reference Example 148 Ethyl 5- (4-chlorophenyl) -5-oxopentanoate (30 g) was dissolved in diethyl ether (300 ml), and bromine (6.55 g) was added dropwise at room temperature. An aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was neutralized with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue is ethanol (200 mL)
The resulting mixture was dissolved in, thiourea (8.85 g) and sodium acetate (14.3 g) were added, and the mixture was stirred with heating under reflux for 2 hr. The reaction mixture was poured into water, the precipitated solid was collected by filtration,
3- [2-amino-4- (4-chlorophenyl) -1,
Ethyl 3-thiazol-5-yl] propionate (3
0.2 g, 80%) was obtained as a colorless powder. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.5Hz), 2.58 (2H, t, J = 7H
z), 3.08 (2H, t, J = 7Hz), 4.13 (2H, q, J = 7.5Hz), 4.97 (2H,
s), 7.3-7.5 (4H, m). This compound (30g) was added to tetrahydrofuran (300m).
1) -ethanol (150 ml) dissolved in a mixed solvent, 2
Add normal sodium hydroxide solution at 0 ° C and add 1 at 60 ° C.
Stir for hours. The reaction mixture was poured into water, 1N hydrochloric acid was added, and the precipitated solid was collected by filtration and 3- [2-amino-4-
(4-Chlorophenyl) -5-thiazolyl] propionic acid (25.9 g, 94%) was obtained as a yellow powder. Recrystallization from ethanol gave yellow prism crystals. Melting point 116
~ 118 ° C. Reference Example 149 4- (4-chlorophenyl) -5- [3- (1,1-dioxide-4-thiomorpholinyl) -3-oxopropyl] -1,3-thiazol-2-amine In the same manner as in Reference Example 148. The title compound was prepared. Yield: 22%. Colorless prism, melting point 220-222 ° C
(Recrystallized from ethanol-diisopropyl ether).

Example 1 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] propionic acid (0.50 g), oxalyl chloride (0.27 g), N, N-dimethylformamide (0. A mixture of 1 ml) and tetrahydrofuran (15 ml) was stirred at room temperature for 1 hour. The reaction mixture is concentrated,
The residue was dissolved in tetrahydrofuran (15 ml), and triethylamine (0.21 g) and diethyl 4-aminobenzylphosphonate (0.37 g) were added. 1. At room temperature
After stirring for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate,
Then, it was washed with saturated saline, dried (MgSO ₄ ), and concentrated to obtain a colorless powder (0.80 g). Recrystallization from ethanol gave 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide as colorless prism crystals (660 mg). , 74%). Melting point 137-138
° C.

The compounds of Examples 2 to 60 were synthesized in the same manner as in Example 1. Example 2 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] -N- {4-[(2-oxide-1,3,2-
Dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 22%. Colorless prism, melting point 172-173 ° C
(Recrystallized from ethanol). Example 3 3- [4- (4-chlorophenyl) -2- (2-methyl-1)
-Imidazolyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 10%. Pale yellow prism, melting point 158-159
C (recrystallized from ethanol). Example 4 3- [4- (4-chlorophenyl) -2- (2-methyl-1)
-Imidazolyl) -5-oxazolyl] -N- {4-[(2
-Oxide-1,3,2-dioxaphosphinan-2-
Yield) methyl] phenyl} propionamide yield: 33%. Colorless prism, melting point 173-174 ° C
(Recrystallized from ethanol). Example 5 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Diethylphosphonomethyl) phenyl] propionamide yield: 63%. Colorless prism, melting point 159-160 ° C
(Recrystallized from ethyl acetate-hexane). Example 6 3- [4- (4-chlorophenyl) -2- (4-morpholinyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 76%. Pale yellow prism, melting point 186-187
C (recrystallized from ethyl acetate-hexane). Example 7 3- {4- (4-chlorophenyl) -2-[(4-methylphenyl) sulfanyl] -5-oxazolyl}}-N- [4
-(Diethylphosphonomethyl) phenyl} propionamide yield: 99%. Yellow oil. NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7Hz), 2.35 (3H, s), 2.
71 (2H, t, J = 8.5Hz), 3.09 (2H, d, J = 22Hz), 3.22
(2H, d, J = 8.5Hz), 3.95-4.05 (4H, m), 7.16 (2H, d,
J = 8 Hz), 7.15-7.2 (2H, m), 7.35-7.4 (2H, m), 7.36
(2H, d, J = 8.5Hz), 7.46 (2H, d, J = 8Hz), 7.61 (2H,
d, J = 8.5Hz), 8.00 (1H, s). Example 8 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-oxazolyl] propionamide yield: 47%. Pale yellow prism, melting point 265-266
C (recrystallized from chloroform-ethanol). Example 9 3- [4- (4-Chlorophenyl) -2- (4-morpholinyl) -5-oxazolyl] propionamide yield: 70%. Colorless prism, melting point 180-181 ° C
(Recrystallized from ethyl acetate-hexane). Example 10 3- [4- (4-chlorophenyl) -2-[(4-methylphenyl) sulfanyl] -5-oxazolyl] propionamide yield: 50%. Colorless prism, melting point 155-156 ° C
(Recrystallized from ethyl acetate).

Example 11 N- (4-{[bis (ethylamido) phosphoryl] methyl} phenyl) -3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] propionamide Yield: 44% . Colorless prism, melting point 122-123 ° C
(Recrystallized from ethyl acetate-hexane). Example 12 3- {4- (4-chlorophenyl) -2- [3,4- (methylenedioxy) phenyl] -5-oxazolyl} -N- [4
Yield of-(diethylphosphonomethyl) phenyl] propionamide: 84%. Colorless prism, melting point 155-156 ° C
(Recrystallized from ethyl acetate-hexane). Example 13 3- [4- (4-chlorophenyl) -2-cyclohexyl-5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 76%. Colorless prism, melting point 133-134 ° C
(Recrystallized from ethyl acetate-hexane). Example 14 3- [2-benzyl-4- (4-chlorophenyl) -5-
Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 76%. Colorless prism crystals, melting point 161-162 ° C
(Recrystallized from ethyl acetate-hexane). Example 15 3- [4- (4-chlorophenyl) -2- (4,5-dimethyl-1-imidazolyl) -5-oxazolyl] -N- [4
-(Diethylphosphonomethyl) phenyl] propionamide yield: 58%. Colorless prism, melting point 179-180 ° C
(Recrystallized from ethyl acetate-hexane). Example 16 3- {4- (4-chlorophenyl) -2- [3,4- (methylenedioxy) phenyl] -5-oxazolyl} propionamide yield: 84%. Colorless prism crystal, melting point 210 ~ 211 ℃
(Recrystallized from ethyl acetate). Example 17 3- [4- (4-chlorophenyl) -2-cyclohexyl-5-oxazolyl] propionamide yield: 70%. Colorless prism, melting point 142-143 ° C
(Recrystallized from ethyl acetate-hexane). Example 18 3- [2-benzyl-4- (4-chlorophenyl) -5-
Oxazolyl] propionamide yield: 74%. Colorless prism, melting point 169-170 ° C
(Recrystallized from ethyl acetate-hexane). Example 19 3- [4- (4-chlorophenyl) -2- (4,5-dimethyl-1-imidazolyl) -5-oxazolyl] propionamide yield: 50%. Colorless prism, melting point 232-233 ° C
(Recrystallized from ethyl acetate-hexane). Example 20 3- [4- (4-Chlorophenyl) -2- (4-fluorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 19%. Colorless prism, melting point 148-149 ° C
(Recrystallized from ethyl acetate-hexane).

Example 21 3- [4- (4-chlorophenyl) -2- (2-naphthyl)
-5-Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 76%. Colorless prism, melting point 191-192 ° C
(Recrystallized from ethanol). Example 22 3- [4- (4-chlorophenyl) -2- (2-thienyl)
-5-Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 77%. Colorless prism, melting point 164-165 ° C
(Recrystallized from ethyl acetate-hexane). Example 23 3- [4- (4-chlorophenyl) -2- (4-fluorophenyl) -5-oxazolyl] propionamide Yield: 22%. Colorless prism, melting point 212-213 ° C
(Recrystallized from ethyl acetate). Example 24 3- [4- (4-chlorophenyl) -2- (2-naphthyl)
-5-Oxazolyl] propionamide yield: 84%. Colorless prism, melting point 206-207 ° C
(Recrystallized from ethyl acetate). Example 25 3- [4- (4-chlorophenyl) -2- (2-thienyl)
-5-Oxazolyl] propionamide yield: 78%. Colorless prism, melting point 226-227 ° C
(Recrystallized from ethanol). Example 26 3- [4- (4-chlorophenyl) -2- (4-methoxyphenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 85%. Colorless prism, melting point 141-142 ° C
(Recrystallized from ethyl acetate-hexane). Example 27 3- [4- (4-chlorophenyl) -2-propyl-5-
Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 64%. Colorless prism, melting point 108-109 ° C
(Recrystallized from ethyl acetate-hexane). Example 28 3- [4- (4-chlorophenyl) -2- (4-methoxyphenyl) -5-oxazolyl] propionamide Yield: 72%. Colorless prism, melting point 215-216 ° C
(Recrystallized from ethyl acetate). Example 29 3- [4- (4-chlorophenyl) -2-propyl-5-
Oxazolyl] propionamide yield: 74%. Colorless prism, melting point 150-151 ° C
(Recrystallized from ethyl acetate-hexane). Example 30 3- [4- (4-chlorophenyl) -2- (4-phenyl-
1-Piperazinyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 70%. Yellow oil. NMR (CDCl ₃ ) δ: 1.22 (6H, t, J = 7Hz), 2.72 (2H, t, J
= 7.5Hz), 3.09 (2H, d, J = 22Hz), 3.2-3.3 (6H, m),
3.64 (4H, t, J = 5Hz), 3.95-4.05 (4H, m), 6.9-7.0 (3
H, m), 7.2-7.45 (8H, m), 7.59 (2H, d, J = 8.5Hz), 7.
91 (1H, s).

Example 31 3- [4- (4-chlorophenyl) -2- (4-phenyl-
1-Piperazinyl) -5-oxazolyl] propionamide yield: 68%. Colorless prism, melting point 187-188 ° C
(Recrystallized from ethyl acetate). Example 32 3- [4- (4-Chlorophenyl) -2- (2-pyrimidinylsulfanyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 70%. Colorless prism crystal, melting point 146-147 ° C
(Recrystallized from ethyl acetate). Example 33 3- [4- (4-chlorophenyl) -2- (2-pyrimidinylsulfanyl) -5-oxazolyl] propionamide yield: 78%. Colorless prism, melting point 194-195 ° C
(Recrystallized from ethanol). Example 34 3- [2- (Benzylamino) -4- (4-chlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 21%. Colorless prism, melting point 156-157 ° C
(Recrystallized from ethyl acetate). Example 35 3- [4- (4-chlorophenyl) -2- (2-pyridinylsulfanyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 72% . Colorless prism crystal, melting point 146-147 ° C
(Recrystallized from ethyl acetate). Example 36 3- [4- (4-chlorophenyl) -2- (2-pyridinylsulfanyl) -5-oxazolyl] propionamide yield: 67%. Colorless prism, melting point 162-163 ° C
(Recrystallized from ethyl acetate). Example 37 3- [4- (4-chlorophenyl) -2-phenoxy-5
-Oxazolyl] -N- [4- (diethylphosphonomethyl)
Phenyl] propionamide yield: 76%. Colorless prism, melting point 149-150 ° C
(Recrystallized from ethyl acetate). Example 38 3- [4- (4-chlorophenyl) -2-phenoxy-5
-Oxazolyl] propionamide yield: 60%. Colorless prism, melting point 139-140 ° C
(Recrystallized from ethyl acetate). Example 39 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- {4-[(5,5-dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 62%. Colorless prism, melting point 193-194 ° C
(Recrystallized from ethyl acetate-hexane). Example 40 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- {4-[(2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
Propionamide yield: 18%. Colorless prism, melting point 224-225 ° C
(Recrystallization from chloroform-ethanol).

Example 41 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- (3-pyridinyl) propionamide yield: 80%. Colorless prism, melting point 204-205 ° C
(Recrystallization from chloroform-ethanol). Example 42 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (methoxycarbonyl) phenyl] propionamide yield: 73%. Colorless prism, melting point 198-200 ° C
(Recrystallized from ethyl acetate-hexane). Example 43 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] propionamide yield: 79%. Colorless prism, melting point 207-208 ° C
(Recrystallization from chloroform-ethanol). Example 44 3- [2- (1H-imidazol-1-yl) -4- (4-
Chlorophenyl) -5-oxazolyl] -N- (4-{[(methylamino) sulfonyl] methyl} phenyl) propionamide yield: 54%. Colorless prism, melting point 224-225 ° C
(Recrystallized from tetrahydrofuran-isopropyl ether). Example 45 3- [4- (4-chlorophenyl) -2-phenyl-5-
Thiazolyl] -N- [4- (methoxycarbonyl) phenyl] propionamide yield: 91%. Colorless prism, melting point 177-178 ° C
(Recrystallized from ethyl acetate). Example 46 3- [4- (4-chlorophenyl) -2-phenyl-5-
Thiazolyl] propionamide yield: 71%. Colorless prism, melting point 175-176 ° C
(Recrystallized from ethyl acetate). Example 47 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] butanamide Yield: 73%. Colorless prism, melting point 152-153 ° C
(Recrystallized from ethyl acetate-ethanol). Example 48 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- {4-[(2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
Butanamide yield: 50%. Colorless prism, melting point 224-225 ° C
(Recrystallization from chloroform-ethanol). Example 49 N-Ethyl-4- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] butanamide Yield: 78%. Colorless prism, melting point 127-128 ° C
(Recrystallized from ethyl acetate). Example 50 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (methoxycarbonyl) phenyl] butanamide Yield: 74%. Colorless prism, melting point 170-171 ° C
(Recrystallized from ethyl acetate).

Example 51 1- {4- [4- (4-chlorophenyl) -2-phenyl-
5-Oxazolyl] butanoyl} -4-phenylpiperazine Yield: 30%. Colorless prism, melting point 104-105 ° C
(Recrystallized from ethyl acetate-hexane). Example 52 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] butanamide yield: 75%. Colorless prism crystals, melting point 168-169 ° C (recrystallized from ethyl acetate). Example 53 2- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] acetamide yield: 41%. Colorless prism, melting point 173-174 ° C
(Recrystallized from ethanol). Example 54 (2E) -3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propenamide Yield: 70%. Pale yellow prism, melting point 204-206
C (recrystallized from ethanol). Example 55 (2E) -3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] propenamide Yield: 72%. Colorless prism, melting point 240-241 ° C
(Recrystallized from ethyl acetate-hexane). Example 56 (2E) -3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] -N- [4- (ethoxycarbonyl) phenyl] propenamide Yield: 98%. Colorless prism crystals, melting point 135-140 ° C (recrystallized from ethyl acetate). Example 57 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide yield: 74%. Colorless prism crystals, melting point 153-154 ° C
(Recrystallized from ethanol-hexane). Example 58 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- {4-[(2-oxide-1,3,2
-Dioxaphosphinan-2-yl) methyl] phenyl}
Propionamide yield: 77%. Colorless prism, melting point 177-178 ° C
(Recrystallized from ethanol-hexane). Example 59 3- [4- (4-chlorophenyl) -2-phenyl-5-
Thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 89%. Colorless prism, melting point 164-165 ° C
(Recrystallized from dichloromethane-isopropyl ether). Example 60 3- [4- (4-chlorophenyl) -2-phenyl-5-
Thiazolyl] -N- [4- (diethylphosphono) phenyl]
Propionamide yield: 83%. Colorless prism, melting point 186-187 ° C
(Recrystallized from dichloromethane-isopropyl ether).

Example 61 To a mixture of 4- (4-chlorophenyl) -2-phenyl-5-oxazolepropionic acid (500 mg), triethylamine (230 mg) and tetrahydrofuran (10 ml) was added ethyl chlorocarbonate (250 mg) at -40 ° C. After addition, the mixture was stirred for 1 hour, diethyl 4-aminophenylphosphonate (420 mg) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography, ethyl acetate-chloroform (1: 1, volume ratio).
From the eluate, 3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] -N- [4- (diethylphosphono) phenyl] propionamide (295 mg, yield 36
%) Was obtained as colorless prism crystals. Melting point 139-140
C (recrystallized from dichloromethane-isopropyl ether). Example 62 In the same manner as in Example 61, 3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide was synthesized. Yield: 95%. Colorless prism, melting point 143-
144 ° C (recrystallized from dichloromethane-isopropyl ether). Example 63 3- [4- (4-chlorophenyl) -2-phenyl-5-
A mixture of oxazolyl] -N- [4- (ethoxycarbonyl) phenyl] propionamide (0.70 g), potassium hydroxide (0.26 g), ethanol (20 ml), tetrahydrofuran (10 ml) was added at room temperature for 5 hours, and further 50 Stir at ℃ for 3 hours. Pour the reaction mixture into water,
The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a colorless powder. Recrystallized from chloroform-ethanol to give 4-({3- [4- (4-
Chlorophenyl) -2-phenyl-5-oxazolyl] propanoyl} amino) benzoic acid was obtained as colorless prism crystals (0.51 g, 75%). Melting point 243-244 ° C

The compounds of Examples 64 and 65 were synthesized in the same manner as in Example 63. Example 64 4-({3- [4- (4-chlorophenyl) -2-phenyl-5-thiazolyl] propanoyl} amino) benzoic acid Yield: 95%. Colorless prism, melting point 294-295 ° C
(Recrystallized from chloroform-ethanol). Example 65 4-({(2E) -3- [4- (4-chlorophenyl) -2
-Phenyl-5-oxazolyl] propenoyl} amino)
Benzoic acid yield: 40%. Colorless prism, melting point 275-276 ° C
(Recrystallized from ethyl acetate-hexane).

Example 66 4-({3- [4- (4-chlorophenyl) -2-phenyl-5-oxazolyl] propanoyl} amino) benzoic acid (0.30 g), oxalyl chloride (0.10 g), N ，
A mixture of N-dimethylformamide (0.1 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in tetrahydrofuran (15 ml), and 25% aqueous ammonia (3 ml) was added.
Was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, and dried (M
gSO ₄ ) and then concentrated to give a colorless powder (0.27
g). Recrystallize from chloroform-ethanol to 4-
({3- [4- (4-chlorophenyl) -2-phenyl-5
-Oxazolyl] propanoyl} amino) benzamide was obtained as colorless prism crystals (0.15 g, 50%). Melting point 268-269 ° C

The compounds of Examples 67 and 68 were synthesized in the same manner as in Example 66. Example 67 4-({3- [4- (4-chlorophenyl) -2-phenyl-5-thiazolyl] propanoyl} amino) benzamide Yield: 55%. Colorless prism crystals, melting point 300 ° C or higher (decomposition) (recrystallization from tetrahydrofuran). Example 68 4-({(2E) -3- [4- (4-chlorophenyl) -2
-Phenyl-5-oxazolyl] propenoyl} amino)
Benzamide yield: 54%. Colorless prism, melting point 274-275 ° C
(Recrystallized from ethanol).

Example 69 Diethyl 4-aminobenzylphosphonate (0.73
g), 2- (1H-benzimidazol-1-yl) -4
-[4- (Trifluoromethyl) phenyl] -5-oxazolepropionic acid (0.85 g), 1-hydroxy-1
H-1,2,3-benzotriazole hydrate (0.4
6 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.56 g) and N, N-
A mixture of dimethylformamide (20 ml) was added at room temperature to 1
Stir for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was subjected to silica gel column chromatography, and from the elution part of ethyl acetate-hexane (2: 1, volume ratio), 3- {2- (1H-benzimidazol-1-yl) -4- [4- (tri Fluoromethyl) phenyl] -5-
Oxazolyl} -N-[(4-diethylphosphonomethyl) phenyl] propionamide (0.70 g, yield 52%)
Was obtained as colorless crystals. Recrystallization from acetone-isopropyl ether gave colorless prism crystals. Melting point 208-
209 ° C.

Similar to Example 69, Examples 70-2
23 compounds were synthesized. Example 70 3- [4- (4-chlorophenyl) -5-oxazolyl]-
N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 92%. Colorless prism, melting point 130-131 ° C
(Recrystallized from ethyl acetate-hexane). Example 71 3- [4- (4-chlorophenyl) -2- (2-methyl-1)
-Imidazolyl) -5-oxazolyl] -N- (2-methoxyphenyl) propionamide yield: 90%. Colorless prism crystals, melting point 153-154 ° C
(Recrystallized from ethyl acetate-hexane). Example 72 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [3
-(Diethylphosphono) propyl] propionamide yield: 80%. Colorless prism, melting point 130-131 ° C
(Recrystallized from ethyl acetate). Example 73 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
[(4-Dimethylphosphonomethyl) phenyl] propionamide yield: 65%. Colorless prism, melting point 206-207 ° C
(Recrystallized from ethanol-hexane). Example 74 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(2-Oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 67%. Colorless prism, melting point 240-241 ° C
(Recrystallization from tetrahydrofuran-ethanol). Example 75 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(5,5-Dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 58%. Colorless prism, melting point 206-207 ° C
(Recrystallization from tetrahydrofuran-ethanol). Example 76 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Ethoxycarbonylmethyl) phenyl] propionamide yield: 53%. Colorless prism, melting point 181-182 ° C
(Recrystallization from tetrahydrofuran-ethanol). Example 77 1- (4-chlorophenyl) -4- {4- [4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)-
5-Oxazolyl] butanoyl} piperazine yield: 67%. amorphous. NMR (CDCl ₃ ) δ: 2.05-2.2 (2H, m), 2.43 (2H, t, J = 7H
z), 2.78 (3H, s), 3.0-3.1 (6H, m), 3.52 (2H, t, J =
5Hz), 3.75 (2H, t, J = 5Hz), 6.82 (2H, d, J = 9Hz),
7.00 (1H, d, J = 2Hz), 7.23 (2H, d, J = 9Hz), 7.41
(2H, d, J = 9Hz), 7.47 (1H, d, J = 2Hz), 7.66 (2H, d,
J = 9Hz). Example 78 4- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] -N-[(4-diethylphosphonomethyl) phenyl] butanamide Yield: 57%. amorphous. NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7Hz), 2.1-2.2 (2H,
m), 2.44 (2H, t, J = 7.5Hz), 2.98 (2H, t, J = 7Hz), 3.
11 (2H, d, J = 21Hz), 3.9-4.1 (4H, m), 7.15-7.25 (2H,
m), 7.35 (2H, d, J = 8.5Hz), 7.35-7.5 (2H, m), 7.56
(2H, d, J = 8.5Hz), 7.68 (1H, s). Example 79 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Chlorophenyl) propionamide yield: 76%. Colorless prism, melting point 248-249 ° C
(Recrystallization from tetrahydrofuran-ethanol Example 80 3- [4- (4-chlorophenyl) -2- (4,5-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] -N-[(4 -Diethylphosphonomethyl) phenyl] propionamide yield: 58%, colorless prism crystals, melting point 198-199 ° C.
(Recrystallized from ethanol-hexane

Example 81 3- [4- (4-chlorophenyl) -2- [4- (trifluoromethyl) phenyl] -N-[(4-dimethylphosphonomethyl) phenyl] propionamide Yield: 81% . Colorless prism, melting point 138-139 ° C
(Recrystallization from ethanol-hexane Example 82 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
[(4-Dimethylphosphonomethyl) phenyl] butanamide Yield: 72%. Colorless prism, melting point 172-174 ° C
(Recrystallization from ethanol-hexane Example 83 4- [4- (4-chlorophenyl) -2- (4,5-dimethyl-1H-benzimidazol-1-yl) -5-oxazolyl] -N-[(4 -Diethylphosphonomethyl) phenyl] butanamide Yield: 72%, colorless prism crystals, melting point 172-174 ° C.
(Recrystallized from ethanol-hexane). Example 84 4- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N-[(4-dimethylphosphonomethyl) phenyl] butanamide Yield: 54%. Colorless prism, melting point 145-146 ° C
(Recrystallized from ethanol-hexane). Example 85 3- [2- (1H-benzimidazol-1-yl) -4
-(3,4-Dichlorophenyl) -5-oxazolyl]-
N-[(4-diethylphosphonomethyl) phenyl] propionamide yield: 59%. Pale yellow prism, melting point 175-176
C (recrystallized from ethanol-hexane). Example 86 3- [4- (3,4-Dichlorophenyl) -2-phenyl-5-oxazolyl] -N-[(4-dimethylphosphonomethyl) phenyl] propionamide yield: 85%. Pale yellow prism, melting point 162-163
C (recrystallized from ethanol-hexane). Example 87 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-{[N-methyl-N- (4-tetrahydropyranyl) amino] methyl} phenyl) propionamide yield: 60%. Colorless prism crystal, melting point 182-184 ° C
(Recrystallized from tetrahydrofuran-ethyl acetate). Example 88 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(1-Piperidinyl) methyl] phenyl} propionamide yield: 73%. Colorless prism, melting point 194-195 ° C
(Recrystallized from acetone-isopropyl ether). Example 89 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Cyanomethyl) phenyl] propionamide yield: 7
3%. Pale yellow prism, melting point 212-214 ° C (recrystallized from tetrahydrofuran-hexane). Example 90 4-({3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} amino) phenylacetic acid Yield: 55%. Pale yellow prism, melting point 247-248
C (recrystallized from tetrahydrofuran-hexane).

Example 91 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Methoxycarbonyl) phenyl] propionamide yield: 70%. Pale yellow prism, melting point 249-250
C (recrystallized from tetrahydrofuran-hexane). Example 92 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(2-Pyridinyl) ethyl] propionamide yield: 7
0%. Pale yellow prism, melting point 150-151 ° C (recrystallized from acetone-hexane). Example 93 1- {3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -4- (2-pyridinyl) piperazine Yield: 79%. Pale yellow prism, melting point 174-176
C (recrystallized from ethyl acetate-hexane). Example 94 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- (4-{[N-methyl-N- (4-tetrahydropyranyl) amino] methyl} phenyl) propionamide yield: 89%. Colorless prism, melting point 154-155 ° C
(Recrystallized from ethyl acetate-isopropyl ether). Example 95 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- {4-[(1-piperidinyl) methyl]
Phenyl} propionamide yield: 70%. Pale yellow prism, melting point 223-225
C (recrystallized from tetrahydrofuran-ethyl acetate). Example 96 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-(Methylsulfanyl) phenyl} propionamide yield: 47%. Pale yellow prism, melting point 276-277
C (recrystallized from ethyl acetate-hexane). Example 97 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-(Cyanomethyl) phenyl} butanamide yield: 85%. NMR (CDCl ₃ ) δ: 2.0-2.2 (2H, m), 2.49 (2H, t, J = 7.5H
z), 3.12 (2H, d, J = 7.5Hz), 3.70 (2H, s), 7.23 (2H,
d, J = 8.5Hz), 7.35-7.5 (6H, m), 7.70 (2H, d, J =
8.5Hz), 7.85-7.90 (1H, m), 8.02 (1H, s) 8.2-8.3 (1H,
m), 8.57 (1H, s). Example 98 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(2-Oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} butanamide Yield: 59%. Pale yellow prism, melting point 206-207
C (recrystallized from tetrahydrofuran-isopropyl ether). Example 99 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(5-Methyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} butanamide Yield: 43%. Pale yellow prism, melting point 202-203
C (more recrystallized). Example 100 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [3
-(Diethylphosphonomethyl) phenyl] butanamide yield: 68%. Pale yellow prism, melting point 135-136
C (recrystallized from ethanol-hexane).

Example 101 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(4,6-Dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} butanamide Yield: 89%. Pale yellow prism, melting point 149-150
C (recrystallized from ethanol-hexane). Example 102 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Diethylphosphonomethyl) -2-methylphenyl] butanamide Yield: 46%. Pale yellow prism, melting point 118-119
C (recrystallized from ethanol-hexane). Example 103 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Diethylphosphono) phenyl] butanamide Yield: 75
%. Pale yellow prism, melting point 162-163 ° C (recrystallized from ethanol-hexane). Example 104 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-{[(2-thiazolyl) amino] sulfonyl} phenyl)
Butanamide yield: 79%. Pale yellow prism, melting point 243-244
C (recrystallized from tetrahydrofuran-ethyl acetate). Example 105 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- [4- (cyanomethyl) phenyl] propionamide yield: 76%. Pale yellow prism, melting point 212-214
C (recrystallized from ethyl acetate-hexane). Example 106 2- [4-({3- [2- (1H-benzimidazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) phenyl] -N, N-diethylacetamide yield: 72%. Colorless prism, melting point 209-210 ° C
(Recrystallized from tetrahydrofuran-isopropyl ether). Example 107 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Diethylphosphono) phenyl] propionamide yield: 69%. Pale yellow prism, melting point 249-250
C (recrystallized from ethyl acetate-hexane). Example 108 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [3
-(Hydroxymethyl) phenyl] propionamide yield: 87%. Pale yellow prism, melting point 206-207
C (recrystallized from ethanol-hexane). Example 109 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Hydroxymethyl) phenyl] propionamide yield: 93%. Pale yellow prism, melting point 159-160
C (recrystallized from ethanol-hexane). Example 110 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [3
-(Cyanomethyl) phenyl] propionamide yield: 7
5%. Colorless prism crystals, melting point 188-189 ° C (recrystallized from acetone-hexane).

Example 111 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Cyanomethyl) phenyl] propionamide yield: 76%. Pale yellow prism, melting point 235-236
C (recrystallized from acetone-hexane). Example 112 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Cyanophenyl) propionamide yield: 86%. Pale yellow prism, melting point 216-217
C (recrystallized from ethyl acetate-hexane). Example 113 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Cyanophenyl) propionamide yield: 77%. Pale yellow prism, melting point 186-187
C (recrystallized from ethyl acetate-hexane). Example 114 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Methoxyphenyl) propionamide yield: 77%. Colorless prism, melting point 240-241 ° C
(Recrystallized from ethanol-hexane). Example 115 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Methoxyphenyl) propionamide yield: 70%. Colorless prism, melting point 194-195 ° C
(Recrystallization from tetrahydrofuran-ethanol). Example 116 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Cyclohexylphenyl) propionamide yield: 66%. Colorless prism, melting point 216-217 ° C
(Recrystallized from ethanol-hexane). Example 117 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Tert-Butylphenyl) propionamide yield: 74%. Colorless prism, melting point 219-220 ° C
(Recrystallization from ethanol-hexane Example 118 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(4,6-Dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 48%. Colorless prism, melting point 190-191 ° C
(Recrystallization from ethanol-hexane Example 119 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(5-Methyl-2-oxide-1,3,2-dioxaphosphinan-2-yl) methyl] phenyl} propionamide yield: 92%. Pale yellow prism, melting point 205-206
C. (recrystallized from ethanol-hexane Example 120 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-oxazolyl] -N-phenylpropionamide yield: 78%. Pale yellow prism, melting point 226-227
° C (recrystallized from ethanol-hexane

Example 121 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
Yield of-(trifluoromethyl) phenyl] propionamide: 72%. Colorless prism, melting point 259-263 ° C
(Recrystallization from ethanol-hexane Example 122 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
Yield of-(trifluoromethoxy) phenyl] propionamide: 66%. Colorless prism, melting point 174-175 ° C
(Recrystallization from ethanol-hexane Example 123 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Dibutylphosphonomethyl) phenyl] butanamide yield: 99%. Yellow oil. NMR (CDCl ₃ ) δ: 0.89 (6H, t, J = 7Hz), 1.3-1.8 (8H,
m), 2.2-2.4 (2H, m), 2.4-2.6 (2H, m), 3.0-3.2 (4H, m),
3.8-4.2 (4H, m), 7.1-7.3 (2H, m), 7.3-7.5 (7H, m), 7.71
(2H, d, J = 8.5Hz), 7.8-7.9 (1H, m), 8.2-8.3 (1H, m), 8.5
8 (1H, s). Example 124 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Diethylphosphonomethyl) phenyl] butanamide yield: 66%. Pale yellow prism, melting point 133-136
C. (recrystallized from ethanol-hexane Example 125 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Methylbenzyl) propionamide yield: 53%. Colorless prism crystals, melting point 241-242 ° C
(Recrystallization from ethanol-hexane Example 126 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Isopropylphenyl) propionamide yield: 82%. Colorless prism, melting point 232-233 ° C
(Recrystallization from ethanol-hexane Example 127 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(3,4,5-Trimethoxyphenyl) propionamide yield: 85%. Colorless prism crystals, melting point 228-229 ° C
(Recrystallization from ethanol-hexane Example 128 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Fluorophenyl) propionamide yield: 63%. Colorless prism crystals, melting point 221 to 222 ° C
(Recrystallization from ethanol-hexane Example 129 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[(Methoxycarbonyl) methyl] -2-thiazolyl} propionamide yield: 72%. Pale yellow prism, melting point 233-234
C. (Recrystallized from acetone-isopropyl ether. Example 130 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Dimethylamino) phenyl] propionamide yield: 61%. Pale yellow prism, melting point 212-214
° C.

Example 131 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- {4
-[2- (Diethylphosphono) ethyl] phenyl} butanamide yield: 72%. Pale yellow prism, melting point 116-117
C. (recrystallized from acetone-isopropyl ether Example 132 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-oxazolyl] -N-benzylpropionamide yield: 76%. Colorless prism, melting point 205-206 ° C
(Recrystallization from tetrahydrofuran-ethanol Example 133 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Methoxybenzyl) propionamide yield: 77%. Colorless prism crystal, melting point 210 ~ 211 ℃
(Recrystallization from ethanol-hexane Example 134 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Chlorobenzyl) propionamide yield: 56%. Colorless prism, melting point 222-223 ° C
(Recrystallization from ethanol-hexane Example 135 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Dimethylamino) benzyl] propionamide yield: 60%. Colorless prism, melting point 184-185 ° C
(Recrystallized from ethanol-hexane). Example 136 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Phenylethyl) propionamide yield: 84%. Colorless prism, melting point 164-165 ° C
(Recrystallized from acetone-hexane). Example 137 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Fluorobenzyl) propionamide yield: 61%. Colorless prism, melting point 202-203 ° C
(Recrystallized from ethanol-hexane). Example 138 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(Trifluoromethyl) benzyl] propionamide yield: 55%. Colorless prism, melting point 194-195 ° C
(Recrystallized from ethanol-hexane). Example 139 2- [4- (N- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) phenyl] -N- ( 2-Methoxyphenyl) acetamide yield: 79%. Colorless prism, melting point 258-259 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 140 2- [4- (N- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) phenyl] -N- [ 4- (Dimethylamino) phenyl] acetamide yield: 69%. Colorless prism, melting point 169-170 ° C
(Recrystallization from tetrahydrofuran-ethanol).

Example 141 3- [4- (4-chlorophenyl) -2- (2-methyl-1)
-Imidazolyl) -5-oxazolyl] -N- [4- (cyanomethyl) phenyl] propionamide yield: 74%. Colorless prism, melting point 187-188 ° C
(Recrystallized from acetone-hexane). Example 142 2- [4-({3- [2- (1H-benzimidazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) phenyl] -N, N-dimethylacetamide yield: 75%. Colorless prism, melting point 207-208 ° C
(Recrystallized from acetone-hexane). Example 143 2- [4-({3- [2- (1H-benzimidazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) phenyl] -N-methylacetamide yield: 61%. Colorless prism, melting point 219-221 ° C
(Recrystallized from acetone-hexane). Example 144 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-Tert-Butylbenzyl] propionamide yield: 75%. Colorless prism, melting point 170-171 ° C
(Recrystallized from acetone-hexane). Example 145 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Methoxybenzyl) propionamide yield: 84%. Colorless prism, melting point 210-212 ° C
(Recrystallized from acetone-hexane). Example 146 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Methylbenzyl) propionamide yield: 86%. Colorless prism, melting point 210-212 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 147 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(3,4-Dichlorobenzyl) propionamide yield: 63%. Colorless prism, melting point 190-191 ° C
(Recrystallized from acetone-hexane). Example 148 2-({3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) -N-benzylacetamide Yield: 78%. Colorless prism, melting point 186-187 ° C
(Recrystallized from acetone-hexane). Example 149 2-({3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} amino) -N-phenylacetamide Yield: 67%. Colorless prism, melting point 250-251 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 150 3- [2- (1H-Benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [4
-(1,2,3-thiadiazol-4-yl) benzyl]
Propionamide yield: 74%. Colorless prism, melting point 173-174 ° C
(Recrystallized from acetone-hexane).

Example 151 N- [4- (aminosulfonyl) benzyl] -3- [2-
(1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propionamide yield: 77%. Colorless prism, melting point 255-256 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 152 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Chlorobenzyl) propionamide yield: 80%. Colorless prism, melting point 190-191 ° C
(Recrystallized from acetone-hexane). Example 153 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Phenylbenzyl) propionamide yield: 76%. Colorless prism, melting point 214-216 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 154 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Pyridinylmethyl) propionamide yield: 68%. Colorless prism, melting point 157-158 ° C
(Recrystallized from acetone-hexane). Example 155 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Pyridinylmethyl) propionamide yield: 70%. Colorless prism, melting point 214-216 ° C
(Recrystallized from acetone-hexane). Example 156 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(2,6-Difluorobenzyl) propionamide yield: 97%. Colorless prism, melting point 225-226 ° C
(Recrystallized from acetone-hexane). Example 157 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Trifluoromethyl) benzyl] propionamide yield: 97%. Colorless prism, melting point 208-209 ° C
(Recrystallized from acetone-hexane). Example 158 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(2,5-Difluorobenzyl) propionamide yield: 90%. Colorless prism, melting point 197-198 ° C
(Recrystallized from acetone-hexane). Example 159 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Chloro-2-fluorobenzyl) propionamide yield: 94%. Colorless prism, melting point 189-191 ° C
(Recrystallized from acetone-hexane). Example 160 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(2,4-Difluorobenzyl) propionamide yield: 98%. Colorless prism, melting point 190-191 ° C
(Recrystallized from acetone-hexane).

Example 161 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(2,4,6-Trimethoxybenzyl) propionamide yield: 95%. Colorless prism, melting point 206-208 ° C
(Recrystallized from acetone-hexane). Example 162 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (2
-Phenoxyethyl) propionamide yield: 95%. Colorless prism, melting point 156-157 ° C
(Recrystallized from acetone-hexane). Example 163 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [3
-Fluoro-5- (trifluoromethyl) benzyl] propionamide yield: 90%. Colorless prism, melting point 198-200 ° C
(Recrystallized from acetone-hexane). Example 164 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(3,5-Difluorobenzyl) propionamide yield: 70%. Colorless prism, melting point 155-156 ° C
(Recrystallized from acetone-hexane). Example 165 N- [4- (aminosulfonyl) benzyl] -3- [4-
(4-Chlorophenyl) -2-phenyl-5-oxazolyl] propionamide yield: 92%. Colorless prism, melting point 225-227 ° C
(Recrystallized from acetone-hexane). Example 166 3- [4- (4-chlorophenyl) -2-phenyl-5-
Oxazolyl] -N- (4-methylbenzyl) propionamide yield: 98%. Colorless prism, melting point 193-194 ° C
(Recrystallized from acetone-hexane). Example 167 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (5-
Bromo-2-fluorobenzyl) propionamide yield: 96%. Colorless prism, melting point 183-184 ° C
(Recrystallized from acetone-hexane). Example 168 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (2-
Chloro-4-fluorobenzyl) propionamide yield: 92%. Colorless prism, melting point 196-198 ° C
(Recrystallized from acetone-hexane). Example 169 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3,
4,5-Trimethoxybenzyl) propionamide yield: 87%. Colorless prism, melting point 169-170 ° C
(Recrystallized from acetone-hexane). Example 170 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3-
Bromo-4-fluorobenzyl) propionamide yield: 75%. Colorless needle crystals, melting point 206-207 ° C (recrystallized from acetone-hexane).

Example 171 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3-
Bromobenzyl) propionamide yield: 95%. Colorless prism, melting point 181-183 ° C
(Recrystallized from acetone-hexane). Example 172 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (4-
Bromobenzyl) propionamide yield: 84%. Colorless prism, melting point 205-206 ° C
(Recrystallized from acetone-hexane). Example 173 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3-
Chloro-4-fluorobenzyl) propionamide yield: 83%. Colorless prism crystal, melting point 188-189 ° C
(Recrystallized from acetone-hexane). Example 174 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (2,
5-Dichlorobenzyl) propionamide yield: 78%. Colorless prism, melting point 205-207 ° C
(Recrystallized from acetone-hexane). Example 175 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (2,
4-Dimethylbenzyl) propionamide yield: 76%. Colorless prism, melting point 218-219 ° C
(Recrystallized from acetone-hexane). Example 176 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (5-
Chloro-2-methylbenzyl) propionamide yield: 80%. Colorless prism, melting point 217-219 ° C
(Recrystallized from acetone-hexane). Example 177 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3-
Phenylbenzyl) propionamide yield: 70%. Colorless prism, melting point 201-202 ° C
(Recrystallized from acetone-hexane). Example 178 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (4-
Chloro-2-methylbenzyl) propionamide yield: 80%. Colorless prism, melting point 200-201 ° C
(Recrystallized from acetone-hexane). Example 179 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (2,
5-Dimethoxybenzyl) propionamide yield: 68%. Colorless prism, melting point 193-194 ° C
(Recrystallized from acetone-hexane). Example 180 3- [2- (1H-Benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (3,
5-Dimethoxybenzyl) propionamide yield: 40%. Colorless prism, melting point 198-200 ° C
(Recrystallized from acetone-hexane).

Example 181 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- (2,
5-Dimethylbenzyl) propionamide yield: 76%. Colorless prism, melting point 218-219 ° C
(Recrystallized from acetone-hexane). Example 182 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N- [2-
(3,4-Dimethoxyphenyl) ethyl] -N-methylpropionamide yield: 71%. amorphous. Elemental _{analysis: C 30 H 29 ClN 4 O} 4 and a theoretical C, 66.11; H, 5.36; N, 10.28. Found C, 66.06; H, 5.28; N, 10.12. Example 183 3- [2- (1H-benzimidazol-1-yl) -4-
(4-Chlorophenyl) -5-oxazolyl] -N-benzyl-N-methylpropionamide yield: 75%. amorphous. Elemental analysis: theoretical value as C ₂₇ H ₂₃ ClN ₄ O ₂ C, 68.86; H, 4.92; N, 11.90. Found C, 68.77; H, 4.89; N, 11.87. Example 184 1- {3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -2- (ethoxycarbonyl) piperidine Yield: 96%. amorphous. Elemental analysis: theoretical value as C ₂₇ H ₂₇ ClN ₄ O ₄ C, 63.96; H, 5.37; N, 11.05. Found C, 63.77; H, 5.33; N, 10.99. Example 185 1- {3- [2- (1H-benzimidazol-1-yl)
-3-4- (4-chlorophenyl) -5-oxazolyl]
Propanoyl} piperazine hydrochloride yield: 52%. Colorless prism, melting point 240-243 ° C
(Recrystallized from ethanol-isopropyl ether). Example 186 3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-oxazolyl] -N- [2
-(4-morpholinyl) ethyl] propionamide yield:
61%. Yellow oil. NMR (CDCl ₃ ) δ: 2.3-2.5 (6H, m), 2.74 (2H, t, J = 7.5H
z), 3.3-3.4 (4H, m), 3.55-3.65 (4H, m), 7.4-7.5 (4H, m),
7.75 (2H, d, J = 8.5Hz), 7.85-7.9 (1H, m), 8.2-8.25
(1H, m), 8.57 (1H, s). Example 187 3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-oxazolyl] -N- [3
Yield:-(4-morpholinyl) propyl] propionamide: 66%. Yellow oil. NMR (CDCl ₃ ) δ: 1.5-1.7 (2H, m), 2.3-2.45 (6H, m), 2.63
(2H, t, J = 7.5Hz), 3.3-3.4 (4H, m), 3.55-3.65 (4H,
m), 7.06 (1H, s), 7.4-7.55 (4H, m), 7.75 (2H, d, J =
8.5Hz), 7.85-7.9 (1H, m), 8.2-8.25 (1H, m), 8.57 (1H,
s). Example 188 3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-oxazolyl] -N- [2
-(1-Piperidinyl) ethyl] propionamide yield: 55%. Yellow oil. NMR (CDCl ₃ ) δ: 1.3-1.6 (4H, m), 2.25-2.45 (6H, m), 2.7
0 (2H, t, J = 7.5Hz), 3.3-3.4 (6H, m), 6.31 (1H, s),
7.4-7.55 (4H, m), 7.74 (2H, d, J = 8.5Hz), 7.85-7.9
(1H, m), 8.2-8.25 (1H, m), 8.58 (1H, s). Example 189 3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-oxazolyl] -N- [2
-(1-Pyrrolidinyl) ethyl] propionamide yield: 79%. Yellow oil. NMR (CDCl ₃ ) δ: 1.9-2.1 (4H, m), 2.82 (2H, t, J = 7.5H
z), 2.9-3.1 (6H, m), 3.37 (2H, d, J = 7.5Hz), 3.5-3.6 (2
H, m), 7.4-7.55 (4H, m), 7.76 (2H, d, J = 8.5Hz), 7.8
5-7.9 (1H, m), 8.25-8.3 (1H, m), 8.63 (1H, s). Example 190 3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-oxazolyl] -N- [3
-(1-Imidazolyl) propyl] propionamide yield: 59%. Yellow oil. NMR (CDCl ₃ ) δ: 1.95-2.1 (2H, m), 2.65 (2H, t, J = 7.5H
z), 3.2-3.4 (4H, m), 3.9-4.0 (2H, m), 6.88 (1H, s), 7.11
(1H, s), 7.35-7.5 (4H, m), 7.74 (2H, d, J = 8.5Hz),
7.85-7.9 (1H, m), 8.2-8.25 (1H, m), 8.51 (1H, s).

Example 191 (3S) -1- {3- [2- (1H-benzimidazole-
1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} -3- (trifluoroacetamide)
Pyrrolidine yield: 82%. Colorless prism, melting point 190-191
C (recrystallized from acetone-hexane). Example 192 1- {3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -4-piperidinol Yield: 85%. Colorless prism crystal, melting point 182-183
C (recrystallized from acetone-hexane). Example 193 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-oxazolyl] -N-methyl-N- (1-methyl-4-piperidinyl) propionamide yield: 75%. Colorless prism, melting point 133-134
C (recrystallized from acetone-hexane). Example 194 4- {3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1-dioxide Yield: 83%. Colorless prism, melting point 227-228
C (recrystallized from acetone-hexane). Example 195 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (5
-Bromo-2-fluorobenzyl) butanamide yield: 62%. Colorless prism, melting point 196-198 ° C
(Recrystallized from acetone-hexane). Example 196 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Methylbenzyl) butanamide yield: 60%. Colorless prism, melting point 190-191 ° C
(Recrystallized from acetone-hexane). Example 197 4- [4- (4-chlorophenyl) -2- (1-pyrrolidinyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] butanamide Yield: 25%. Pale yellow prism, melting point 127-128
C (recrystallized from acetone-hexane). Example 198 4- {4- (4-chlorophenyl) -2- [4- (2-pyridinyl) -1-piperazinyl] -5-oxazolyl] -N
-[4- (Diethylphosphonomethyl) phenyl] butanamide Yield: 11%. Pale yellow prism, melting point 114-116
C (recrystallized from acetone-hexane). Example 199 4- {4- (4-chlorophenyl) -2- [4- (2-oxo-2,3-dihydro-1H-benzimidazole-1
-Yl) -1-piperazinyl] -5-oxazolyl} -N
-[4- (Diethylphosphonomethyl) phenyl] butanamide Yield: 11%. Pale yellow prism, melting point 205-209
C (recrystallized from acetone-hexane). Example 200 4- [4- (4-chlorophenyl) -2- (N-benzyl-
N-methylamino) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] butanamide Yield: 39
%. Yellow oil. NMR (CDCl ₃ ) δ: 1.24 (6H, t, J = 7Hz), 2.05-2.15 (2H, m),
2.34 (2H, t, J = 7Hz), 2.88 (2H, t, J = 7Hz), 3.02 (3H, s),
3.11 (2H, d, J = 22Hz), 3.95-4.05 (4H, m), 4.61 (2H, s),
7.15-7.4 (12H, m), 7.57 (2H, d, J = 8.5Hz).

Example 201 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide yield: 62%. Colorless prism, melting point 150-151 ° C
(Recrystallized from acetone-hexane). Example 202 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-thiazolyl] -N- (5-
Bromo-2-fluorobenzyl) propionamide yield: 70%. Colorless prism crystal, melting point 188-189 ° C
(Recrystallized from acetone-hexane). Example 203 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-thiazolyl] -N- (4-
Methylbenzyl) propionamide yield: 70%. Colorless prism, melting point 191-192 ° C
(Recrystallized from tetrahydrofuran-hexane). Example 204 3- [2- (1H-benzimidazol-1-yl) -4
-Phenyl-5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 64%. Colorless prism, melting point 142-143 ° C
(Recrystallized from acetone-hexane). Example 205 1- {3- [4- (4-chlorophenyl) -2- (1H-benzimidazol-1-yl) -5-thiazolyl) propanoyl) -4-piperidinol Yield: 92%. Pale yellow solid, HPLC analysis: Purity 99.
8% (retention time: 3.348 min) MS (ESI +): 433 (M + H) Example 206 1- {3- [4- (4-chlorophenyl) -2- (1H-benzimidazole-1- Yield) -5-thiazolyl) propanoyl) thiomorpholine-1,1-dioxide yield: 92%. Pale yellow solid, HPLC analysis: Purity 99.
7% (retention time: 3.570 min) MS (ESI +): 467 (M + H) Example 207 1- {3- [4- (4-chlorophenyl) -2- (1H-benzimidazole-1- Iyl) -5-thiazolyl) propanoyl) thiomorpholine-1-oxide pale yellow solid, HPLC analysis: Purity 88.9% (retention time: 3.245 min) MS (ESI +): 451 (M + H) Examples 208 (3S) -1- {3- [4- (4-chlorophenyl) -2-
(1H-benzimidazol-1-yl) -5-thiazolyl} propanoyl) -3- (trifluoroacetamido) pyrrolidine Yield: 92%. Pale yellow solid, HPLC analysis: Purity 98.
3% (retention time: 3.778 minutes) MS (ESI +): 514 (M + H) Example 209 (2E) -3- [2- (1H-benzimidazole-1-
Yl) -4-Methyl-5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propenamide Yield: 6
8%. Colorless prism crystals, melting point 150-151 ° C (recrystallized from acetone-hexane). Example 210 (2E) -3- [2- (1H-benzimidazol-1-
Yl) -4-tert-butyl-5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] propenamide yield: 67%. Colorless prism, melting point 211-212 ° C
(Recrystallized from acetone-hexane).

Example 211 (2E) -3- [2- (1H-benzimidazole-1-
Yl) -4-isopropyl-5-thiazolyl] -N- [4
-(Diethylphosphonomethyl) phenyl] propenamide yield: 49%. Colorless prism, melting point 198-199 ° C
(Recrystallized from acetone-hexane). Example 212 (2E) -3- [2- (1H-benzimidazole-1-
Yield) -4-phenyl-5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propenamide Yield: 37%. Yellow prism, melting point 229-230 ° C
(Recrystallized from acetone-hexane). Example 213 3- [2- (1H-benzimidazol-1-yl) -4
-Tert-Butyl-5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 70%. Colorless prism, melting point 155-156 ° C
(Recrystallized from acetone-hexane). Example 214 3- [2- (1H-benzimidazol-1-yl) -4
-Isopropyl-5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 71%. Yellow prism, melting point 171-172 ° C
(Recrystallized from acetone-hexane). Example 215 4- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] butanamide Yield: 75%. Colorless prism, melting point 140-141 ° C
(Recrystallized from acetone-hexane). Example 216 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-thiazolyl] -N- (5-
Bromo-2-fluorobenzyl) butanamide yield: 82%. Colorless prism, melting point 160-161 ° C
(Recrystallized from acetone-hexane). Example 217 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-thiazolyl] -N- (4-
Methylbenzyl) butanamide yield: 73%. Colorless prism, melting point 138-139 ° C
(Recrystallized from acetone-hexane). Example 218 2- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] acetamide yield: 87%. Colorless prism, melting point 154-155 ° C
(Recrystallized from acetone-isopropyl ether). Example 219 2- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Cyanomethyl) phenyl] acetamide yield: 75%. Colorless prism, melting point 245-246 ° C
(Recrystallized from tetrahydrofuran-isopropyl ether). Example 220 6- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] hexanamide yield: 70%. Colorless prism, melting point 149-151 ° C
(Recrystallized from ethanol-hexane). Example 221 6- [4- (4-chlorophenyl) -2-phenyl-5-
Thiazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] hexanamide yield: 81%. Colorless prism, melting point 164-165 ° C
(Recrystallized from ethanol-hexane). Example 222 5- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] pentanamide yield: 67%. Colorless prism, melting point 168-169 ° C
(Recrystallized from ethanol-hexane). Example 223 5- [2- (1H-benzimidazol-1-yl) -4
-(4-Chlorophenyl) -5-thiazolyl] -N- [4-
(Cyanomethyl) phenyl] pentanamide yield: 68%. Colorless prism, melting point 187-188 ° C
(Recrystallized from ethanol-hexane).

Example 224 3- [2-chloro-4- (4-chlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide (0.40 g), imidazole (0 .20 g), potassium carbonate (0.41 g), and N, N-dimethylformamide (5 ml) in a mixture of 1
Stir at 20 ° C. for 2 hours. The reaction mixture was poured into water, the precipitated crystals were filtered through a glass filter, the obtained crystals were washed with water, dried by ventilation, and recrystallized from acetone-isopropyl ether to give 3- [4- (4-chlorophenyl)).
-2- (1-Imidazolyl) -5-oxazolyl] -N
-[4- (Diethylphosphonomethyl) phenyl] propionamide was obtained as pale yellow prism crystals (0.33 g, 7
8%). Melting point 196-197 [deg.] C.

Similar to Example 224, Example 225
And 226 compounds were synthesized. Example 225 3- [2- (1H-1,2,3-benzotriazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 33%. Pale yellow prism, melting point 91-92 ° C
(Recrystallized from acetone-isopropyl ether). Example 226 4- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
[(4-Diethylphosphonomethyl) phenyl] butanamide Yield: 19%. Pale yellow prism, melting point 177-179
C (recrystallized from acetone-isopropyl ether).

Example 227A 2-Amino-4- (4-chlorophenyl) -5-thiazolepropionic acid (8.35 g), diethyl cyanophosphate (5.78 g), diethyl 4-aminobenzylphosphonate (7.18 gg) , N, N-dimethylformamide (100 ml) solution at 0 ° C. with triethylamine (3.0 ml).
g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated to give 3-
[2-Amino-4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl]
Crystals of propionamide were obtained (8.28 g, 55
%). Recrystallization from ethyl acetate-methanol gave colorless prism crystals. Melting point 177-178 [deg.] C. Example 227B 3- [2-amino-4- (4-chlorophenyl) -5-
Thiazolyl] propionic acid (2.67 g), diethyl cyanophosphate (1.69 g), thiomorpholine-1,1-dioxide hydrochloride (1.62 g), triethylamine (2.9 ml), N, N-dimethylformamide ( 40
(ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 0.1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The precipitated solid is collected by filtration, and 4- {3-
[2-Amino-4- (4-chlorophenyl) -5-thiazolyl] propanoyl} thiomorpholine-1,1-dioxide was obtained as a colorless powder. Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. Melting point 22
0-222 ° C.

Example 228 3- [2-Amino-4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide (500 mg), N, N-dimethyl Formamide dimethyl acetal (155 mg),
A mixture of N, N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography. 5% methanol
From the ethyl acetate eluate, 3- (4- (4-chlorophenyl) -2-{(E)-[(dimethylamino) methylidene] amino} -5-thiazolyl) -N- [4- (diethylphosphonomethyl) Crystals of phenyl] propionamide were obtained (510
mg, yield: 92%). Recrystallization from ethyl acetate gave colorless prism crystals. Melting point 150-151 [deg.] C. Example 229 3- [2-amino-4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide (500 mg), pyridine-2-
Carboxylic acid (145 mg), 1-hydroxybenztriazole (180 mg), hydrochloric acid 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide (225m
A mixture of g) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3- {4-
Crystals of (4-chlorophenyl) -2-[(2-pyridinylcarbonyl) amino] -5-thiazolyl} -N- [4- (diethylphosphonomethyl) phenyl] propionamide were obtained (560 mg). Recrystallization from ethyl acetate gave colorless prism crystals (350 mg, yield: 58%). Melting point 184
~ 185 ° C.

Example 230 3- [2-Amino-4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide (400 mg), tert-butyl isocyanate A mixture of (780 mg) and toluene (10 ml) was stirred at 70-80 ° C for 20 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography. From the elution part of 3% methanol-ethyl acetate, 3- (4- (4-chlorophenyl) -2-{[(tert-butylamino) carbonyl] amino} -5-thiazolyl) -N
Crystals of-[4- (diethylphosphonomethyl) phenyl] propionamide were obtained (395 mg, yield: 83%). Recrystallization from ethyl acetate gave colorless prism crystals. Melting point 1
80-181 ° C.

Similar to Examples 229 and 230,
Reaction of 3- [2-amino-4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide with carboxylic acid or isocyanate (thioisocyanate) Performed, Example 2
Compounds 31 to 239 were synthesized. Example 231 3- (4- (4-chlorophenyl) -2-{[(methylamino) carbonyl] amino} -5-thiazolyl) -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide yield: 61%. Colorless prism, melting point 206-207 ° C
(Recrystallized from ethyl acetate). Example 232 3- [4- (4-chlorophenyl) -2-({[(dimethylamino) methyl] carbonyl} amino) -5-thiazolyl]-
N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 54%. amorphous. Elemental analysis: C ₂₇ H ₃₄ ClN ₄ O ₅ PS.0.5H ₂ O, theoretical value C, 53.86; H, 5.86; N, 9.31. Found C, 53.97; H, 5.73; N, 9.41. Example 233 3- (4- (4-chlorophenyl) -2-{[(benzylamino) carbonyl] amino} -5-thiazolyl) -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide yield: 97%. Colorless needle crystals, melting point 144-145 ° C (recrystallized from methanol-ethyl acetate). Example 234 3- (4- (4-chlorophenyl) -2-{[(phenylamino) carbonyl] amino} -5-thiazolyl) -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide yield: 91%. Colorless prism, melting point 175-176 ° C
(Recrystallized from methanol-ethyl acetate). Example 235 3- {4- (4-chlorophenyl) -2-[(phenylsulfonyl) amino] -5-thiazolyl} -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield:
91%. Colorless needle crystals, melting point 213-214 ° C (recrystallized from methanol-ethyl acetate). Example 236 3- [2- (benzoylamino) -4- (4-chlorophenyl) -5-thiazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 91%. Colorless prism, melting point 171-172 ° C
(Recrystallized from ethyl acetate-isopropyl ether). Example 237 3- (4- (4-chlorophenyl) -2-{[(benzylamino) thiocarbonyl] amino} -5-thiazolyl) -N-
[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 39%. Colorless prism, melting point 202-203 ° C
(Recrystallized from methanol-ethyl acetate). Example 238 3- (4- (4-chlorophenyl) -2-{[(benzoylamino) thiocarbonyl] amino} -5-thiazolyl) -N-
[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 72%. Pale yellow prism, melting point 208-209
C (recrystallized from acetone-isopropyl ether). Example 239 3- {4- (4-chlorophenyl) -2-[(3-phenylpropanoyl) amino] -5-thiazolyl} -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide yield: 72%. Pale yellow prism, melting point 208-209
C (recrystallized from acetone-isopropyl ether).

Example 240 3- [4- (4-chlorophenyl) -2-methyl-5-oxazolyl] propionic acid (50 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole ( 37 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (42 mg) and N, N-.
A mixture of dimethylformamide (0.5 ml) was stirred at room temperature overnight. 0.1N aqueous hydrochloric acid solution (2 ml) was added to the reaction mixture, and the reaction mixture was mixed with ethyl acetate (5 ml).
It was extracted with. After concentrating the organic layer, Megabond Elute S
CX (manufactured by Varian) (developing solvent: developed with ethyl acetate and then developed with 2M ammonia / methanol solution), and purified with 3- [4- (4-chlorophenyl) -2-methyl-5.
-Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide (78.0 mg, yield 7
9%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point 155-156 [deg.] C. MS (ESI +): 491 (M + H)

Similar to Example 240, Example 241
˜258 compounds were synthesized. Example 241 4- {3- [4- (4-chlorophenyl) -2-methyl-5
-Oxazolyl] propanoyl} thiomorpholine-1,1
-Dioxide yield: 65%. Colorless prism, melting point 124-125 ° C
(Recrystallized from ethyl acetate-hexane). MS (ESI +): 383 (M + H) Example 242 1- {3- [4- (4-chlorophenyl) -2-methyl-5.
-Oxazolyl] propanoyl} -4-piperidinol Yield: 74% HPLC analysis: Purity 96.0% (retention time: 3.243)
Min) MS (ESI +): 349 (M + H) Example 243 3- [2- (1H-benzimidazol-1-yl) -4.
-Phenyl-5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide yield: 60%. Yellow prism, melting point 148-149 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 95.3% (retention time: 4.045
Min) MS (ESI +): 559 (M + H) Example 244 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Methoxyphenyl) -5-oxazolyl] -N-
[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 31%. Yellow prism, melting point 143-144 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 97.5% (retention time: 4.025
Min) MS (ESI +): 589 (M + H) Example 245 4- {3- [2- (1H-benzimidazol-1-yl).
-4-Phenyl-5-oxazolyl] propanoyl} thiomorpholine-1,1'-dioxide yield: 28%. Colorless prism, melting point 177-179 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 98.5% (retention time: 3.727
Min) MS (ESI +): 451 (M + H) Example 246 4- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Methoxyphenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1'-dioxide Yield: 44%. Yellow prism, melting point 214-215 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 98.0% (retention time: 3.725
Min) MS (ESI +): 481 (M + H) Example 247 1- {3- [2- (1H-benzimidazol-1-yl).
-4-Phenyl-5-oxazolyl] propanoyl} -4
-Piperidinol yield: 61%. Colorless prism, melting point 157-158 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 96.8% (retention time: 3.588
Min) MS (ESI +): 417 (M + H) Example 248 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Methoxyphenyl) -5-oxazolyl] propanoyl} -4-piperidinol Yield: 46%. Yellow prism, melting point 161-162 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 97.7% (retention time: 3.581
Min) MS (ESI +): 447 (M + H) Example 249 1- {3- [2- (1H-benzimidazol-1-yl).
-4-Phenyl-5-oxazolyl] propanoyl} -4
-[(1-Methyl-4-piperidinyl) methyl] piperazine Yield: 11% HPLC analysis: Purity 99.0% (Retention time: 2.981
Min) MS (ESI +): 513 (M + H) Example 250 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Methoxyphenyl) -5-oxazolyl] propanoyl} -4-[(1-methyl-4-piperidinyl) methyl] piperazine Yield: 17%. Yellow prism crystals, decomposed at a melting point of 170 ° C. (recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 94.3% (retention time: 2.979)
Min) MS (ESI +): 543 (M + H)

Example 251 1- {3- [2- (1H-benzimidazol-1-yl)
-4-Phenyl-5-oxazolyl] propanoyl} -4
-[(1-Methylpiperidin-3-yl) methyl] piperazine Yield: 24% HPLC analysis: Purity 95.3% (retention time: 2.976)
Min) MS (ESI +): 513 (M + H) Example 252 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Methoxyphenyl) -5-oxazolyl] propanoyl} -4-[(1-methylpiperidin-3-yl)
Methyl] piperazine yield: 26%. Yellow prism, melting point 151-152 ° C
(Recrystallized from ethyl acetate-hexane). HPLC analysis: Purity 96.6% (retention time: 2.981
Min) MS (ESI +): 543 (M + H) Example 253 3- [2- (1H-benzimidazol-1-yl) -4
-(3-Chlorophenyl) -5-oxazolyl] -N-
[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 64%. Yellow prism crystal, melting point 98-99 ° C (recrystallized from ethyl acetate-hexane). MS (ESI +): 593 (M + H) Example 254 3- [2- (1H-benzimidazol-1-yl) -4
-(4-Fluorophenyl) -5-oxazolyl] -N-
[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 61%. Yellow prism crystal, melting point 95-96 ° C (recrystallized from ethyl acetate-hexane). MS (ESI +): 577 (M + H) Example 255 4- {3- [2- (1H-benzimidazol-1-yl).
-4- (3-Chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1'-dioxide Yield: 53%. Colorless prism, melting point 186-187 ° C
(Recrystallized from ethyl acetate-hexane). MS (ESI +): 485 (M + H) Example 256 4- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Fluorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1'-dioxide Yield: 59%. Colorless prism, melting point 224-225 ° C
(Recrystallized from ethyl acetate-hexane). MS (ESI +): 469 (M + H) Example 257 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (3-Chlorophenyl) -5-oxazolyl] propanoyl} -4-piperidinol Yield: 63%. Colorless prism crystals, melting point 97-98 ° C (recrystallized from ethyl acetate-hexane). MS (ESI +): 451 (M + H) Example 258 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Fluorophenyl) -5-oxazolyl] propanoyl} -4-piperidinol Yield: 58%. Yellow prism, melting point 158-159 ° C
(Recrystallized from ethyl acetate-hexane). MS (ESI +): 435 (M + H)

Example 259 Thiazolidine (145 mg), 3- {3- [2- (1H-
Benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propionic acid (300 m
g), 1-hydroxy-7-aza-1H-1,2,3-
Benzotriazole (222 mg), 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide (25
3 mg) and N, N-dimethylformamide (1 m
The mixture of l) was stirred at room temperature overnight. A 0.1 N aqueous hydrochloric acid solution (16 ml) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (5 ml). After concentrating the organic layer,
Introduced into preparative HPLC for purification and 3- {3- [2- (1
H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} thiazolidine (165 mg, 46%) was obtained. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. Melting point 125
~ 126 ° C. HPLC analysis: Purity 100% (retention time: 4.291)
Min) MS (ESI +): 439 (M + H)

Similar to Example 259, Example 260
~ 296 compounds were synthesized. Example 260 1-[(1-Methyl-4-piperidinyl) methyl] -4-
[3- (4-phenyl-5-oxazolyl) propanoyl]
Piperazine 2 trifluoroacetate Yield: 29% HPLC analysis: Purity 93.1% (retention time: 2.168)
Min) MS (ESI +): 397 (M + H) Example 261 1-[(1-methyl-4-piperidinyl) methyl] -4-
(3- {4-phenyl-2-[(E) -2-phenylethenyl] -5-oxazolyl} propanoyl) piperazine 2 trifluoroacetate yield: 46% HPLC analysis: Purity 79.1% (retention time : 2.998
Min) MS (ESI +): 499 (M + H) Example 262 1- [2-methyl-3- (2-methyl-4-phenyl-5).
-Oxazolyl) propanoyl] -4-[(1-methyl-4
-Piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 45% HPLC analysis: Purity 100% (retention time: 2.307
Min) MS (ESI +): 425 (M + H) Example 263 1- [2,2-Dimethyl-3- (2-methyl-4-phenyl-5-oxazolyl) propanoyl] -4-[(1- Methyl-4-piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 44% HPLC analysis: Purity 100% (retention time: 2.350
Min) MS (ESI +): 439 (M + H) Example 264 1-[(1-methyl-4-piperidinyl) methyl] -4-
[3- (2-Pentyl-4-phenyl-5-oxazolyl) propanoyl] piperazine 2 trifluoroacetate Yield: 47% HPLC analysis: Purity 95.1% (retention time: 2.898)
Min) MS (ESI +): 467 (M + H) Example 265 1- {3- [4- (4-chlorophenyl) -2- (propylsulfanyl) -5-oxazolyl] propanoyl} -4
-[(1-Methyl-4-piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 33% HPLC analysis: Purity 77.8% (retention time: 3.105
Min) MS (ESI +): 505 (M + H) Example 266 1-[(1-methyl-4-piperidinyl) methyl] -4-
{3- [2-methyl-4- (5,6,7,8-tetrahydro-
2-Naphthalenyl) -5-oxazolyl] propanoyl}
Piperazine 2 trifluoroacetate Yield: 22% HPLC analysis: Purity 92.4% (retention time: 2.708
Min) MS (ESI +): 465 (M + H) Example 267 1- {3- [4- (4-chlorophenyl) -2- (4-methyl-1-piperazinyl) -5-oxazolyl] propanoyl}- 4-[(1-Methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 38% HPLC analysis: Purity 91.7% (retention time: 2.198)
Min) MS (ESI +): 529 (M + H) Example 268 1- {3- [4- (4-chlorophenyl) -2- (1-pyrrolidinyl) -5-oxazolyl] propanoyl} -4-
[(1-Methyl-4-piperidinyl) methyl] piperazine 3
Trifluoroacetate yield: 43% HPLC analysis: Purity 86.9% (retention time: 2.180
Min) MS (ESI +): 500 (M + H) Example 269 1- {3- [4- (4-chlorophenyl) -2- (cyclohexylamino) -5-oxazolyl] propanoyl} -4
-[(1-Methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 27% HPLC analysis: Purity 91.7% (retention time: 2.582)
Min) MS (ESI +): 528 (M + H) Example 270 1- (3- {4- (4-chlorophenyl) -2-[(2-pyridinylmethyl) sulfanyl] -5-oxazolyl} propanoyl) -4 -[(1-Methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 44% HPLC analysis: Purity 94.5% (retention time: 2.488)
Min) MS (ESI +): 554 (M + H)

Example 271 1- (3- {4- (4-chlorophenyl) -2-[(4-methyl-pyrimidin-2-yl) sulfanyl] -5-oxazolyl} propanoyl) -4-[(1- Methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 33% HPLC analysis: Purity 92.2% (retention time: 2.874)
Min) MS (ESI +): 555 (M + H) Example 272 1- (3- {4- (4-chlorophenyl) -2-[(4-methyl-4H-1,2,4-triazol) -3-yl) sulfanyl] -5-oxazolyl} propanoyl) -4-[(1
-Methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 42% HPLC analysis: Purity 90.6% (retention time: 2.566
Min) MS (ESI +): 544 (M + H) Example 273 1- {3- [4- (4-chlorophenyl) -2- (2-isopropyl-1H-imidazol-1-yl) -5. -Oxazolyl] propanoyl} -4-[(1-methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 45% HPLC analysis: Purity 96.3% (retention time: 2.597
Min) MS (ESI +): 539 (M + H) Example 274 1- {3- [4- (4-chlorophenyl) -2- (3,5-dimethyl-1H-pyrazol-1-yl). -5-Oxazolyl] propanoyl} -4-[(1-methyl-4-piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 22% HPLC analysis: Purity 86.3% (retention time: 3.028
Min) MS (ESI +): 525 (M + H) Example 275 1- (3- {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl ] -5-
Oxazolyl} propanoyl) -4-[(1-methyl-4-)
Piperidinyl) methyl] piperazine 3 trifluoroacetate Yield: 38% HPLC analysis: Purity 94.7% (retention time: 2.737
Min) MS (ESI +): 575 (M + H) Example 276 1- {3- [2- (1,3-benzodioxo-l-5-yl) -4- (4-chlorophenyl) -5-oxazolyl. ] Propanoyl} -4-[(1-methyl-4-piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 18% HPLC analysis: Purity 82.2% (retention time: 3.711)
Min) MS (ESI +): 551 (M + H) Example 277 1- {3- [2-benzyl-4- (4-chlorophenyl)-
5-oxazolyl] propanoyl} -4-[(1-methyl-
4-Piperidinyl) methyl] piperazine 2 trifluoroacetate yield: 9% HPLC analysis: Purity 92.9% (retention time: 3.003
Min) MS (ESI +): 521 (M + H) Example 278 1- {3- [4- (4-chlorophenyl) -2- (2-naphthyl) -5-oxazolyl] propanoyl} -4-[( 1-
Methyl-4-piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 14% HPLC analysis: Purity 78.8% (retention time: 3.391)
Min) MS (ESI +): 557 (M + H) Example 279 1- {3- [4- (4-chlorophenyl) -2- (2-thienyl) -5-oxazolyl] propanoyl} -4-[( 1-
Methyl-4-piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 43% HPLC analysis: Purity 80.6% (retention time: 3.020
Min) MS (ESI +): 513 (M + H) Example 280 1- {3- [4- (4-chlorophenyl) -2-propyl-
5-oxazolyl] propanoyl} -4-[(1-methyl-
4-Piperidinyl) methyl] piperazine 2 trifluoroacetate Yield: 35% HPLC analysis: Purity 94.4% (retention time: 2.825)
Min) MS (ESI +): 473 (M + H)

Example 281 3- [4- (4-chlorophenyl) -2- (1-naphthyl)
-5-Oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 13% HPLC analysis: Purity 99.4% (retention time: 4.846)
Min) MS (ESI +): 603 (M + H) NMR (CDCl ₃ ) δ: 1.12-1.22 (6H, m), 2.29 (2H, t, J =
7.5Hz), 3.07 (2H, t, J = 21.5Hz), 3.47 (2H, t, J = 7.
5Hz), 3.88-4.02 (4H, m), 7.12-7.22 (2H, m), 7.38-7.6
8 (7H, m), 7.81 (2H, d, J = 9Hz), 7.92 (2H, dd, J = 1
3, 8Hz), 8.16 (1H, d, J = 7Hz), 9.35 (1H, d, J = 8.5
Hz) Example 282 3- [4- (4-chlorophenyl) -2- (3,4-dichlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide Yield: 22 % HPLC analysis: 100% purity (retention time: 4.785
Min) MS (ESI +): 621 (M + H) Example 283 3- [4- (4-chlorophenyl) -2- (1-methyl-1).
H-indol-3-yl) -5-oxazolyl] -N
-[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 56% HPLC analysis: Purity 99.7% (retention time: 4.395)
Min) MS (ESI +): 606 (M + H) Example 284 3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] -N- [4- (Diethylphosphonomethyl) phenyl] propionamide yield: 35% HPLC analysis: Purity 98.8% (retention time: 4.216)
Min) MS (ESI +): 593 (M + H) Example 285 1- {3- [4- (4-chlorophenyl) -2- (1-naphthyl) -5-oxazolyl] propanoyl} -4-piperidinol yield Rate: 48% HPLC analysis: Purity 99.0% (retention time: 4.428
Min) MS (ESI +): 461 (M + H) Example 286 1- {3- [4- (4-chlorophenyl) -2- (3,4-)
Dichlorophenyl) -5-oxazolyl] propanoyl}
-4-Piperidinol yield: 39% HPLC analysis: Purity 99.4% (retention time: 4.358)
Min) MS (ESI +): 479 (M + H) Example 287 1- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-3-yl) -5-oxazolyl. ]
Propanoyl} -4-piperidinol Yield: 45% HPLC analysis: Purity 99.7% (retention time: 3.939)
Min) MS (ESI +): 464 (M + H) NMR (CDCl ₃ ) δ: 1.40-1.52 (2H, m), 1.80-1.92 (2H,
m), 2.87 (2H, t, J = 7.5Hz), 3.18-3.30 (2H, m), 3.
36 (2H, t, J = 7.5Hz), 3.66-3.80 (2H, m), 3.91 (3H,
s), 4.00-4.10 (1H, m), 7.30-7.46 (3H, m), 7.45 (2H,
d, J = 8.5Hz) 7.71 (2H, d, J = 8.5Hz), 8.15 (1H, s),
8.18 (1H, d, J = 7Hz) Example 288 1- {3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] propanoyl} -4-piperidinol yield Rate: 4% HPLC analysis: Purity 100% (retention time: 3.719
Min) MS (ESI +): 451 (M + H) Example 289 4- {3- [4- (4-chlorophenyl) -2- (1-naphthyl) -5-oxazolyl] propanoyl} thiomorpholine-1, 1'-Dioxide yield: 9% HPLC analysis: Purity 100% (retention time: 4.595
Min) MS (ESI +): 495 (M + H) Example 290 4- {3- [4- (4-chlorophenyl) -2- (3,4-).
Dichlorophenyl) -5-oxazolyl] propanoyl}
Thiomorpholine-1,1'-dioxide yield: 16% HPLC analysis: Purity 100% (retention time: 4.530
Min) MS (ESI +): 513 (M + H)

Example 291 4- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-3-yl) -5-oxazolyl]
Propanoyl} thiomorpholine-1,1'-dioxide yield: 54% HPLC analysis: Purity 99.5% (retention time: 4.166
Min) MS (ESI +): 498 (M + H) Example 292 4- {3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] propanoyl} thio. Morpholine-1,1′-dioxide yield: 44% HPLC analysis: Purity 100% (retention time: 3.977)
Min) MS (ESI +): 485 (M + H) Example 293 1- {3- [4- (4-chlorophenyl) -2- (1-naphthyl) -5-oxazolyl] propanoyl} -4-[( 1-
Methyl-4-piperidinyl) methyl] piperazine Yield: 59% HPLC analysis: Purity 99.7% (retention time: 3.413)
Min) MS (ESI +): 557 (M + H) Example 294 1- {3- [4- (4-chlorophenyl) -2- (3,4-
Dichlorophenyl) -5-oxazolyl] propanoyl}
-4-[(1-Methyl-4-piperidinyl) methyl] piperazine Yield: 61% HPLC analysis: Purity 99.9% (retention time: 3.347)
Min) MS (ESI +): 575 (M + H) Example 295 1- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-3-yl) -5-oxazolyl. ]
Propanoyl} -4-[(1-methyl-4-piperidinyl)
Methyl] piperazine Yield: 45% HPLC analysis: Purity 100% (Retention time: 3.188)
Min) MS (ESI +): 560 (M + H) Example 296 1- {3- [4- (4-chlorophenyl) -2- (1H-indazol-3-yl) -5-oxazolyl] propanoyl}- 4-[(1-Methyl-4-piperidinyl) methyl] piperazine Yield: 3% HPLC analysis: Purity 100% (Retention time: 3.141
Min) MS (ESI +): 547 (M + H)

Example 297 Diethyl bromodifluoromethylphosphonate (4.8 g)
Zinc powder (1.17 g) was added to a solution of N, N-dimethylacetamide (9 ml) under a nitrogen stream, and the reaction solution was stirred at room temperature for 2 hours.
Stir for hours. After filtering the insoluble matter, copper (I) bromide (2.58 g) was added to the filtrate under a nitrogen stream. Reaction mixture at room temperature 30
After stirring, 4-iodophenylcarbamic acid tert-
Butyl (2.87 g) was added and stirred overnight. Ethyl acetate was added to the reaction solution, insoluble matter was filtered off, and the filtrate was concentrated. After purification by preparative HPLC, ethyl acetate was added, 4N hydrochloric acid-ethyl acetate solution (3 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the crystals were collected by filtration to obtain α, α-difluoro-4-amino-benzylphosphonic acid diethyl hydrochloride (250 mg, yield 10%). The obtained hydrochloride salt (100 mg), 3- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-
Oxazolyl] propionic acid (30 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (22 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (29 mg) and N, N
A mixture of dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (1 ml), and the reaction mixture was mixed with ethyl acetate (2 ml).
It was extracted with. After concentrating the organic layer, it was introduced into preparative HPLC for purification and 3- [2- (1H-benzimidazole-1-
Yl) -4- (4-chlorophenyl) -5-oxazolyl]
-N- {4-[(diethylphosphono) (difluoro) methyl]
Phenyl} propionamide (51.4 mg, yield 50
%) Was obtained. Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. Melting point 155-156
° C. Example 298 Diethyl 4-amino-α-hydroxybenzylphosphonate (50 mg), 3- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-
Oxazolyl] propionic acid (54 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (38 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (43 mg) and N, N
A mixture of dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (2 ml), and the reaction mixture was mixed with ethyl acetate (2 ml).
It was extracted with. After concentrating the organic layer, it was introduced into preparative HPLC for purification and 3- [2- (1H-benzimidazole-1-
Yl) -4- (4-chlorophenyl) -5-oxazolyl]
-N- {4-[(diethylphosphono) (hydroxy) methyl]
Phenyl} propionamide (52 mg, 58%) was obtained. Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. Melting point 171-172 [deg.] C. MS (ESI +): 609 (M + H)

Example 299 was carried out in the same manner as Example 298.
˜342 compounds were synthesized. Example 299 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
{4-[(diethylphosphono) (methoxy) methyl] phenyl}
Propionamide yield: 65%. Colorless prism, melting point 191-192 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 623 (M + H) Example 300 1- {3- [2- (1H-benzimidazol-1-yl)
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -3-piperidinol yield 81%. Colorless prism crystals, melting point 104-105 ° C (recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 451 (M + H) Example 301 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Ethylsulfonyl) ethyl] propanamide yield 54
%. Colorless prism crystals, melting point 182-183 ° C (recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 487 (M + H) Example 302 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Methylsulfonyl) ethyl] propanamide was obtained. Yield 62%. Colorless prism, melting point 194-195 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 473 (M + H) Example 303 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- [2
-(Methylsulfonyl) ethyl] -N-methylpropanamide yield 85%. Colorless prism, melting point 141-142 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 487 (M + H) Example 304 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N- (4
-Hydroxycyclohexyl) propanamide yield 70%. Colorless prism, melting point 204-206 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 465 (M + H) Example 305 (1- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl. } -4-Piperidinyl) methanol yield 86%. Yellow prism, melting point 101-102 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 465 (M + H) Example 306 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -4-bromopiperidine yield 78%. Colorless prism, melting point 116-117 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 514 (M + H) Example 307 1- {3- [2- (1H-benzimidazol-1-yl).
-4- (4-Chlorophenyl) -5-oxazolyl] propanoyl} -4- (methylsulfonyl) piperidine Yield 8
0%. Colorless prism crystals, melting point 215 to 216 ° C (recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 513 (M + H) Example 308 3- [2- (1H-benzimidazol-1-yl) -4
-(4-chlorophenyl) -5-oxazolyl] -N-
(1,1-dioxide tetrahydro-2H-thiopyran-
4-yl) propanamide yield 52%. Yellow prism, melting point 236-238 ° C
(Recrystallized from ethyl acetate-isopropyl ether). MS (ESI +): 499 (M + H) Example 309 4- {3- [2- (1H-benzimidazol-1-yl).
-4-Chlorophenyl-5-oxazolyl] propanoyl} 1,4-thiazepan-1,1'-dioxide Yield 90
%. Yellow prism crystal, melting point 142-144 ° C. (recrystallized from ethyl acetate-isopropyl ether). . MS (ESI +): 499 (M + H) Example 310 1- (3- {4-phenyl-2-[(E) -2-phenylethenyl] -5-oxazolyl} propanoyl) -4-piperidino- Yield: 27% HPLC analysis: purity 83.5% (retention time: 3.792
Min) MS (ESI +): 403 (M + H)

Example 311 1- {3- [4- (4-chlorophenyl) -2- (propylsulfanyl) -5-oxazolyl] propanoyl} -4
-Piperidinol yield: 49% HPLC analysis: Purity 98.6% (retention time: 4.009)
Min) MS (ESI +): 409 (M + H) Example 312 1- {3- [4- (4-chlorophenyl) -2- (1-methylcyclohexyl) -5-oxazolyl] propanoyl}
-4-Piperidinol yield: 39% HPLC analysis: Purity 96.3% (retention time: 4.360
Min) MS (ESI +): 431 (M + H) Example 313 1- {3- [4- (4-chlorophenyl) -2- (cyclohexylsulfanyl) -5-oxazolyl] propanoyl} -4-piperidinol Yield: 61% HPLC analysis: Purity 96.6% (retention time: 4.491)
Min) MS (ESI +): 449 (M + H) Example 314 1- (3- {4- (4-chlorophenyl) -2-[(2-pyridinylmethyl) sulfanyl] -5-oxazolyl} propanoyl) -4 -Piperidinol yield: 21% HPLC analysis: Purity 94.8% (retention time: 2.909
Min) MS (ESI +): 458 (M + H) Example 315 1- {3- [4- (4-chlorophenyl) -2- (2-isopropyl-1H-imidazol-1-yl) -5. -Oxazolyl] propanoyl} -4-piperidinol Yield: 82% HPLC analysis: Purity 95.7% (retention time: 3.013
Min) MS (ESI +): 443 (M + H) Example 316 1- (3- {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl ] -5-
Oxazolyl} propanoyl) -4-piperidinol Yield: 35% HPLC analysis: Purity 96.3% (retention time: 3.316)
Min) MS (ESI +): 479 (M + H) Example 317 1- {3- [4- (4-chlorophenyl) -2- (3,5-dimethyl-1H-pyrazol-1-yl). -5-Oxazolyl] propanoyl} -4-piperidinol Yield: 44% HPLC analysis: Purity 97.5% (retention time: 3.760
Min) MS (ESI +): 429 (M + H) Example 3181- {3- [2-benzyl-4- (4-chlorophenyl) -5-oxazolyl] propanoyl} -4-
Piperidinol yield: 7% HPLC analysis: Purity 91.1% (retention time: 3.806
Min) MS (ESI +): 425 (M + H) Example 319 1- {3- [4- (4-chlorophenyl) -2- (2-thienyl) -5-oxazolyl] propanoyl} -4-piperidino- Yield: 12% HPLC analysis: purity 93.5% (retention time: 3.873
Min) MS (ESI +): 417 (M + H) Example 320 1- {3- [4- (4-chlorophenyl) -2-propyl-
5-oxazolyl] propanoyl} -4-piperidinol Yield: 25% HPLC analysis: Purity 97.2% (retention time: 3.544
Min) MS (ESI +): 377 (M + H)

Example 321 4- (3- {4-phenyl-2-[(E) -2-phenylethenyl] -5-oxazolyl} propanoyl) thiomorpholine-1,1-dioxide Yield: 40% HPLC Analysis: Purity 99.0% (retention time: 4.038
Min) MS (ESI +): 437 (M + H) Example 322 4- {3- [4- (4-chlorophenyl) -2- (propylsulfanyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1. -Dioxide yield: 48% HPLC analysis: 100% purity (retention time: 4.285)
Min) MS (ESI +): 443 (M + H) Example 323 4- {3- [4- (4-chlorophenyl) -2- (1-methylcyclohexyl) -5-oxazolyl] propanoyl}
Thiomorpholine-1,1-dioxide Yield: 47% HPLC analysis: Purity 100% (Retention time: 4.588
Min) MS (ESI +): 465 (M + H) Example 324 4- {3- [4- (4-chlorophenyl) -2- (cyclohexylsulfanyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1 -Dioxide yield: 31% HPLC analysis: 100% purity (retention time: 4.689)
Min) MS (ESI +): 483 (M + H) Example 325 4- {3- [4- (4-chlorophenyl) -2- (cyclohexylamino) -5-oxazolyl] propanoyl} thiomorpholine-1,1 -Dioxide yield: 35% HPLC analysis: Purity 87.6% (retention time: 3.209
Min) MS (ESI +): 466 (M + H) Example 326 4- (3- {4- (4-chlorophenyl) -2-[(2-pyridinylmethyl) sulfanyl] -5-oxazolyl} propanoyl) thiomorpholine -1,1-Dioxide yield: 42% HPLC analysis: Purity 99.8% (retention time: 3.073
Min) MS (ESI +): 492 (M + H) Example 327 4- (3- {4- (4-chlorophenyl) -2-[(4-methyl-4H-1,2,4-triazole) -3-yl) sulfanyl] -5-oxazolyl} propanoyl) thiomorpholine-1,1-dioxide Yield: 32% HPLC analysis: Purity 99.8% (retention time: 3.204
Min) MS (ESI +): 482 (M + H) Example 328 4- {3- [4- (4-chlorophenyl) -2- (2-isopropyl-1H-imidazol-1-yl) -5. -Oxazolyl] propanoyl} thiomorpholine-1,1-dioxide Yield: 59% HPLC analysis: Purity 100% (Retention time: 3.171
Min) MS (ESI +): 477 (M + H) Example 329 4- (3- {4- (4-chlorophenyl) -2- [2- (hydroxymethyl) -1H-imidazol-1-yl ] -5-
Oxazolyl} propanoyl) thiomorpholine-1,1-
Dioxide yield: 19% HPLC analysis: Purity 99.6% (retention time: 2.893)
Min) MS (ESI +): 465 (M + H) Example 330 4- {3- [2- (4-tert-butylphenoxy) -4-
(4-Chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1-dioxide Yield: 28% HPLC analysis: Purity 93.1% (retention time: 4.856)
Min) MS (ESI +): 517 (M + H)

Example 331 4- (3- {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl] -5-
Oxazolyl} propanoyl) thiomorpholine-1,1-
Dioxide yield: 14% HPLC analysis: Purity 100% (retention time: 3.559
Min) MS (ESI +): 513 (M + H) Example 332 4- {3- [4- (4-chlorophenyl) -2- (4-methyl-1-piperazinyl) -5-oxazolyl] propanoyl} thio. Morpholine-1,1-dioxide Yield: 25% HPLC analysis: Purity 88.3% (retention time: 2.754
Min) MS (ESI +): 467 (M + H) Example 333 4- {3- [4- (4-chlorophenyl) -2- (3,5-dimethyl-1H-pyrazol-1-yl). -5-Oxazolyl] propanoyl} thiomorpholine-1,1-dioxide Yield: 39% HPLC analysis: Purity 100% (retention time: 4.033
Min) MS (ESI +): 463 (M + H) Example 334 4- {3- [2-benzyl-4- (4-chlorophenyl)-
5-oxazolyl] propanoyl} thiomorpholine-1,
1-Dioxide yield: 50% HPLC analysis: Purity 99.8% (retention time: 4.043)
Min) MS (ESI +): 459 (M + H) Example 335 4- {3- [4- (4-chlorophenyl) -2- (2-thienyl) -5-oxazolyl] propanoyl} thiomorpholine-1, 1-Dioxide yield: 31% HPLC analysis: Purity 99.0% (retention time: 4.115)
Min) MS (ESI +): 451 (M + H) Example 336 4- {3- [4- (4-chlorophenyl) -2-propyl-
5-oxazolyl] propanoyl} thiomorpholine-1,
1-Dioxide yield: 25% HPLC analysis: Purity 100% (retention time: 3.816
Min) MS (ESI +): 411 (M + H) Example 337 3- [4- (4-chlorophenyl) -2- (1-methyl-1)
H-indol-2-yl) -5-oxazolyl] -N
-[4- (Diethylphosphonomethyl) phenyl] propionamide yield: 48% HPLC analysis: Purity 100% (retention time: 4.958)
Min) MS (ESI +): 606 (M + H) Example 338 3- [4- (4-chlorophenyl) -2- (1H-indazol-1-yl) -5-oxazolyl] -N- [4- (Diethylphosphonomethyl) phenyl] propionamide yield: 78% HPLC analysis: Purity 99.7% (retention time: 4.576
Min) MS (ESI +): 593 (M + H) Example 339 4- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-2-yl) -5-oxazolyl. ]
Propanoyl} thiomorpholine-1,1'-dioxide Yield: 73% HPLC analysis: Purity 100% (Retention time: 4.724)
Min) MS (ESI +): 498 (M + H) Example 340 4- {3- [4- (4-chlorophenyl) -2- (1H-indazol-1-yl) -5-oxazolyl] propanoyl} thio. Morpholine-1,1′-dioxide yield: 71% HPLC analysis: Purity 93.8% (retention time: 4.347)
Min) MS (ESI +): 485 (M + H) Example 341 1- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-2-yl) -5-oxazolyl. ]
Propanoyl} -4-piperidinol Yield: 51% HPLC analysis: Purity 99.2% (retention time: 4.374)
Min) MS (ESI +): 464 (M + H) Example 342 1- {3- [4- (4-chlorophenyl) -2- (1-methyl-1H-indol-2-yl) -5-oxazolyl. ]
Propanoyl} -4-piperidinol Yield: 65% HPLC analysis: Purity 98.9% (retention time: 4.067
Min) MS (ESI +): 451 (M + H)

Example 343 3- {3- [2- (1H-benzimidazol-1-yl)
To a mixture of -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} thiazolidine (25 mg) and tetrahydrofuran (10 mL), m-chloroperbenzoic acid (14.4 mg) was added with stirring under ice cooling, and the mixture was stirred at room temperature overnight. Stir it. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was introduced into preparative HPLC for purification and 3- {3- [2
-(1H-benzimidazol-1-yl) -4- (4-
Chlorophenyl) -5-oxazolyl] propanoyl} thiazolidine-1-oxide (7.3 mg, yield 28%)
Got HPLC analysis: Purity 98.5% (retention time: 3.628
Min) MS (ESI +): 455 (M + H) Example 344 3- {3- [2- (1H-benzimidazol-1-yl).
To a mixture of -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} thiazolidine (25 mg) and tetrahydrofuran (10 mL) was added m-chloroperbenzoic acid (28.8 mg) with stirring under ice cooling, and the mixture was stirred at room temperature overnight. Stir it. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO ₄ ), and concentrated. The residue was introduced into preparative HPLC for purification and 3- {3- [2
-(1H-benzimidazol-1-yl) -4- (4-
Chlorophenyl) -5-oxazolyl] propanoyl} thiazolidine-1,1-dioxide (10.7 mg, yield 40%) was obtained. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. Melting point 136-137 [deg.] C. HPLC analysis: Purity 94.8% (retention time: 4.053)
Min) MS (ESI +): 471 (M + H) Example 345 Mixture of 4-[(diethylphosphono) (fluoro) methyl] nitrobenzene (74 mg), 10% Pd-C (10 mg) and ethanol (2 ml). Under a hydrogen stream at room temperature
Stir for hours. Pd-C was removed from the reaction mixture by filtration,
The filtrate was concentrated. The residue is 3- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl)
-5-oxazolyl] propionic acid (25 mg), 1-
Hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (27 mg) and N, N-dimethylformamide (0.5 ml) were added. In addition,
Stir overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After concentrating the ethyl acetate layer, preparative HPLC
Was purified by introducing it into 3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-
Oxazolyl] -N- {4-[(diethylphosphono) (fluoro) methyl] phenyl} propionamide was obtained. Recrystallization from ethyl acetate-isopropyl ether gave colorless prism crystals (5 mg, yield 12%). Melting point 152-1
55 ° C. MS (ESI +): 611 (M + H)

Example 346 3- [4- (4-chlorophenyl) -2-propyl-5-
Oxazolyl] propionic acid (41.7 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (46 mg), 4-
A mixture of [(1-methyl-4-piperidinyl) methyl] piperazine (60 mg) and N, N-dimethylformamide (0.5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then introduced into preparative HPLC for purification. Ethyl acetate was added to the obtained oily matter, and washed with saturated aqueous sodium hydrogen carbonate.
To the ethyl acetate layer was added 4N hydrochloric acid-ethyl acetate solution, and the mixture was concentrated to give 1- {3- [4- (4-chlorophenyl)-
2-Propyl-5-oxazolyl] propanoyl} -4-
[(1-Methyl-4-piperidinyl) methyl] piperazine
Dihydrochloride (25.0 mg, yield 32%) was obtained. Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. Melting point 218 [deg.] C (decomposition). MS (ESI +): 473 (M + H) Example 347 3- [4- (4-chlorophenyl) -2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-oxazolyl]
Propionic acid (51.5 mg), 1-hydroxy-7-
Aza-1H-1,2,3-benzotriazole (41m
g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (46 mg), 4-[(1-methyl-
A mixture of 4-piperidinyl) methyl] piperazine (60 mg) and N, N-dimethylformamide (0.5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After concentrating the ethyl acetate layer, preparative HP
It was introduced into LC and purified. Ethyl acetate was added to the obtained oily matter, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ), and concentrated to give 1-
{3- [4- (4-chlorophenyl) -2- (3,5-dimethyl-1H-pyrazol-1-yl) -5-oxazolyl]
Propanoyl} -4-[(1-methyl-4-piperidinyl)
Methyl] piperazine (54.5 mg, 72% yield) was obtained. Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. Melting point 126-127 [deg.] C. MS (ESI +): 525 (M + H) Example 348 3- {4- (4-chlorophenyl) -2- [2- (methylsulfonyl) -1H-imidazol-1-yl] -5-oxazolyl. } Propionic acid (50 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (46 mg), 4- [ (1-Methyl-4-piperidinyl) methyl] piperazine (60 m
g) and N, N-dimethylformamide (0.5 m
The mixture of l) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then introduced into preparative HPLC for purification. Ethyl acetate was added to the obtained oily matter, and washed with saturated aqueous sodium hydrogen carbonate. To the ethyl acetate layer was added 4N hydrochloric acid-ethyl acetate solution, and the mixture was concentrated to give 1- (3- {4- (4-chlorophenyl) -2- [2-
(Methylsulfonyl) -1H-imidazol-1-yl]
-5-Oxazolyl} propanoyl) -4-[(1-methyl-4-piperidinyl) methyl] piperazine 3 hydrochloric acid (6
5.0 mg, yield 66%) was obtained. HPLC analysis: Purity 100% (retention time: 2.737
Min) MS (ESI +): 575 (M + H)

Example 349 2- (1H-benzimidazol-1-yl) -4- (4
-Chlorophenyl) -5-oxazolepropionic acid (19 mg), (S) -3- (N-Boc-amino) pyrrolidine (10 mg), 1-hydroxybenztriazole (8 mg), 1-ethyl-3- (3-hydrochloride). A mixture of dimethylaminopropyl) carbodiimide (10 mg) and N, N-dimethylformamide (1 ml) was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was filtered with and concentrated, and the residue was dissolved in 4N hydrochloric acid-ethyl acetate solution and allowed to stand for 5 minutes.
Concentrated. Benzoic acid (10 mg), 1-hydroxy-7-azabenztriazole (8 mg) and hydrochloric acid 1 were added to the residue.
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (10 mg) and N, N-dimethylformamide (1 ml) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was directly injected into preparative HPLC for purification to obtain the desired product. Examples 350-394 It carried out similarly to Example 349, and obtained the target object. Example 34
The structures and purities of the target compounds of 9 to 394 are LC-MS, H
It was confirmed by PLC. The data of yield, structure, purity and mass spectrum of the target product are shown in [Table 1-1] to [Table 1-4].

[0186]

[Table 1]

[Table 2]

[0187]

[Table 3]

[Table 4]

Example 395 2- (1H-benzimidazol-1-yl) -4- (4
-Chlorophenyl) -5-oxazolepropionic acid (22 mg), 3-amino-1-Boc-pyrrolidine (12 mg), 1-hydroxy-7-azabenztriazole (10 mg), 1-ethyl-3- (3-dimethyl hydrochloride). Aminopropyl) carbodiimide (12 mg),
A mixture of N, N-dimethylformamide (1 ml) was agitated at room temperature for 8 hours. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was filtered with and concentrated, and the residue was dissolved in a 4N hydrochloric acid-ethyl acetate solution, allowed to stand for 5 minutes, and then concentrated. To the residue (2
R) -tetrahydrofuran-2-carboxylic acid (12 m
g), 1-hydroxybenztriazole (20 m
g), dicyclohexylcarbodiimide (13 mg),
N, N-Dimethylformamide (1 ml) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was injected into a Megabond Elute SCX column (1 g) manufactured by Varian, which had been equilibrated with acetonitrile in advance, and impurities were washed out with acetonitrile. The desired product was eluted with a 2N ammonia methanol solution and concentrated. Examples 396-454 It carried out similarly to Example 395, and obtained the target object. Example 39
The structures and purities of the target compounds of 5 to 454 are LC-MS, H
It was confirmed by PLC. The data of the yield, structure, purity and mass spectrum of the target product are shown in [Table 2-1] to [Table 2-8].

[0189]

[Table 5]

[Table 6]

[0190]

[Table 7]

[Table 8]

[0191]

[Table 9]

[Table 10]

[0192]

[Table 11]

[Table 12]

Example 455 2- (1H-benzimidazol-1-yl) -4- (4
-Chlorophenyl) -5-oxazolepropionic acid (37 mg), 4- (2-cyanoethyl) piperazine (20 mg), 1-hydroxy-7-azabenztriazole (20 mg), 1-ethyl-3- (3-dimethylaminopropyl). ) Carbodiimide (20 mg), N, N
A mixture of dimethylformamide (1 ml) at room temperature for 8
It took time. The reaction mixture was directly injected into preparative HPLC for purification to obtain the desired product. Examples 456 to 461 In the same manner as in Example 455, the intended products were obtained. Example 45
The structures and purities of the target compounds of 5 to 461 are LC-MS, H
It was confirmed by PLC. The data of yield, structure, purity and mass spectrum of the target product are shown in [Table 3].

[0194]

[Table 13]

Example 462 4- (4-chlorophenyl) -2-phenyl-5-oxazolebutanoic acid (35 mg), N, N-dimethylethylenediamine (15 mg), 1-hydroxy-7-azabenztriazole (20 mg), 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide (20m
A mixture of g) and N, N-dimethylformamide (1 ml) was agitated at room temperature for 8 hours. The reaction mixture was directly injected into preparative HPLC for purification to obtain the desired product. Examples 463 to 502 In the same manner as in Example 462, the intended products were obtained. Example 46
The structures and purities of the target compounds of 2 to 502 are LC-MS, H
It was confirmed by PLC. The structure, purity (HPLC retention time), and mass spectrum data of the desired product are shown in [Table 4-1]-
It is shown in [Table 4-5].

[0196]

[Table 14]

[Table 15]

[0197]

[Table 16]

[Table 17]

[Table 18]

Example 503 2- (1H-benzimidazol-1-yl) -4- (4
-Chlorophenyl) -5-oxazolepropionic acid (37 mg), 4-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] aniline (35 mg), 1
-Hydroxy-7-azabenztriazole (20m
g), 1-ethyl-3- (3-dimethylaminopropyl)
A mixture of carbodiimide (20 mg) and N, N-dimethylformamide (1 ml) was stirred at room temperature for 8 hours. The reaction mixture was directly injected into preparative HPLC for purification,
I got the object. Examples 504 to 508 In the same manner as in Example 503, the intended product was obtained. Example 50
The structures and purities of the desired compounds of 3 to 508 are LC-MS, H
It was confirmed by PLC. The structure, purity (HPLC retention time), and mass spectrum data of the desired product are shown in [Table 5].

[0199]

[Table 19]

Examples 509 to 874 Carboxylic acid (0.06 mmol), amine (0.06 mmo)
l), Argonaute PS-carbodiimide resin (0.94 meq / g, 96 mg), dichloromethane (0.
7 ml) of the mixture was agitated for 20 hours using a plate with a 96-well Flexchem filter. The resin was removed by filtration, the filtrate was concentrated, and the residue was purified by preparative HPLC to obtain the desired product. The structure, purity (HPLC retention time), and mass spectrum data of the desired product are shown in [Table 6-1]-
[Table 6-4], [Table 7-1] to [Table 7-4], [Table 8-
1] to [Table 8-2], [Table 9-1] to [Table 9-4],
[Table 10-1] to [Table 10-4], [Table 11-1] to
[Table 11-4], [Table 12-1] to [Table 12-4],
It is shown in [Table 13-1] to [Table 13-4] and [Table 14].

[0201]

[Table 20]

[Table 21]

[0202]

[Table 22]

[Table 23]

[0203]

[Table 24]

[Table 25]

[0204]

[Table 26]

[Table 27]

[0205]

[Table 28]

[Table 29]

[0206]

[Table 30]

[Table 31]

[0207]

[Table 32]

[Table 33]

[0208]

[Table 34]

[Table 35]

[0209]

[Table 36]

[Table 37]

[0210]

[Table 38]

[Table 39]

[0211]

[Table 40]

[Table 41]

[0212]

[Table 42]

[Table 43]

[0213]

[Table 44]

[Table 45]

[0214]

[Table 46]

[Table 47]

[0215]

[Table 48]

[Table 49]

[Table 50]

Example 875 [4-({3- [2-amino-4- (4-chlorophenyl) -1,3-thiazol-5-yl] propanoyl}}
Amino) benzyl] diethylphosphonate (100m
g), ethyl carbamate (50 mg), carbonyldiimidazole (38 mg), diisopropylethylamine (85 μl), N, N-dimethylformamide (0.
5 ml) mixture was stirred at room temperature for 8 hours. The reaction mixture was directly injected into preparative HPLC for purification to obtain the desired product. Examples 876 to 953 The intended products were obtained in the same manner as in Example 875. Example 87
The structures and purities of the target compounds of 5 to 953 are LC-MS, H
It was confirmed by PLC. The data of yield, structure, purity and mass spectrum of the desired product are shown in [Table 15-1] to [Table 15-
4], [Table 16-1] to [Table 16-4] and [Table 1]
7].

[0217]

[Table 51]

[Table 52]

[0218]

[Table 53]

[Table 54]

[0219]

[Table 55]

[Table 56]

[0220]

[Table 57]

[Table 58]

[Table 59]

Example 954 [4-({3- [2-amino-4- (4-chlorophenyl) -1,3-thiazol-5-yl] propanoyl}}
Amino) benzyl] diethylphosphonate (100m
g), cyclohexanecarboxylic acid (38 mg), 1-hydroxy-7-azabenztriazole (31 mg),
A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (76 mg) and N, N-dimethylformamide (0.4 ml) was stirred at room temperature for 8 hours.
The reaction mixture was directly injected into preparative HPLC for purification to obtain the desired product. Examples 955 to 993 The intended product was obtained in the same manner as in Example 954. Example 95
The structures and purities of the target compounds of 4 to 993 are LC-MS, H
It was confirmed by PLC. The data of yield, structure, purity and mass spectrum of the desired product are shown in [Table 18-1] to [Table 18-2].
And [Table 19-1] to [Table 19-2].

[0222]

[Table 60]

[Table 61]

[0223]

[Table 62]

[Table 63]

Test Example 1 Male 6-week-old SD rats (CLEA Japan, Inc.) were injected with 70 mg / kg body weight of streptozotocin (STZ) by tail injection to prepare a diabetic neuropathy model. After breeding for 1 month, the rats were orally administered with 3 mg / kg of the compound (the compound of Example 5 or Example 226) suspended in 0.5% methylcellulose for 1 month.
The control group was administered with a 0.5% aqueous methylcellulose suspension containing no compound. After the administration, the rats were anesthetized with Nembutal, the body temperature was kept constant using a hot plate of 37 ° C and a table lamp, and the needle electrodes were placed on the upper knee side and the ankle, and Neuropack 2 (Neuropack 2, Nihon Kohden) was placed. As a general rule, it was stimulated with 1.6 mA and the evoked potential was detected from the plantar part. The motor nerve conduction velocity (MNCV, Motor Nerve Conduction Velocity)
city) was calculated. After evaluating the nerve conduction velocity, sciatic nerve was collected from the rat, and 20 times the sciatic nerve wet weight was used for crushing buffer (1 M sodium chloride, 2% BSA, 2 mM EDT.
A, 0.1 M containing 80 trypsin units / L aprotinin
Tris-hydrochloric acid buffer, pH 7.6) was added and ultrasonically disrupted,
After centrifuging the disrupted solution (15,000 rpm, 60 minutes), the content of BDNF in the supernatant was measured. BDNF content is based on anti-BDNF polyclonal antibody (Promega) and biotinylated anti-BDNF
Sandwich ELISA using antibody (G1641, Promega)
It was measured by the method. The results are shown in [Table 20]. [Table 20] MNCV (m / s) BDNF (ng / g) Control group 45.1 ± 4.4 2.0 ± 0.4 Compound administration group of Example 5 52.7 ± 5.0 ** 2.6 ± 0.7 ** Compound administration group of Example 226 52.3 ± 2.4 ** 3.6 ± 0.4 * Mean ± SD (n = 7-8) *: p <0.05 vs control group (t-test) **: p <0.01 vs control group (t-test) [Table 20] As shown, the compounds of the present invention increased motor nerve conduction velocity and nerve BDNF content.

Formulation Example 1 (Production of Capsule) 1) Compound of Example 1 30 mg 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) And 4) are mixed and filled into a gelatin capsule. Formulation Example 2 (Production of tablets) 1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets Total 140 g 1), The whole amount of 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder, and the mixture is compressed with a tableting machine. Thus, 1 tablet of compound 30 of Example 1
1000 tablets containing mg are obtained.

[0226]

The compound of the present invention has an excellent neurotrophic factor production / secretion promoting action and is useful for the prevention / treatment of diabetic neuropathy and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/433 A61K 31/433 31/4439 31/4439 31/454 31/454 31/496 31/496 31 / 506 31/506 31/5377 31/5377 31/54 31/54 31/541 31/541 31/551 31/551 31/662 31/662 A61P 3/10 A61P 3/10 25/00 25/00 25 / 04 25/04 43/00 105 43/00 105 111 111 111 C07D 263/32 C07D 263/32 263/48 263/48 277/20 413/04 277/30 413/12 277/40 413/14 413/04 417/04 413/12 417/14 413/14 C07F 9/653 417/04 9/6539 417/14 C07M 7:00 C07F 9/653 C07D 277/30 9/6539 277/40 // C07M 7:00 ( 72) Inventor Masasa Satoshi 2-7-28-102, Satsukioka, Ikeda-shi, Osaka F-term (reference) 4C033 AD08 AD09 AD13 AD17 AD20 4C056 AA01 AB01 AC02 AD01 AE03 BA03 BA07 BA13 BB02 BB11 BC01 4C 063 AA01 AA03 AA05 BB01 BB02 BB07 BB08 BB09 CC52 CC61 CC62 CC67 CC78 CC81 CC92 DD06 DD10 DD12 DD22 DD25 DD26 DD29 DD52 EE01 4C086 AA01 AA02 AA03 BC69 BC73 BC01 BC01 GA01 GA01 GA14 GA01 GA10 GA01 GA14 GA07 GA08 GA07 GA08 GA07 GA08 GA07 GA08 GA08 GA08 GA07 GA01 GA10 GA01 GA14 ZC35 ZC41 4H050 AA01 AA03 AB20 AB21 AB27

Claims (19)

[Claims] 1. A compound represented by the formula (I): [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group,
A hydroxy group which may be substituted, a thiol group which may be substituted or an amino group which may be substituted, A is a cyclic amino group which may be substituted or -N
R ² —WD (R ² represents a hydrogen atom or an alkyl group,
Represents a bond or a divalent acyclic hydrocarbon group, D represents a cyclic group which may be substituted, an amino group which may be substituted or an acyl group which may be substituted), and B is a substituent. An optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and Y is a bond or a divalent acyclic hydrocarbon group. Or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is an optionally substituted heterocyclic group. 3. The compound according to claim 1, wherein A is an optionally substituted cyclic amino group. 4. A is —NR ² —WD (R ² is a hydrogen atom or an alkyl group, W is a bond or a divalent acyclic hydrocarbon group, and D is an optionally substituted cyclic group. Is an optionally substituted amino group or an optionally substituted acyl group). 5. The compound according to claim 4, wherein D is an optionally substituted cyclic group. 6. The compound according to claim 1, wherein B is an optionally substituted aryl group having 6 to 14 carbon atoms. 7. The compound according to claim 1, wherein X is an oxygen atom. 8. The compound according to claim 1, wherein Y is C _1-4 alkylene. 9. 3- [2- (1H-benzimidazole-1
-Yl) -4- (4-chlorophenyl) -5-oxazolyl] -N- [4- (diethylphosphonomethyl) phenyl] propionamide; 3- [4- (4-chlorophenyl) -2
-(4-morpholinyl) -5-oxazolyl] -N- [4-
(Diethylphosphonomethyl) phenyl] propionamide; 3- [4- (4-chlorophenyl) -2-phenyl-
5-oxazolyl] -N- [4- (dimethylphosphonomethyl) phenyl] propionamide; 3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5-oxazolyl]- N- {4-[(2-oxide-
1,3,2-Dioxaphosphinan-2-yl) methyl]
Phenyl} propionamide; 4- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl)
-5-oxazolyl] -N-[(4-dimethylphosphonomethyl) phenyl] butanamide; 1- {3- [2- (1H-benzimidazol-1-yl) -4- (4-chlorophenyl) -5- Oxazolyl] propanoyl} -4-piperidinol; 4- {3- [2- (1H-benzimidazole-
1-yl) -4- (4-chlorophenyl) -5-oxazolyl] propanoyl} thiomorpholine-1,1-dioxide; 4- [2- (1H-benzimidazol-1-yl)
-4- (4-chlorophenyl) -5-oxazolyl] -N
-[(4-Diethylphosphonomethyl) phenyl] butanamide; or 4- {3- [4- (4-chlorophenyl) -2-
The compound according to claim 1, which is (1-methyl-1H-indol-3-yl) -5-oxazolyl] propanoyl} thiomorpholine-1,1′-dioxide; 10. A pharmaceutical comprising the compound according to claim 1 or a prodrug thereof. 11. The pharmaceutical according to claim 10, which is a prophylactic / therapeutic agent for diabetic neuropathy. 12. The medicine according to claim 10, which is a pain improving agent. 13. A neurotrophic factor production / secretion promoter comprising the compound according to claim 1 or a prodrug thereof. 14. Use of the compound according to claim 1 or a prodrug thereof for producing a prophylactic / therapeutic agent for diabetic neuropathy. 15. A method for preventing or treating diabetic neuropathy in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to the mammal. 16. A method for producing a pain improving agent according to claim 1.
Use of the described compound or a prodrug thereof. 17. A method for improving pain in a mammal, which comprises administering to the mammal an effective amount of the compound according to claim 1 or a prodrug thereof. 18. Use of the compound according to claim 1 or a prodrug thereof for producing a neurotrophic factor production / secretion promoter. 19. A method for promoting the production or secretion of neurotrophic factor in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to the mammal.