JPH09291082A - Isoxazol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an isoxazol derivative having an excellent A type monoamine oxidase-inhibiting action, weak in toxicity and useful for a medicine for treating and preventing depression, Parkinson's disease, Alzheimer's disease, etc. SOLUTION: An isoxazol derivative of formula I [R<1> is a five or six- membered heterogeneous ring group which has one or two heterogeneous atoms selected from a group consisting of N, O and S and which may have one to three substituents selected from a substituent group consisting of a halogen, a 1-6C alkyl, etc.; R<2> is H, a halogen, etc.; R<3> is amino, a mono 1-6C alkylamino, etc.; X is O, S; (n) is an integer of 2-6] or its pharmacologically acceptable salt. For example, 3-(2-aminoethoxy)-5-phenylisoxazol. The compound of formula I is obtained by reacting a compound of formula II with a halogenating agent and subsequently reacting the obtained compound of formula III (Z is a halogen) with a compound of formula IV (R<3> a is R<3> wherein the amino and the mono 1-6C alkylamino are each protected).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an isoxazole derivative having an excellent A-type monoamine oxidase inhibitory activity, or a pharmacologically acceptable salt thereof or an active ingredient thereof, depression, Parkinson's disease, Alzheimer's dementia ( The present invention relates to a therapeutic or prophylactic drug for a neurological disease (particularly depression) such as cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognitive impairment based on cerebrovascular dementia).

[0002]

2. Description of the Related Art Depression is a disease of mood disorders whose main symptom is suppression of mood, and is considered to be one of the causes of dysfunction of brain serotonin and noradrenaline nervous system. Serotonin and noradrenaline are decomposed and metabolized mainly by A-type monoamine oxidase among monoamine oxidases to lose biological activity. The A-type monoamine oxidase inhibitor is considered to be useful as an antidepressant, and its research and development have been actively conducted. Recently, moclobemide as a selective A-type monoamine oxidase inhibitor has been clinically provided.

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventor has conducted extensive studies for many years on the synthesis of isoxazole derivatives and their pharmacological actions with the aim of developing excellent therapeutic agents for depression, etc., and as a result, isoxazole having a unique structure. Derivatives have a strong inhibitory effect on type A monoamine oxidase, such as depression, Parkinson's disease, Alzheimer's dementia (such as cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (such as cognitive impairment based on cerebrovascular dementia) The present invention has been completed by discovering that it has a therapeutic effect or a preventive effect (particularly a therapeutic effect) on a neurological disease (particularly depression). The present invention
Provided are an isoxazole derivative having an excellent A-type monoamine oxidase inhibitory action, a method for producing the same, and a monoamine oxidase inhibitor containing the isoxazole derivative as an active ingredient.

[0004]

The isoxazole derivative of the present invention has the general formula (I).

[0005]

Embedded image

In the above formula, R ¹ is the same or different and is a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups or 1 to 3 substituents. A 5-membered to 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent. [Wherein the group of substituents is halogen; C ₁ -C ₆ alkyl;
C substituted with halogen or C ₁ -C ₆ alkoxy
₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; same or different and may have 1 to 3 substituents selected from the following group, C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ Aralkyl, C ₆ -C ₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy (the group of the substituent is halogen, C ₁ -C ₆
Alkyl or C ₁ -C ₆ alkoxy. ); Cyano; nitro; hydroxyl group; C ₁ -C ₇ alkanoyl; C _1-
C ₇ alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl and the same or different and selected from the following groups Mono C ₇ -C ₁₅ arylcarbonylamino which may have 1 to 3 substituents (the group of the substituents is halogen, C _1-).
A C ₆ alkyl or C ₁ -C ₆ alkoxy. ). ], R ² is a hydrogen atom; a halogen atom; C ₁ -C ₆
Alkyl group; C ₁ -C ₆ alkyl group substituted by halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; C ₃ -C ₁₀ cycloalkyl group; C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; a cyano group; a carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; a carbamoyl group; a mono (C ₁ -C ₆ alkyl) A carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, wherein R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, a mono C _1- C
₇ alkanoylamino group, mono C ₂ -C ₇ alkoxycarbonylamino group, mono C ₇ — which may be the same or different and may have 1 to 3 substituents selected from the following groups:
A C ₁₅ arylcarbonylamino group (the group of the substituents is
Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. Or a 5- to 6-membered saturated heterocyclic group containing one nitrogen atom and optionally one nitrogen atom or oxygen atom, provided that the group is bonded on the nitrogen atom.
X is an oxygen atom or a sulfur atom, and n is 2
Is an integer from 6 to 6.

The active ingredient of the monoamine oxidase inhibitor of the present invention is an isoxazole derivative having the general formula (I).

In the above general formula (I), the substituent contained in R ¹ and the "halogen atom" in the definition of R ² may be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and are preferable. Is a fluorine atom or a chlorine atom, and more preferably a chlorine atom.

In the above, the "C ₁ -C ₆ alkyl group" in the definitions of the substituents contained in R ¹ and R ² is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group. , Isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2
-Methylpentyl group, 1-methylpentyl group, 3,3-
Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 1,
It may be a straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as a 3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group, and the substituent contained in R ¹ is preferable. Is a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group. R ² is preferably a C ₁ -C ₄ alkyl group, more preferably an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, and particularly preferably an isopropyl group.

In the above, in the definition of R ² , "C _2-
C ₆ alkenyl group "is, for example, vinyl group, 1-propenyl group, allyl group, 1-methyl-1-propenyl group, 1
-Methyl-2-propenyl group, 2-methyl-1-propenyl group, isopropenyl group, allenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, isoprenyl group, 5-hexenyl group Group or a linear or branched alkenyl group having 1 to 2 double bonds such as 1,4-hexadienyl group and having 2 to 6 carbon atoms, preferably vinyl group, 1-propenyl group, Allyl group,
1-methyl-1-propenyl group, isopropenyl group, 2
-Butenyl group or 3-butenyl group, more preferably allyl group, isopropenyl group or 2-butenyl group, and particularly preferably allyl group.

In the above, "C _2- " in the definition of R ²
“C ₆ alkynyl group” is, for example, ethynyl group, 1-propynyl group, propargyl group, 1-methyl-2-propynyl group, 2-methyl-2-propynyl group, 2-ethyl-2.
-Propynyl group, 2-butynyl group, 1-methyl-2-butynyl group, 2-methyl-2-butynyl group, 3-butynyl group, 2-pentynyl group, 5-hexynyl group or 2-methyl-4-pentynyl group A straight chain or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, propargyl group, 2-butynyl group or 3-butynyl group, and more preferably propargyl group. is there.

In the above, "C _3- " in the definition of R ²
“C ₁₀ cycloalkyl group” is, for example, a 3- to 10-membered saturated cyclic hydrocarbon which may be condensed, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, norbornyl group or adamantyl group. It may be a group, preferably a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, more preferably a cyclopropyl group.

In the above, "C _3- " in the definition of R ²
C ₁₀ cycloalkenyl group "is, for example, 2-cyclopropenyl group, 2-cyclobutenyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group , 3-cyclohexenyl group, 2-cycloheptenyl group, 3-norborenyl group or 3-adamantenyl group, which has one double bond and may be condensed 3 to 10 membered unsaturated cyclic carbonization It may be a hydrogen group, preferably a 2-cyclopentenyl group, a 3-cyclopentenyl group, a 2-cyclohexenyl group or a 3-cyclohexenyl group, and more preferably a 2-cyclopentenyl group. The At a, C ₁ substituted with "halogen or C ₁ -C ₆ alkoxy in the definition of substituents and R ² contained in R ¹
The "-C ₆ alkyl group" is a group in which 1 to 5 of the above "halogen atom" is bonded to the above "C ₁ -C ₆ alkyl group" or the following "C ₁ -C ₆ alkoxy" is the above C ₁ -C ₆ Examples of the group in which a halogen is bonded to a C ₁ -C ₆ alkyl group are shown as a group bonded to an alkyl group, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group and 2-
Fluoroethyl group, 2-chloroethyl group, 2,2,2-
Trifluoroethyl group, 3-fluoropropyl group, 3-
It may be a chloropropyl group, a 3-bromopropyl group, a 4-fluorobutyl group or a 6-iodohexyl group, and C _1-
Examples of the group in which C ₆ alkoxy is bonded to the C ₁ -C ₆ alkyl group include methoxymethyl group, ethoxymethyl group, propoxymethyl group, butoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, butoxyethyl group. Group, a propoxypropyl group, a butoxybutyl group or a hexyloxyhexyl group, and the substituent contained in R ¹ is preferably 1 to 3 halogens or 1
C ₁ -C ₆ alkyl group substituted by C ₁ -C ₄ alkoxy, more preferably fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group or methoxyethyl group, and more preferably trifluoromethyl group, 2,
It is a 2,2-trifluoroethyl group or a methoxymethyl group, and a trifluoromethyl group is particularly preferable. or,
R ² is preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, 1
-Chloroethyl group, 2-chloroethyl group, 2,2,2-
A trifluoroethyl group, a methoxymethyl group or a methoxyethyl group, more preferably a trifluoromethyl group, a 2-fluoroethyl group, a 1-chloroethyl group or 2
A -chloroethyl group, particularly preferably a 1-chloroethyl group.

In the above, the substituents contained in R ¹ , such as R ^1
2 and “C ₁ -C” in the definition of the substituent contained in R ^2.
_The “ ₆ alkoxy group” refers to a group in which the above “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, and s-butoxy group. Group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, neopentoxy group, 1-ethylpropoxy group,
Hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-
Dimethylbutoxy group, 1,1-dimethylbutoxy group,
It may be a 1,2-dimethylbutoxy group, a 1,3-dimethylbutoxy group, a 2,3-dimethylbutoxy group or a 2-ethylbutoxy group, preferably a C ₁ -C ₄ alkoxy group, and more preferably A methoxy group or an ethoxy group, and particularly preferably a methoxy group.

In the above, in the definition of the substituent contained in R ¹ , "a C ₆ -C ₁₄ aryl group which may be the same or different and may have 1 to 3 substituents selected from the following group: (The group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.) ”Has 1 to 3 substituents which are the same or different from the group of the substituents. May be an aromatic hydrocarbon group having 6 to 14 carbon atoms, for example, phenyl group, fluorophenyl group, chlorophenyl group, dichlorophenyl group, methylphenyl group,
Trimethylphenyl group, methoxyphenyl group, indenyl group, methylindenyl group, naphthyl group, dichloronaphthyl group, phenanthrenyl group, hexylphenanthrenyl group, anthracenyl group, dimethylanthracenyl group or hexyloxyanthracenyl group It is preferably a phenyl group which may have 1 or 2 substituents which are the same or different and are selected from the group consisting of fluorine, chlorine, methyl and methoxy, more preferably a phenyl group and 4- A fluorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group, a 4-methylphenyl group or a 4-methoxyphenyl group, and a phenyl group is particularly preferable.

In the above, in the definition of the substituent contained in R ¹ , "a C ₇ -C ₁₈ aralkyl group which may be the same or different and may have 1 to 3 substituents selected from the following groups: (The group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.) ”Has 1 to 3 substituents which are the same or different from the group of the substituents. Optionally, 1 or 2 phenyl groups or 1 naphthyl group represents a group bonded to the above-mentioned “C ₁ -C ₆ alkyl”, for example, benzyl group, fluorobenzyl group, difluorobenzyl group , Trifluorobenzyl group, chlorobenzyl group, dichlorobenzyl group, trichlorobenzyl group, bromobenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, ethylbenzyl group,
Propylbenzyl group, methoxybenzyl group, dimethoxybenzyl group, ethoxybenzyl group, hexyloxybenzyl group, diphenylmethyl group, naphthylmethyl group, fluoronaphthylmethyl group, difluoronaphthylmethyl group,
Chloronaphthylmethyl group, dichloronaphthylmethyl group,
Methylnaphthylmethyl group, dimethylnaphthylmethyl group,
Ethylnaphthylmethyl group, phenethyl group, fluorophenethyl group, difluorophenethyl group, chlorophenethyl group, dichlorophenethyl group, methylphenethyl group, trimethylphenethyl group, naphthylethyl group, fluoronaphthylethyl group, chloronaphthylethyl group, phenylpropyl group, Fluorophenylpropyl group, chlorophenylpropyl group, dichlorophenylpropyl group, methylphenylpropyl group, dimethylphenylpropyl group, trimethylphenylpropyl group, naphthylpropyl group, iodonaphthylpropyl group, hexylnaphthylpropyl group, methoxynaphthylpropyl group, hexyloxynaphthyl group Propyl group, phenylbutyl group, fluorophenylbutyl group, difluorophenylbutyl group, chlorophenylbutyl group, dichlorophenyl group Nirubuchiru group which may be trimethylphenyl butyl group or naphthylbutyl group, preferably a halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ from the group consisting of alkoxy same or different 1 to 3 is selected A benzyl group or a phenethyl group which may have a substituent, more preferably 1 selected from the group consisting of fluorine, chlorine, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.
Benzyl group which may have one substituent, and more preferably benzyl group, fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, methylbenzyl group, dimethylbenzyl group or methoxybenzyl group. A group, and particularly preferably a benzyl group.

In the above, in the definition of the substituent contained in R ¹ , "C ₆ -C ₁₄ aryloxy which may be the same or different and may have 1 to 3 substituents selected from the following groups: The group (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) is the same as or different from 1 to 3 selected from the following groups.
C ₆ -C ₁₄ aryl groups which may have 4 substituents (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C _1-).
It is C ₆ alkoxy. ) ”Represents a group bonded to an oxygen atom, for example, a phenoxy group, a fluorophenoxy group,
Chlorophenoxy group, dichlorophenoxy group, methylphenoxy group, trimethylphenoxy group, methoxyphenoxy group, indenyloxy group, methylindenyloxy group, naphthyloxy group, dichloronaphthyloxy group, phenanthrenyloxy group, hexylphenane group It may be a threnyloxy group, anthracenyloxy group, dimethylanthracenyloxy group or hexyloxyanthracenyloxy group, preferably the same or different selected from the group consisting of fluorine, chlorine, methyl and methoxy. It is a phenoxy group which may have 1 or 2 substituents, more preferably a phenoxy group, a 4-fluorophenoxy group, a 4-chlorophenoxy group, a 2,4-dichlorophenoxy group, and a 4 group.
It is a -methylphenoxy group or a 4-methoxyphenoxy group, particularly preferably a phenoxy group.

In the above, in the definition of the substituent contained in R ¹ , "C ₇ -C ₁₈ aralkyloxy which may be the same or different and may have 1 to 3 substituents selected from the following groups: The group (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) is the same as or different from 1 to 3 selected from the following groups.
C ₇ -C ₁₈ aralkyl groups which may have 4 substituents (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁
-C is ₆ alkoxy. ) ”Represents a group bonded to an oxygen atom, and examples thereof include a benzyloxy group, a fluorobenzyloxy group, a difluorobenzyloxy group, a trifluorobenzyloxy group, a chlorobenzyloxy group, a dichlorobenzyloxy group, a trichlorobenzyloxy group, and a bromo group. Benzyloxy group, methylbenzyloxy group, dimethylbenzyloxy group, trimethylbenzyloxy group, ethylbenzyloxy group, propylbenzyloxy group, methoxybenzyloxy group, dimethoxybenzyloxy group, ethoxybenzyloxy group, hexyloxybenzyloxy group, Diphenylmethoxy group, naphthylmethoxy group, fluoronaphthylmethoxy group, difluoronaphthylmethoxy group, chloronaphthylmethoxy group, dichloronaphthylmethoxy group, methylnaphthylmethoxy group, Methyl naphthyl methoxy group, an ethyl naphthyl methoxy, phenylethoxy group, fluorophenyl ethoxy group, difluorophenyl ethoxy, chlorophenyl ethoxy group,
Dichlorophenylethoxy group, methylphenylethoxy group, trimethylphenylethoxy group, naphthylethoxy group, fluoronaphthylethoxy group, chloronaphthylethoxy group, phenylpropoxy group, fluorophenylpropoxy group, chlorophenylpropoxy group, dichlorophenylpropoxy group, methylphenylpropoxy group, Dimethylphenylpropoxy group, trimethylphenylpropoxy group, naphthylpropoxy group, iodonaphthylpropoxy group, hexylnaphthylpropoxy group, methoxynaphthylpropoxy group, hexyloxynaphthylpropoxy group, phenylbutoxy group, fluorophenylbutoxy group, difluorophenylbutoxy group, chlorophenyl Butoxy group, dichlorophenylbutoxy group, trimethylphenylbutoxy group or Be a Nafuchirubutokishi group, preferably a halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄
It is a benzyloxy group or a phenylethoxy group which may have 1 to 3 substituents which are the same or different and are selected from the group consisting of alkoxy, more preferably fluorine, chlorine and C ₁ -C ₄ alkyl. And a benzyloxy group which may have one substituent selected from the group consisting of C ₁ -C ₄ alkoxy, and more preferably benzyloxy group, 4-fluorobenzyloxy group, 4- Chlorobenzyloxy group, 2,4-difluorobenzyloxy group,
2,4-dichlorobenzyloxy group, 4-methylbenzyloxy group, 2,4-dimethylbenzyloxy group or 4
-Methoxybenzyloxy group, particularly preferably benzyloxy group.

In the above, the substituent contained in R ¹ and R
The “C ₁ -C ₇ alkanoyl group” in the definition of ^{2 represents} a group in which a hydrogen atom or the above “C ₁ -C ₆ alkyl” is bonded to a carbonyl group, and examples thereof include a formyl group, an acetyl group, a propionyl group and a butyryl group. It may be an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group or a heptanoyl group, preferably a formyl group or an acetyl group, particularly preferably an acetyl group.

In the above, "C ₁ -C ₇ alkanoyloxy group" in the definition of the substituent contained in R ¹ is a group in which the above "C ₁ -C ₇ alkanoyl group" is bonded to an oxygen atom, For example, formyloxy group, acetoxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group,
It may be a pivaloyloxy group, a hexanoyloxy group or a heptanoyloxy group, preferably a formyloxy group or an acetoxy group, particularly preferably an acetoxy group.

In the above, the substituent contained in R ¹ and R
"C ₂ -C ₇ alkoxycarbonyl group" in the ^two definitions, a group wherein the above "C ₁ -C ₆ alkoxy group" is bonded to a carbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
Isopropoxycarbonyl group, butoxycarbonyl group,
Isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentoxycarbonyl group, isopentoxycarbonyl group, 2-methylbutoxycarbonyl group, neopentoxycarbonyl group, 1-ethylpropoxycarbonyl group, hexyloxy Carbonyl group, 4-methylpentoxycarbonyl group, 3-methylpentoxycarbonyl group, 2-methylpentoxycarbonyl group, 1-methylpentoxycarbonyl group, 3,3-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxy group Carbonyl group, 1,1-dimethylbutoxycarbonyl group, 1,2-dimethylbutoxycarbonyl group, 1,3-
It may be a dimethylbutoxycarbonyl group, a 2,3-dimethylbutoxycarbonyl group or a 2-ethylbutoxycarbonyl group, preferably a C ₂ -C ₅ alkoxycarbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group. And particularly preferably a methoxycarbonyl group.

In the above, "mono C" in the definition of R ³
₁ -C ₆ alkylamino group "refers to a group wherein the above" C ₁ -C ₆ alkyl group "is bonded to an amino group, for example methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino Group, isobutylamino group, s-butylamino group, t-butylamino group, pentylamino group or hexylamino group, preferably mono C ₁ -C ₄ alkylamino group, more preferably methylamino. Group or an ethylamino group, and particularly preferably a methylamino group.

[0023] At a above, "di (C in the definition of R ³
₁ -C ₆ alkyl) amino group ", for example, N, N- dimethylamino group, N- ethyl -N- methylamino group, N
-Methyl-N-propylamino group, N-isopropyl-
N-methylamino group, N-butyl-N-methylamino group, N-isobutyl-N-methylamino group, Ns-butyl-N-methylamino group, Nt-butyl-N-methylamino group, N, N-diethylamino group, N-ethyl-
N-propylamino group, N-ethyl-N-isobutylamino group, N, N-dipropylamino group, N, N-dibutylamino group, N, N-dipentylamino group or N, N-
It may be a dihexylamino group, preferably di (C ₁ -C ₄
Alkyl) amino group, more preferably N, N-dimethylamino group or N, N-diethylamino group, and particularly preferably N, N-dimethylamino group.

In the above, "C _1- " in the definition of R ³
“C ₇ alkanoylamino group” refers to a group in which the above-mentioned “C ₁ -C ₇ alkanoyl group” is bonded to an amino group.
Formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group, hexanoylamino group or heptanoylamino group, preferably formylamino group An amino group or an acetylamino group, particularly preferably an acetylamino group.

In the above, in the definition of R ³ , "C _2-
The “C ₇ alkoxycarbonylamino group” means the above “C ₂ —
C ₇ alkoxycarbonyl group ”represents a group bonded to an amino group, and examples thereof include a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, an isopropoxycarbonylamino group, a butoxycarbonylamino group, an isobutoxycarbonylamino group, s
-Butoxycarbonylamino group, t-butoxycarbonylamino group, pentoxycarbonylamino group, isopentoxycarbonylamino group, 2-methylbutoxycarbonylamino group, neopentoxycarbonylamino group, 1
-Ethylpropoxycarbonylamino group, hexyloxycarbonylamino group, 4-methylpentoxycarbonylamino group, 3-methylpentoxycarbonylamino group, 2-methylpentoxycarbonylamino group, 1-methylpentoxycarbonylamino group, 3 , 3-dimethylbutoxycarbonylamino group, 2,2-dimethylbutoxycarbonylamino group, 1,1-dimethylbutoxycarbonylamino group, 1,2-dimethylbutoxycarbonylamino group, 1,3-dimethylbutoxycarbonylamino group, 2 , 3-dimethylbutoxycarbonylamino group or 2-ethylbutoxycarbonylamino group, preferably C ₂ -C ₅ alkoxycarbonylamino group,
A methoxycarbonylamino group or an ethoxycarbonylamino group is more preferred, and a methoxycarbonylamino group is particularly preferred.

In the above, R¹ And substituents contained in R
^Two In the definition of "mono (C₁ -C ₆ Alkyl) carb
A “moyl group” means, for example, a methylcarbamoyl group, an ethylcarbo group.
Lubamoyl group, propylcarbamoyl group, isopropyl
Carbamoyl group, butylcarbamoyl group, isobutylcarba
Lubamoyl group, s-butylcarbamoyl group, t-butyl
Carbamoyl group, pentylcarbamoyl group or hexyl
It may be a carbamoyl group, preferably mono (C₁ -C_Four A
Alkyl) carbamoyl group, more preferably methylcarboxyl.
It is a luvamoyl group or an ethylcarbamoyl group.

In the above, the substituent contained in R ¹ and R
The “di (C ₁ -C ₆ alkyl) carbamoyl group” in the definition of ² is, for example, an N, N-dimethylcarbamoyl group,
N-ethyl-N-methylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-
Dibutylcarbamoyl group, N, N-diisobutylcarbamoyl group, N, N-di-s-butylcarbamoyl group,
It may be an N, N-di-t-butylcarbamoyl group, an N, N-dipentylcarbamoyl group or an N, N-dihexylcarbamoyl group, preferably a di (C ₁ -C ₄ alkyl) carbamoyl group, and more preferably Is an N, N-dimethylcarbamoyl group or N, N-diethylcarbamoyl group, particularly preferably an N, N-dimethylcarbamoyl group.

In the above, the substituent contained in R ¹ and R
^In the definition of ³ , “mono C ₇ — which may be the same or different and may have 1 to 3 substituents selected from the following groups:
The "C ₁₅ arylcarbonylamino group (the group of the substituent is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy)" is the same as or different from 1 to 1 selected from the following groups. C _6-, which may have 3 substituents
C ₁₄ aryl group (the group of the substituent is halogen, C ₁ -C
₆ alkyl or C ₁ -C ₆ alkoxy. ) ”Represents a group bonded to a carbonylamino group, and includes, for example, a benzoylamino group, a fluorobenzoylamino group, a chlorobenzoylamino group, a dichlorobenzoylamino group, a toluoylamino group, a trimethylbenzoylamino group, an anisoylamino group, and an index group. Noylamino group, methylindenoylamino group, naphthoylamino group, dichloronaphthoylamino group, phenanthrenoylamino group, hexylphenanthrenoylamino group, anthracenoylamino group, dimethylanthracenoylamino group or hexyl It may be an oxyanthracenoylamino group, preferably a benzoylamino group optionally having 1 or 2 substituents selected from the same or different from the group consisting of fluorine, chlorine, methyl and methoxy, More preferably, a benzoylamino group, 4 Fluorobenzoyl group, 4-chlorobenzoyl group, 2,4-dichloro-benzoylamino group, 4-toluoyl-amino group or a 4-anisoyl group, particularly preferably a benzoylamino group.

[0029] The above At a includes "one nitrogen atom in the definition of R ^3, further one nitrogen atom or oxygen atom which may contain 5-membered or 6-membered saturated Hajime Tamaki (provided that the base Is bonded on a nitrogen atom.) ”Can be, for example, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group or a morpholinyl group, and is preferably a piperidyl group or a morpholinyl group.

In the above, "a C ₆ -C ₁₄ aryl group which may be the same or different and has 1 to 3 substituents selected from the following substituent groups" in the definition of R ¹ is, for example, , May be a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, or an anthracenyl group which may be substituted by the substituent, and preferably 1 to 3 of the following substituents, which are the same or different and are selected from each other. It may have a substituent is a good C ₆ -C ₁₄ aryl group [the group of the substituents are halogen; C ₁ -C ₆ alkyl; C ₁ -C substituted by halogen or C ₁ -C ₆ alkoxy ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and may have 1 to 3 substituents selected from the following groups (the substituent group is halogen, C
It is ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4 -Methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇
Alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆
Alkyl) carbamoyl; benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. ], More preferably, it is a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents which are the same or different and are selected from the following substituent groups. ; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted by; C ₁ -C ₆ alkoxy; same or different 1 to 3 of which are selected from the following group C ₆ -C ₁₄ aryl which may have a substituent (the group of the substituent is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); cyano; C ₂ -C ₇ alkoxy Carbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. And more preferably a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents which are the same or different and are selected from the following substituent groups. , C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4- Fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ], And more preferably a phenyl group which may have 1 to 3 substituents which are the same or different and are selected from the following substituent groups [the group of the substituents is halogen, methyl, ethyl , Trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. And even more preferably a phenyl group which may have 1 or 2 substituents which are the same or different and are selected from the following substituent groups: [wherein the substituent group is fluorine, chlorine, Methyl, ethyl, trifluoromethyl and methoxy. ], Particularly preferably a phenyl group, a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group or a methylphenyl group, and most preferably a phenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, 2, 4-difluorophenyl group or 2,
It is a 4-dichlorophenyl group. The number of substituents on the aryl group is preferably 1 to 3, and more preferably 1
2 to 2, and particularly preferably 2.

In the above, 1 to 3 which are the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may have 1 to 3 said substituents in the definition of R ¹ The “5- to 6-membered aromatic heterocyclic group having two hetero atoms” is, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, which may be substituted by the substituent.
Furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group,
It may be a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group, and is preferably a nitrogen atom, an oxygen atom and a sulfur atom which may be the same or different and may have 1 to 3 substituents selected from the following substituent groups. A 5- to 6-membered aromatic heterocyclic group having 1 to 2 heteroatoms selected from the same or different from the group consisting of [the group of the substituents is halogen; C ₁ -C ₆ alkyl; Halogen or C ₁ −
C ₁ -C ₆ alkyl substituted with C ₆ alkoxy; C ₁
-C ₆ alkoxy; C ₆ -C ₁₄ which may be the same or different and may have 1 to 3 substituents selected from the following groups:
Aryl (the group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxy. Benzyl; phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4- Difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-
Methylbenzyloxy, 2,4-dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl group; acetoxy; C ₂ -C ₇ alkoxycarbonyl;
Amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl;
Benzoylamino, 4-fluorobenzoylamino, 4
-Chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. ], More preferably, the same or different, and optionally having 1 to 3 substituents selected from the following substituent group, the same or different selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A 5- to 6-membered aromatic heterocyclic group having 1 to 2 heteroatoms, wherein [the group of the substituents is halogen; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy] C ₁ -C ₆ alkyl substituted; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and may have 1 to 3 substituents selected from the following groups The group of groups is halogen,
C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. ], More preferably, the same or different, and optionally the same or different, selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which may have 1 or 2 substituents selected from the following substituent groups. Having 1 to 2 heteroatoms
A 6-membered aromatic heterocyclic group [the group of the substituents is halogen, C ₁ -C ₄ alkyl, fluoromethyl,
Difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ], More preferably, it is a furyl group, a thienyl group or a pyridyl group, which may have 1 or 2 substituents which are the same or different and are selected from the following substituent groups. Is halogen, methyl, ethyl, trifluoromethyl, methoxy,
Phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N,
It is N-dimethylcarbamoyl. ], And even more preferably, it is a furyl group, a thienyl group or a pyridyl group, which may have one substituent selected from the following substituent group. , Methyl, ethyl,
Trifluoromethyl and methoxy. ], Particularly preferably, it is 2-furyl group, 3-furyl group, 2-thienyl group or 3-thienyl group, most preferably 2-furyl group or 2-thienyl group. The number of substituents on the aromatic heterocyclic group is preferably 1 to 3, more preferably 1 to 2, and particularly preferably 1. Further, the bond between the aromatic heterocyclic group and the isoxazole ring is preferably a bond through a carbon atom on the aromatic heterocycle.

In the above, X is preferably an oxygen atom.

In the above, n is preferably an integer of 2 to 4, and particularly preferably 2.

The compound (I) of the present invention can be converted into an acid addition salt according to a conventional method. For example, compound (I) in a solvent (eg ethers, esters or alcohols, especially ethers) and the corresponding acid at room temperature for 5 minutes to 3 minutes.
It can be obtained by treating for 0 minutes and filtering the precipitated crystals or distilling off the solvent under reduced pressure. Such salts are, for example, mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonic acid. Salts, sulfonates such as trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; fumarate, succinate, citrate, tartrate, oxalate. Or a carboxylate such as maleate; or an amino acid salt such as glutamate or aspartate, preferably a mineral acid salt (particularly hydrochloride).

The compound (I) of the present invention may have an asymmetric carbon atom in the molecule, and there may be stereoisomers having an R-coordinate and an S-coordinate, respectively. Alternatively, any mixture of them in any proportion is included in the present invention.

The compound (I) of the present invention or a salt thereof is
By leaving it in the air or recrystallizing it,
It absorbs water and may be adsorbed with water or become a hydrate, and a compound salt containing such water is also included in the present invention.

In the compound having the above general formula (I),
Preferably, (1) R¹ Are the same or different and
It may have 1 to 3 substituents selected from the group of groups.
C₆ -C₁₄Having an aryl group or 1 to 3 such substituents
Optionally, a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
More than one or two heteroatoms selected differently
A compound having a 5- to 6-membered aromatic heterocyclic group having a child
[The group of the substituent is halogen; C₁ -C₆ Alkyl;
Halogen or C₁ -C₆ C substituted with alkoxy
₁ -C₆ Alkyl; C₁ -C₆ Alkoxy; same or different
Having 1 to 3 substituents selected from the group
May be C₆-C₁₄Aryl (the group of the substituent is halo
Gen, C₁ -C₆ Alkyl and C₁ -C₆ With alkoxy
is there. ); Benzyl, fluorobenzyl, chlorobenze
, Difluorobenzyl, dichlorobenzyl, methyl ester
Benzyl, dimethylbenzyl, methoxybenzyl; pheno
Xy, 4-fluorophenoxy, 4-chlorophenoxy
Ci, 2,4-dichlorophenoxy, 4-methylphenoxy
Ci, 4-methoxyphenoxy; benzyloxy, 4-fu
Luorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichloro
Benzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy
Cy; cyano; nitro; hydroxyl group; acetoxy; C_Two -C₇ 
Alkoxycarbonyl; Amino; Carbamoyl; Mono
(C₁ -C₆ Alkyl) carbamoyl; di (C₁ -C₆ 
Alkyl) carbamoyl; benzoylamino, 4-fur
Orobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoyl alcohol
Mino and 4-anisoylamino. ], (2) R
¹ Are the same or different and are selected from the following substituent groups 1
To C optionally having 3 to 3 substituents₆ -C₁₄Aryl group
Or a nitrogen atom, which may have 1 to 3 substituents,
Same or different from the group consisting of oxygen atom and sulfur atom
5 members to 6 having 1 or 2 heteroatoms selected
Member which is a membered aromatic heterocyclic group [the group of the substituent is
Halogen; C₁ -C₆ Alkyl; halogen or C ₁ 
-C₆ C substituted with alkoxy₁ -C₆ Alkyl; C
₁ -C₆ Alkoxy; identical or different and selected from the following groups
C optionally having 1 to 3 substituents₆-C₁₄A
Reel (the group of the substituent is halogen, C₁ -C₆ Al
Kill or C₁ -C₆ Alkoxy. ); Shea
No; C_Two -C₇ Alkoxycarbonyl; carbamoyl;
Mono (C₁ -C₆ Alkyl) carbamoyl; and di (C
₁ -C₆ Alkyl) carbamoyl. ], (3)
R¹ Are the same or different and are selected from the following substituent groups.
C which may have 1 to 3 substituents₆ -C₁₄Aryl
A nitrogen atom which may have a group or one or two of said substituents.
Same or different from the group consisting of a child, an oxygen atom and a sulfur atom.
5 member having 1 to 2 heteroatoms selected by
A compound which is a 6-membered aromatic heterocyclic group [group of the substituent]
Is halogen, C₁ -C_Four Alkyl, fluoromethyl,
Difluoromethyl, trifluoromethyl, 2-fluoro
Ethyl, 2,2,2-trifluoroethyl, methoxime
Chill, methoxyethyl, C₁ -C_Four Alkoxy, Pheny
L, 4-fluorophenyl, 4-chlorophenyl, 2,
4-dichlorophenyl, 4-methylphenyl, 4-meth
Xyphenyl, cyano, methoxycarbonyl, ethoxy
Carbonyl, carbamoyl, methylcarbamoyl, ethi
Lucarbamoyl, N, N-dimethylcarbamoyl and
It is N, N-diethylcarbamoyl. ], (4) R
¹ Are the same or different and are selected from the following substituent groups 1
To a phenyl group optionally having 3 substituents or 1 to
A furyl group or a thienyl group which may have two said substituents.
Or a compound which is a pyridyl group [the group of the substituent is halo
Gen, methyl, ethyl, trifluoromethyl, methoki
Ci, phenyl, cyano, methoxycarbonyl, carbamo
And methylcarbamoyl, ethylcarbamoyl and
It is N, N-dimethylcarbamoyl. ], (5) R
¹ Are the same or different and are selected from the following substituent groups.
Phenyl group which may have 1 or 2 substituents or said substituent
May have one furyl group, thienyl group or pyridinium
Compounds which are radicals [the group of said substituents is fluorine, chlorine,
Tyl, ethyl, trifluoromethyl and methoxy
You. ], (6) R¹ Is a phenyl group, fluorophenyl
Group, chlorophenyl group, difluorophenyl group, di group
Rolophenyl group, methylphenyl group, 2-furyl group, 3
-Furyl group, 2-thienyl group or 3-thienyl group
Compound, (7) R¹ Is a phenyl group, 2-chlorophene
Nyl group, 4-chlorophenyl group, 2,4-difluoro group
Phenyl group, 2,4-dichlorophenyl group, 2-furyl group
Or a compound which is a 2-thienyl group, (8) R^Two But water
Elementary atom, halogen atom, C₁ -C₆ Alkyl group, Fluor
Romethyl group, difluoromethyl group, trifluoromethyl
Group, 2-fluoroethyl group, 1-chloroethyl group, 2-
Chloroethyl group, 2,2,2-trifluoroethyl group,
Methoxymethyl group, methoxyethyl group, C_Two -C₆ Al
Kenyl group, C_Two -C₆ Alkynyl group, cyclopropyl
Group, cyclopentyl group, cyclohexyl group, 2-cyclo
Pentenyl group, 3-cyclopentenyl group, 2-cyclohexyl
Xenyl group, 3-cyclohexenyl group, methoxy group,
Toxy group, cyano group, carboxy group, formyl group, aceto group
Cyl group, methoxycarbonyl group, ethoxycarbonyl
Group, carbamoyl group, methylcarbamoyl group, ethylcarbyl group
A luvamoyl group or an N, N-dimethylcarbamoyl group
Compound, (9) R^Two Is a hydrogen atom, a halogen atom,
C₁ -C₆ Alkyl group, C_Two -C₆ Alkenyl group or C
_Two -C₆ A compound which is an alkynyl group, (10) R^Two 
Is a hydrogen atom, halogen atom, C₁ -C_Four Alkyl group,
Allyl group, isopropenyl group, 2-butenyl group or pro
Compounds that are pargyl groups, (11) R^Two But hydrogen
Child, chlorine atom, ethyl group, propyl group, isopropyl
A compound which is a group, an isobutyl group or a t-butyl group, (1
2) R^Two Is a compound in which is a hydrogen atom or an isopropyl group
Things, (13) R^Three Is an amino group, mono C₁ -C₆ Al
Killamino group, di (C₁ -C₆ Alkyl) amino group or
Contains one nitrogen atom, and one more nitrogen atom or oxygen source
5- or 6-membered saturated heterocyclic group which may include a child (however,
The group is attached on the nitrogen atom. ) Is a compound, (1
4) R^Three , Amino group, methylamino group, ethylami
Group, N, N-dimethylamino group, piperidyl group or
A compound which is a rufolinyl group, (15) R^Three But Amino
A compound which is a group, (16) a compound wherein X is an oxygen atom
And (17) a compound in which n is 2, R¹ To
Regarding the above, in order of (1) to (7)
^Two As for, the preferred ranking is from (8) to (12).
R^Three With regard to (13) to (15), the preferred order is
The rank goes up.

The compounds having the general formula (I) include (1)-(7), (8)-(12) and (13).
-2 to 5 can be selected from the group consisting of (15), (16) and (17) and any of them can be combined. Suitable compounds in the combination include, for example, ( 18) R ¹ is the same or different and is a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or R ¹ has 1 to 3 such substituents. Which may be a 5-membered to 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. group, halogen; are the same or different and selected from the following group: C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted; C ₁ -C ₆ alkoxy 1 may have a three substituents C ₆ -C ₁₄ Reel (group of the substituents,
Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. ], R ² is a hydrogen atom, a halogen atom, C ₁
-C ₆ alkyl group, C ₂ -C ₆ alkenyl group or C ₂ -
A C ₆ alkynyl group, R ³ is an amino group, mono C ₁
-C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group or a 5- to 6-membered saturated heterocycle containing one nitrogen atom and optionally one nitrogen atom or oxygen atom A compound which is a group (provided that the group is bonded on the nitrogen atom), (19) R ¹ is the same or different and has 1 to 3 substituents selected from the following substituent group Good C ₆
A -C ₁₄ aryl group or 1 to 2 heteroatoms which may have 1 to 3 said substituents and which are the same or different and are selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. a 5-membered or 6-membered aromatic heterocyclic group [the group of substituents are halogen; C ₁ -C ₆ alkyl; halogen or C ₁ -C C ₁ -C ₆ substituted with ₆ alkoxy alkyl; C _1- C ₆ alkoxy; C which may be the same or different and which may have 1 to 3 substituents selected from the following groups:
_6- C ₁₄ aryl (the group of the substituent is halogen, C ₁
-C is a ₆ alkyl or C ₁ -C ₆ alkoxy. ); Cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C ₁ -C ₆ alkyl) carbamoyl. ], R ² is a hydrogen atom, a halogen atom, C ₁ -C ₆
Alkyl group, a C ₂ -C ₆ alkenyl group or C ₂ -C ₆ alkynyl group, R ³ is amino group, X is an oxygen atom, and n is 2, is (20) R ¹ ,
1 to 3 which are the same or different and are selected from the following substituent groups
C ₆ -C ₁₄ aryl groups optionally having 1 substituent or 1
A 5- to 6-membered aromatic having 1 to 2 heteroatoms, which may be the same as or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and which may have 1 to 2 of the above substituents. A heterocyclic group [the group of the substituents is halogen, C
_1- C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,
2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, Methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ], R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, an isopropenyl group, a 2-butenyl group or a propargyl group, R ³ is an amino group, and X is oxygen. a atom, and n is 2, (21) R ¹ is, same or different following 1 selected from substituent group which may have a three substituents phenyl group, or 1 to 2 A furyl group, a thienyl group or a pyridyl group, which may have one of the above substituents [the group of the substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl. , Methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. ], R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, an isopropenyl group, a 2-butenyl group or a propargyl group, and R ³
Is an amino group, X is an oxygen atom, and n is 2, (22) R ¹ has 1 or 2 substituents which are the same or different and are selected from the following substituent groups. A phenyl group or a furyl group, a thienyl group or a pyridyl group which may have one of the substituents [the group of the substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy. is there. ], R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, R ³ is an amino group, X is an oxygen atom, and n is 2 A compound, (2
3) R ¹ is a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group, a methylphenyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group or a 3-thienyl group, and R ² is Hydrogen atom,
A compound which is a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, R ³ is an amino group, X is an oxygen atom, and n is 2.
(24) R ¹ is a phenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2-furyl group or a 2-thienyl group, and R ² is A hydrogen atom or an isopropyl group, R ³ is an amino group, X is an oxygen atom, and n is 2. With respect to the above, in the order of (18) to (24) Will increase the preferred ranking.

Representative compounds of the present invention include, for example, the compounds shown in the following table, but the present invention is not limited to these compounds. The abbreviations in the table are as follows. Ac: Acetyl All: Allyl Bn: Benzyl Bu: Butyl Bu ^i: isobutyl Bu ^s: secondary butyl Bu ^t: data - tert-butyl Bun (2): 2- butenyl Bz: Benzoyl Et: Ethyl Fur (2): 2- furyl Hex: Hexyl Imid (2): 2-Imidazolyl Inde (1): 1-Indenyl Isothiz (3): 3-Isothiazolyl Isox (3): 3-Isoxazolyl Me: Methyl Moc: Methoxycarbonyl Mor (4): 4-mol: 4-. Np (1): 1- naphthyl Np (2): 2- naphthyl Oxa (2): 2- oxazolyl Pen ^c (2): 2- cyclopentenyl Ph: phenyl Pip (1): 1- piperidyl Piz (1): 1-piperazinyl Pn: pe Chill Pn ^c: Cyclopentyl Pn ^i: isopentyl Pr: propyl Pr ^c: cyclopropyl Pr ^i: isopropyl Pre ^i: isopropenyl Prg: propargyl Pym (2): 2- pyrimidinyl Pyr (2): 2- pyridyl Pyr (3): 3-pyridyl Pyr (4): 4-pyridyl Pyrd (1): 1-pyrrolidinyl Pyrr (3): 3-pyrrolyl Pyz (2): 2-pyrazinyl Pyza (1): 1-pyrazolyl Pyzn (3): 3- Pyridazinyl Thi (2): 2-thienyl Thi (3): 3-thienyl Thiz (2): 2-thiazolyl

[0040]

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[0041]

[Table 1] Compound number R ¹ R ^Two R ^Three X n 1 Ph H NH _Two O 2 2 Ph H NH _Two O 3 3 Ph H NH _Two O 4 4 Ph F NH _Two O 2 5 Ph Cl NH _Two O 2 6 Ph Me NH _Two O 2 7 Ph Et NH _Two O 2 8 Ph Pr NH _Two O 2 9 Ph Pr ⁱ NH _Two O 2 10 Ph Bu NH _Two O 2 11 Ph Bu ⁱ NH _Two O 2 12 Ph Bu ^s NH _Two O 2 13 Ph Bu ^t NH _Two O 2 14 Ph CF _Three NH _Two O 2 15 Ph H NH _Two S 2 16 Ph H NH _Two S 3 17 Ph H NH _Two S 4 18 Ph F NH _Two S 2 19 Ph Cl NH _Two S 2 20 Ph Me NH _Two S 2 21 Ph Et NH _Two S 2 22 Ph Pr NH _Two S 2 23 Ph Pr ⁱ NH _Two S 2 24 Ph Bu NH _Two S 2 25 Ph H NHMe O 2 26 Ph H NHEt O 2 27 Ph HN (Me) _Two O 2 28 Ph H Pip (1) O 2 29 Ph H Mor (4) O 2 30 2-F-Ph H NH _Two O 2 31 2-F-Ph F NH _Two O 2 32 2-F-Ph Cl NH _Two O 2 33 2-F-Ph Me NH _Two O 2 34 2-F-Ph Et NH _Two O 2 35 2-F-Ph Pr NH _Two O 2 36 2-F-Ph Pr ⁱ NH _Two O 2 37 2-F-Ph Bu NH _Two O 2 38 2-F-Ph Bu ⁱ NH _Two O 2 39 2-F-Ph Bu ^s NH _Two O 2 40 2-F-Ph Bu ^t NH _Two O 2 41 2-F-Ph H NH _Two S 2 42 2-F-Ph F NH _Two S 2 43 2-F-Ph Cl NH _Two S 2 44 2-F-Ph Me NH _Two S 2 45 2-F-Ph Et NH _Two S 2 46 2-F-Ph Pr NH _Two S 2 47 2-F-Ph Pr ⁱ NH _Two S 2 48 3-F-Ph H NH _Two O 2 49 3-F-Ph F NH _Two O 2 50 3-F-Ph Cl NH _Two O 2 51 3-F-Ph Me NH _Two O 2 52 3-F-Ph Et NH _Two O 2 53 3-F-Ph Pr NH _Two O 2 54 3-F-Ph Pr ⁱ NH _Two O 2 55 3-F-Ph Bu NH _Two O 2 56 3-F-Ph Bu ⁱ NH _Two O 2 57 3-F-Ph Bu ^s NH _Two O 2 58 3-F-Ph Bu ^t NH _Two O 2 59 3-F-Ph H NH _Two S 2 60 3-F-Ph F NH _Two S 2 61 3-F-Ph Cl NH _Two S 2 62 3-F-Ph Me NH _Two S 2 63 3-F-Ph Et NH _Two S 2 64 3-F-Ph Pr NH _Two S 2 65 3-F-Ph Pr ⁱ NH _Two S 2 66 4-F-Ph H NH _Two O 2 67 4-F-Ph H NH _Two O 3 68 4-F-Ph H NH _Two O 4 69 4-F-Ph F NH _Two O 2 70 4-F-Ph Cl NH _Two O 2 71 4-F-Ph Me NH _Two O 2 72 4-F-Ph Et NH _Two O 2 73 4-F-Ph Pr NH _Two O 2 74 4-F-Ph Pr ⁱ NH _Two O 2 75 4-F-Ph Bu NH _Two O 2 76 4-F-Ph Bu ⁱ NH _Two O 2 77 4-F-Ph Bu ^s NH _Two O 2 78 4-F-Ph Bu ^t NH _Two O 2 79 4-F-Ph H NH _Two S 2 80 4-F-Ph H NH _Two S 3 81 4-F-Ph H NH _Two S 4 82 4-F-Ph F NH _Two S 2 83 4-F-Ph Cl NH _Two S 2 84 4-F-Ph Me NH _Two S 2 85 4-F-Ph Et NH _Two S 2 86 4-F-Ph Pr NH _Two S 2 87 4-F-Ph Pr ⁱ NH _Two S 2 88 4-F-Ph H NHMe O 2 89 4-F-Ph H NHEt O 2 90 4-F-Ph HN (Me) _Two O 2 91 4-F-Ph H Pip (1) O 2 92 4-F-Ph H Mor (4) O 2 93 2,4-diF-Ph H NH _Two O 2 94 2,4-diF-Ph F NH _Two O 2 95 2,4-diF-Ph Cl NH _Two O 2 96 2,4-diF-Ph Me NH _Two O 2 97 2,4-diF-Ph Et NH _Two O 2 98 2,4-diF-Ph Pr NH _Two O 2 99 2,4-diF-Ph Pr ⁱ NH _Two O 2 100 2,4-diF-Ph Bu NH _Two O 2 101 2,4-diF-Ph Bu ⁱ NH _Two O 2 102 2,4-diF-Ph Bu ^s NH _Two O 2 103 2,4-diF-Ph Bu ^t NH _Two O 2 104 2,4-diF-Ph H NH _Two S 2 105 2,4-diF-Ph F NH _Two S 2 106 2,4-diF-Ph Cl NH _Two S 2 107 2,4-diF-Ph Me NH _Two S 2 108 2,4-diF-Ph Et NH _Two S 2 109 2,4-diF-Ph Pr NH _Two S 2 110 2,4-diF-Ph Pr ⁱ NH _Two S 2 111 2-Cl-Ph H NH _Two O 2 112 2-Cl-Ph F NH _Two O 2 113 2-Cl-Ph Cl NH _Two O 2 114 2-Cl-Ph Me NH _Two O 2 115 2-Cl-Ph Et NH _Two O 2 116 2-Cl-Ph Pr NH _Two O 2 117 2-Cl-Ph Pr ⁱ NH _Two O 2 118 2-Cl-Ph H NH _Two S 2 119 2-Cl-Ph F NH _Two S 2 120 2-Cl-Ph Cl NH _Two S 2 121 2-Cl-Ph Me NH _Two S 2 122 2-Cl-Ph Et NH _Two S 2 123 2-Cl-Ph Pr NH _Two S 2 124 2-Cl-Ph Pr ⁱ NH _Two S 2 125 3-Cl-Ph H NH _Two O 2 126 3-Cl-Ph F NH _Two O 2 127 3-Cl-Ph Cl NH _Two O 2 128 3-Cl-Ph Me NH _Two O 2 129 3-Cl-Ph Et NH _Two O 2 130 3-Cl-Ph Pr NH _Two O 2 131 3-Cl-Ph Pr ⁱ NH _Two O 2 132 3-Cl-Ph Bu NH _Two O 2 133 3-Cl-Ph Bu ⁱ NH _Two O 2 134 3-Cl-Ph Bu ^s NH _Two O 2 135 3-Cl-Ph Bu ^t NH _Two O 2 136 3-Cl-Ph H NH _Two S 2 137 3-Cl-Ph F NH _Two S 2 138 3-Cl-Ph Cl NH _Two S 2 139 3-Cl-Ph Me NH _Two S 2 140 3-Cl-Ph Et NH _Two S 2 141 3-Cl-Ph Pr NH _Two S 2 142 3-Cl-Ph Pr ⁱ NH _Two S 2 143 4-Cl-Ph H NH _Two O 2 144 4-Cl-Ph H NH _Two O 3 145 4-Cl-Ph H NH _Two O 4 146 4-Cl-Ph F NH _Two O 2 147 4-Cl-Ph Cl NH _Two O 2 148 4-Cl-Ph Me NH _Two O 2 149 4-Cl-Ph Et NH _Two O 2 150 4-Cl-Ph Pr NH _Two O 2 151 4-Cl-Ph Pr ⁱ NH _Two O 2 152 4-Cl-Ph Bu NH _Two O 2 153 4-Cl-Ph Bu ⁱ NH _Two O 2 154 4-Cl-Ph Bu ^s NH _Two O 2 155 4-Cl-Ph Bu ^t NH _Two O 2 156 4-Cl-Ph H NH _Two S 2 157 4-Cl-Ph H NH _Two S 3 158 4-Cl-Ph H NH _Two S 4 159 4-Cl-Ph F NH _Two S 2 160 4-Cl-Ph Cl NH _Two S 2 161 4-Cl-Ph Me NH _Two S 2 162 4-Cl-Ph Et NH _Two S 2 163 4-Cl-Ph Pr NH _Two S 2 164 4-Cl-Ph Pr ⁱ NH _Two S 2 165 4-Cl-Ph H NHMe O 2 166 4-Cl-Ph H NHEt O 2 167 4-Cl-Ph HN (Me) _Two O 2 168 4-Cl-Ph H Pip (1) O 2 169 4-Cl-Ph H Mor (4) O 2 170 2,4-diCl-Ph H NH _Two O 2 171 2,4-diCl-Ph F NH _Two O 2 172 2,4-diCl-Ph Cl NH _Two O 2 173 2,4-diCl-Ph Me NH _Two O 2 174 2,4-diCl-Ph Et NH _Two O 2 175 2,4-diCl-Ph Pr NH _Two O 2 176 2,4-diCl-Ph Pr ⁱ NH _Two O 2 177 2,4-diCl-Ph Bu NH _Two O 2 178 2,4-diCl-Ph Bu ⁱ NH _Two O 2 179 2,4-diCl-Ph Bu ^s NH _Two O 2 180 2,4-diCl-Ph Bu ^t NH _Two O 2 181 2,4-diCl-Ph H NH _Two S 2 182 2,4-diCl-Ph F NH _Two S 2 183 2,4-diCl-Ph Cl NH _Two S 2 184 2,4-diCl-Ph Me NH _Two S 2 185 2,4-diCl-Ph Et NH _Two S 2 186 2,4-diCl-Ph Pr NH _Two S 2 187 2,4-diCl-Ph Pr ⁱ NH _Two S 2 188 2,6-diCl-Ph H NH _Two O 2 189 2,6-diCl-Ph F NH _Two O 2 190 2,6-diCl-Ph Cl NH _Two O 2 191 2,6-diCl-Ph Me NH _Two O 2 192 2,6-diCl-Ph Et NH _Two O 2 193 2,6-diCl-Ph Pr NH _Two O 2 194 2,6-diCl-Ph Pr ⁱ NH _Two O 2 195 2,6-diCl-Ph Bu NH _Two O 2 196 2,6-diCl-Ph Bu ⁱ NH _Two O 2 197 2,6-diCl-Ph Bu ^s NH _Two O 2 198 2,6-diCl-Ph Bu ^t NH _Two O 2 199 2,6-diCl-Ph H NH _Two S 2 200 2,6-diCl-Ph F NH _Two S 2 201 2,6-diCl-Ph Cl NH _Two S 2 202 2,6-diCl-Ph Me NH _Two S 2 203 2,6-diCl-Ph Et NH _Two S 2 204 2,6-diCl-Ph Pr NH _Two S 2 205 2,6-diCl-Ph Pr ⁱ NH _Two S 2 206 3,5-diCl-Ph H NH _Two O 2 207 3,5-diCl-Ph F NH _Two O 2 208 3,5-diCl-Ph Cl NH _Two O 2 209 3,5-diCl-Ph Me NH _Two O 2 210 3,5-diCl-Ph Et NH _Two O 2 211 3,5-diCl-Ph Pr NH _Two O 2 212 3,5-diCl-Ph Pr ⁱ NH _Two O 2 213 3,5-diCl-Ph Bu NH _Two O 2 214 3,5-diCl-Ph Bu ⁱ NH _Two O 2 215 3,5-diCl-Ph Bu ^s NH _Two O 2 216 3,5-diCl-Ph Bu ^t NH _Two O 2 217 3,5-diCl-Ph H NH _Two S 2 218 3,5-diCl-Ph F NH _Two S 2 219 3,5-diCl-Ph Cl NH _Two S 2 220 3,5-diCl-Ph Me NH _Two S 2 221 3,5-diCl-Ph Et NH _Two S 2 222 3,5-diCl-Ph Pr NH _Two S 2 223 3,5-diCl-Ph Pr ⁱ NH _Two S 2 224 2-Me-Ph H NH _Two O 2 225 2-Me-Ph F NH _Two O 2 226 2-Me-Ph Cl NH _Two O 2 227 2-Me-Ph Me NH _Two O 2 228 2-Me-Ph Et NH _Two O 2 229 2-Me-Ph Pr NH _Two O 2 230 2-Me-Ph Pr ⁱ NH _Two O 2 231 2-Me-Ph Bu NH _Two O 2 232 2-Me-Ph Bu ⁱ NH _Two O 2 233 2-Me-Ph Bu ^s NH _Two O 2 234 2-Me-Ph Bu ^t NH _Two O 2 235 2-Me-Ph H NH _Two S 2 236 2-Me-Ph F NH _Two S 2 237 2-Me-Ph Cl NH _Two S 2 238 2-Me-Ph Me NH _Two S 2 239 2-Me-Ph Et NH _Two S 2 240 2-Me-Ph Pr NH _Two S 2 241 2-Me-Ph Pr ⁱ NH _Two S 2 242 3-Me-Ph H NH _Two O 2 243 3-Me-Ph F NH _Two O 2 244 3-Me-Ph Cl NH _Two O 2 245 3-Me-Ph Me NH _Two O 2 246 3-Me-Ph Et NH _Two O 2 247 3-Me-Ph Pr NH _Two O 2 248 3-Me-Ph Pr ⁱ NH _Two O 2 249 3-Me-Ph Bu NH _Two O 2 250 3-Me-Ph Bu ⁱ NH _Two O 2 251 3-Me-Ph Bu ^s NH _Two O 2 252 3-Me-Ph Bu ^t NH _Two O 2 253 3-Me-Ph H NH _Two S 2 254 3-Me-Ph F NH _Two S 2 255 3-Me-Ph Cl NH _Two S 2 256 3-Me-Ph Me NH _Two S 2 257 3-Me-Ph Et NH _Two S 2 258 3-Me-Ph Pr NH _Two S 2 259 3-Me-Ph Pr ⁱ NH _Two S 2 260 4-Me-Ph H NH _Two O 2 261 4-Me-Ph F NH _Two O 2 262 4-Me-Ph Cl NH _Two O 2 263 4-Me-Ph Me NH _Two O 2 264 4-Me-Ph Et NH _Two O 2 265 4-Me-Ph Pr NH _Two O 2 266 4-Me-Ph Pr ⁱ NH _Two O 2 267 4-Me-Ph Bu NH _Two O 2 268 4-Me-Ph Bu ⁱ NH _Two O 2 269 4-Me-Ph Bu ^s NH _Two O 2 270 4-Me-Ph Bu ^t NH _Two O 2 271 4-Me-Ph H NH _Two S 2 272 4-Me-Ph F NH _Two S 2 273 4-Me-Ph Cl NH _Two S 2 274 4-Me-Ph Me NH _Two S 2 275 4-Me-Ph Et NH _Two S 2 276 4-Me-Ph Pr NH _Two S 2 277 4-Me-Ph Pr ⁱ NH _Two S 2 278 4-Et-Ph H NH _Two O 2 279 4-Et-Ph F NH _Two O 2 280 4-Et-Ph Cl NH _Two O 2 281 4-Et-Ph Me NH _Two O
2 282 4-Et-Ph Et NH _Two O 2 283 4-Et-Ph Pr NH _Two O 2 284 4-Et-Ph Pr ⁱ NH _Two O 2 285 4-Et-Ph Bu NH _Two O 2 286 4-Et-Ph Bu ⁱ NH _Two O 2 287 4-Et-Ph Bu ^s NH _Two O 2 288 4-Et-Ph Bu ^t NH _Two O 2 289 4-Et-Ph H NH _Two S 2 290 4-Et-Ph F NH _Two S 2 291 4-Et-Ph Cl NH _Two S 2 292 4-Et-Ph Me NH _Two S 2 293 4-Et-Ph Et NH _Two S 2 294 4-Et-Ph Pr NH _Two S 2 295 4-Et-Ph Pr ⁱ NH _Two S 2 296 2-CF _Three -Ph H NH _Two O 2 297 2-CF _Three -Ph F NH _Two O 2 298 2-CF _Three -Ph Cl NH _Two O 2 299 2-CF _Three -Ph Me NH _Two O 2 300 2-CF _Three -Ph Et NH _Two O 2 301 2-CF _Three -Ph Pr NH _Two O 2 302 2-CF _Three -Ph Pr ⁱ NH _Two O 2 303 2-CF _Three -Ph Bu NH _Two O 2 304 2-CF _Three -Ph Bu ⁱ NH _Two O 2 305 2-CF _Three -Ph Bu ^s NH _Two O 2 306 2-CF _Three -Ph Bu ^t NH _Two O 2 307 2-CF _Three -Ph H NH _Two S 2 308 2-CF _Three -Ph F NH _Two S 2 309 2-CF _Three -Ph Cl NH _Two S 2 310 2-CF _Three -Ph Me NH _Two S 2 311 2-CF _Three -Ph Et NH _Two S 2312 2-CF _Three -Ph Pr NH _Two S 2 313 2-CF _Three -Ph Pr ⁱ NH _Two S 2 314 3-CF _Three -Ph H NH _Two O 2 315 3-CF _Three -Ph F NH _Two O 2 316 3-CF _Three -Ph Cl NH _Two O 2 317 3-CF _Three -Ph Me NH _Two O 2 318 3-CF _Three -Ph Et NH _Two O 2 319 3-CF _Three -Ph Pr NH _Two O 2 320 3-CF _Three -Ph Pr ⁱ NH _Two O 2 321 3-CF _Three -Ph Bu NH _Two O 2 322 3-CF _Three -Ph Bu ⁱ NH _Two O 2 323 3-CF _Three -Ph Bu ^s NH _Two O 2 324 3-CF _Three -Ph Bu ^t NH _Two O 2 325 3-CF _Three -Ph H NH _Two S 2 326 3-CF _Three -Ph F NH _Two S 2 327 3-CF _Three -Ph Cl NH _Two S 2 328 3-CF _Three -Ph Me NH _Two S 2 329 3-CF _Three -Ph Et NH _Two S 2 330 3-CF _Three -Ph Pr NH _Two S 2 331 3-CF _Three -Ph Pr ⁱ NH _Two S 2 332 4-CF _Three -Ph H NH _Two O 2 333 4-CF _Three -Ph F NH _Two O 2 334 4-CF _Three -Ph Cl NH _Two O 2 335 4-CF _Three -Ph Me NH _Two O 2 336 4-CF _Three -Ph Et NH _Two O 2 337 4-CF _Three -Ph Pr NH _Two O 2 338 4-CF _Three -Ph Pr ⁱ NH _Two O 2 339 4-CF _Three -Ph Bu NH _Two O
2 340 4-CF _Three -Ph Bu ⁱ NH _Two O 2 341 4-CF _Three -Ph Bu ^s NH _Two O 2 342 4-CF _Three -Ph Bu ^t NH _Two O 2 343 4-CF _Three -Ph H NH _Two S 2 344 4-CF _Three -Ph F NH _Two S 2 345 4-CF _Three -Ph Cl NH _Two S 2 346 4-CF _Three -Ph Me NH _Two S 2 347 4-CF _Three -Ph Et NH _Two S 2 348 4-CF _Three -Ph Pr NH _Two S 2 349 4-CF _Three -Ph Pr ⁱ NH _Two S 2 350 4-MeO-Ph H NH _Two O 2 351 4-MeO-Ph F NH _Two O 2 352 4-MeO-Ph Cl NH _Two O 2 353 4-MeO-Ph Me NH _Two O 2 354 4-MeO-Ph Et NH _Two O 2 355 4-MeO-Ph Pr NH _Two O 2 356 4-MeO-Ph Pr ⁱ NH _Two O 2 357 2-MeO-Ph H NH _Two O 2 358 2-MeO-Ph F NH _Two O 2 359 2-MeO-Ph Cl NH _Two O 2 360 2-MeO-Ph Me NH _Two O 2 361 2-MeO-Ph Et NH _Two O 2 362 2-MeO-Ph Pr ⁱ NH _Two O 2 363 3-MeO-Ph H NH _Two O 2 364 3-MeO-Ph Cl NH _Two O 2 365 3-MeO-Ph Me NH _Two O 2 366 3-MeO-Ph Et NH _Two O 2 367 3-MeO-Ph Pr ⁱ NH _Two O 2 368 4-Ph-Ph H NH _Two O 2 369 4-Ph-Ph F NH _Two O 2 370 4-Ph-Ph Cl NH _Two O 2 371 4-Ph-Ph Me NH _Two O 2 372 4-Ph-Ph Et NH _Two O 2 373 4-Ph-Ph Pr NH _Two O 2 374 4-Ph-Ph Pr ⁱ NH _Two O 2 375 4-Ph-Ph Bu NH _Two O 2 376 4-Ph-Ph Bu ⁱ NH _Two O 2 377 4-Ph-Ph Bu ^s NH _Two O 2 378 4-Ph-Ph Bu ^t NH _Two O 2 379 2-Ph-Ph H NH _Two S 2 380 3-Ph-Ph F NH _Two S 2 381 4-Ph-Ph Cl NH _Two S 2 382 2-Ph-Ph Me NH _Two S 2 383 2-Ph-Ph Et NH _Two S 2 384 2-Ph-Ph Pr NH _Two S 2 385 3-Ph-Ph Pr ⁱ NH _Two S 2 386 4-CN-Ph H NH _Two O 2 387 4-CN-Ph F NH _Two O 2 388 4-CN-Ph Cl NH _Two O 2 389 4-CN-Ph Me NH _Two O 2 390 4-CN-Ph Et NH _Two O 2 391 4-CN-Ph Pr NH _Two O 2 392 4-CN-Ph Pr ⁱ NH _Two O 2 393 4-CN-Ph Bu NH _Two O 2 394 4-CN-Ph Bu ⁱ NH _Two O 2 395 4-CN-Ph Bu ^s NH _Two O 2 396 4-CN-Ph Bu ^t NH _Two O 2 397 4-MeOCO-Ph H NH _Two O 2 398 4-MeOCO-Ph F NH _Two O 2 399 4-MeOCO-Ph Cl NH _Two O 2 400 4-MeOCO-Ph Me NH _Two O 2 401 4-MeOCO-Ph Et NH _Two O 2 402 4-MeOCO-Ph Pr NH _Two O 2 403 4-MeOCO-Ph Pr ⁱ NH _Two O 2 404 4-MeOCO-Ph Bu NH _Two O 2 405 4-MeOCO-Ph Bu ⁱ NH _Two O 2 406 4-MeOCO-Ph Bu ^s NH _Two O 2 407 4-MeOCO-Ph Bu ^t NH _Two O 2 408 2-MeOCO-Ph H NH _Two S 2 409 3-MeOCO-Ph F NH _Two S 2 410 4-MeOCO-Ph Cl NH _Two S 2 411 2-MeOCO-Ph Me NH _Two S 2 412 2-MeOCO-Ph Et NH _Two S 2 413 2-MeOCO-Ph Pr NH _Two S 2 414 3-MeOCO-Ph Pr ⁱ NH _Two S 2 415 4-H _Two NCO-Ph H NH _Two O 2 416 4-H _Two NCO-Ph F NH _Two O 2 417 4-H _Two NCO-Ph Cl NH _Two O 2 418 4-H _Two NCO-Ph Me NH _Two O 2 419 4-H _Two NCO-Ph Et NH _Two O 2 420 4-H _Two NCO-Ph Pr NH _Two O 2 421 4-H _Two NCO-Ph Pr ⁱ NH _Two O 2 422 4-H _Two NCO-Ph Bu NH _Two O 2 423 4-H _Two NCO-Ph Bu ⁱ NH _Two O 2 424 4-H _Two NCO-Ph Bu ^s NH _Two O 2 425 4-H _Two NCO-Ph Bu ^t NH _Two O 2 426 2-H _Two NCO-Ph H NH _Two S 2 427 3-H _Two NCO-Ph F NH _Two S 2 428 4-H _Two NCO-Ph Cl NH _Two S 2 429 2-H _Two NCO-Ph Me NH _Two S 2 430 2-H _Two NCO-Ph Et NH _Two S 2 431 2-H _Two NCO-Ph Pr NH _Two S 2 432 3-H _Two NCO-Ph Pr ⁱ NH _Two S 2 433 4-MeNHCO-Ph H NH _Two O 2 434 4-MeNHCO-Ph F NH _Two O 2 435 4-MeNHCO-Ph Cl NH _Two O 2 436 4-MeNHCO-Ph Me NH _Two O 2 437 4-MeNHCO-Ph Et NH _Two O 2 438 4-MeNHCO-Ph Pr NH _Two O 2 439 4-MeNHCO-Ph Pr ⁱ NH _Two O 2 440 4-MeNHCO-Ph Bu NH _Two O 2 441 4-MeNHCO-Ph Bu ⁱ NH _Two O 2 442 4-MeNHCO-Ph Bu ^s NH _Two O 2 443 4-MeNHCO-Ph Bu ^t NH _Two O 2 444 2-MeNHCO-Ph H NH _Two S 2 445 3-MeNHCO-Ph F NH _Two S 2 446 4-MeNHCO-Ph Cl NH _Two S 2 447 2-MeNHCO-Ph Me NH _Two S 2 448 2-MeNHCO-Ph Et NH _Two S 2 449 2-MeNHCO-Ph Pr NH _Two S 2 450 3-MeNHCO-Ph Pr ⁱ NH _Two S 2 451 4- (Me) _Two NCO-Ph H NH _Two O 2 452 4- (Me) _Two NCO-Ph F NH _Two O 2 453 4- (Me) _Two NCO-Ph Cl NH _Two O 2 454 4- (Me) _Two NCO-Ph Me NH _Two O 2 455 4- (Me) _Two NCO-Ph Et NH _Two O 2 456 4- (Me) _Two NCO-Ph Pr NH _Two O 2 457 4- (Me) _Two NCO-Ph Pr ⁱ NH _Two O 2 458 4- (Me) _Two NCO-Ph Bu NH _Two O 2 459 4- (Me) _Two NCO-Ph Bu ⁱ NH _Two O 2 460 4- (Me) _Two NCO-Ph Bu ^s NH _Two O 2 461 4- (Me) _Two NCO-Ph Bu ^t NH _Two O 2 462 2- (Me) _Two NCO-Ph H NH _Two S 2 463 3- (Me) _Two NCO-Ph F NH _Two S 2 464 4- (Me) _Two NCO-Ph Cl NH _Two S 2 465 2- (Me) _Two NCO-Ph Me NH _Two S 2 466 2- (Me) _Two NCO-Ph Et NH _Two S 2 467 2- (Me) _Two NCO-Ph Pr NH _Two S 2 468 3- (Me) _Two NCO-Ph Pr ⁱ NH _Two S 2 (Continued from Table 1) Compound number R ¹ R ^Two R ^Three X n 469 Inde (1) H NH _Two O 2 470 Inde (1) Cl NH _Two O 2 471 Inde (1) Me NH _Two O 2 472 Inde (1) Et NH _Two O 2 473 Inde (1) Pr NH _Two O 2 474 Inde (1) Pr ⁱ NH _Two O 2 475 Np (1) H NH _Two O 2 476 Np (1) Cl NH _Two O 2 477 Np (1) Me NH _Two O 2 478 Np (1) Et NH _Two O 2 479 Np (1) Pr NH _Two O 2 480 Np (1) Pr ⁱ NH _Two O
2 481 Np (2) H NH _Two O 2 482 Np (2) Cl NH _Two O 2 483 Np (2) Me NH _Two O 2 484 Np (2) Et NH _Two O 2 485 Np (2) Pr NH _Two O 2 486 Np (2) Pr ⁱ NH _Two O 2 487 Pyrr (3) H NH _Two O 2 488 Pyrr (3) Cl NH _Two O 2 489 Pyrr (3) Me NH _Two O 2 490 Pyrr (3) Et NH _Two O 2 491 Pyrr (3) Pr NH _Two O 2 492 Pyrr (3) Pr ⁱ NH _Two O 2 493 Imid (2) H NH _Two O 2 494 Imid (2) Cl NH _Two O 2 495 Imid (2) Me NH _Two O 2 496 Imid (2) Et NH _Two O 2 497 Imid (2) Pr NH _Two O 2 498 Imid (2) Pr ⁱ NH _Two O 2 499 Pyza (1) H NH _Two O 2 500 Pyza (1) Cl NH _Two O 2 501 Pyza (1) Me NH _Two O 2 502 Pyza (1) Et NH _Two O 2 503 Pyza (1) Pr NH _Two O 2 504 Pyza (1) Pr ⁱ NH _Two O 2 505 Fur (2) H NH _Two O 2 506 Fur (2) Cl NH _Two O 2 507 Fur (2) Me NH _Two O 2 509 Fur (2) Pr NH _Two O
2 510 Fur (2) Pr ⁱ NH _Two O 2 511 Oxa (2) H NH _Two O 2 512 Oxa (2) Cl NH _Two O 2 513 Oxa (2) Me NH _Two O 2 514 Oxa (2) Et NH _Two O 2 515 Oxa (2) Pr NH _Two O 2 516 Oxa (2) Pr ⁱ NH _Two O 2 517 Isox (3) H NH _Two O 2 518 Isox (3) Cl NH _Two O 2 519 Isox (3) Me NH _Two O 2 520 Isox (3) Et NH _Two O 2 521 Isox (3) Pr NH _Two O 2 522 Isox (3) Pr ⁱ NH _Two O 2 523 Thiz (2) H NH _Two O 2 524 Thiz (2) Cl NH _Two O 2 525 Thiz (2) Me NH _Two O 2 526 Thiz (2) Et NH _Two O 2 527 Thiz (2) Pr NH _Two O 2 528 Thiz (2) Pr ⁱ NH _Two O 2 529 Isothiz (3) H NH _Two O 2 530 Isothiz (3) Cl NH _Two O 2 531 Isothiz (3) Me NH _Two O 2 532 Isothiz (3) Et NH _Two O 2 533 Isothiz (3) Pr NH _Two O 2 534 Isothiz (3) Pr ⁱ NH _Two O 2 535 Thi (2) H NH _Two O 2 536 Thi (2) H NH _Two O 3 537 Thi (2) H NH _Two O 4 538 Thi (2) F NH _Two O 2 539 Thi (2) Cl NH _Two O 2 540 Thi (2) Me NH _Two O 2 541 Thi (2) Et NH _Two O 2 542 Thi (2) Pr NH _Two O 2 543 Thi (2) Pr ⁱ NH _Two O 2 544 Thi (2) Bu NH _Two O 2 545 Thi (2) Bu ⁱ NH _Two O 2 546 Thi (2) Bu ^s NH _Two O 2 547 Thi (2) Bu ^t NH _Two O 2 548 Thi (2) H NH _Two S 2 549 Thi (2) H NH _Two S 3 550 Thi (2) H NH _Two S 4 551 Thi (2) F NH _Two S 2 552 Thi (2) Cl NH _Two S 2 553 Thi (2) Me NH _Two S 2 554 Thi (2) Et NH _Two S 2 555 Thi (2) Pr NH _Two S 2 556 Thi (2) Pr ⁱ NH _Two S 2 557 Thi (2) H NHMe O 2 558 Thi (2) H NHEt O 2 559 Thi (2) HN (Me) _Two O 2 560 Thi (2) H Pip (1) O 2 561 Thi (2) H Mor (4) O 2 562 3-F-Thi (2) H NH _Two O 2 563 3-F-Thi (2) Cl NH _Two O 2 564 3-F-Thi (2) Me NH _Two O 2 565 3-F-Thi (2) Et NH _Two O 2 566 3-F-Thi (2) Pr NH _Two O 2 567 3-F-Thi (2) Pr ⁱ NH _Two O 2 568 4-F-Thi (2) H NH _Two O 2 569 4-F-Thi (2) Cl NH _Two O 2 570 4-F-Thi (2) Me NH _Two O 2 571 4-F-Thi (2) Et NH _Two O 2 572 4-F-Thi (2) Pr NH _Two O 2 573 4-F-Thi (2) Pr ⁱ NH _Two O 2 574 5-F-Thi (2) H NH _Two O 2 575 5-F-Thi (2) Cl NH _Two O 2 576 5-F-Thi (2) Me NH _Two O 2 577 5-F-Thi (2) Et NH _Two O 2 578 5-F-Thi (2) Pr NH _Two O 2 579 5-F-Thi (2) Pr ⁱ NH _Two O 2 580 3-Cl-Thi (2) H NH _Two O 2 581 3-Cl-Thi (2) Cl NH _Two O 2 582 3-Cl-Thi (2) Me NH _Two O 2 583 3-Cl-Thi (2) Et NH _Two O 2 584 3-Cl-Thi (2) Pr NH _Two O 2 585 3-Cl-Thi (2) Pr ⁱ NH _Two O 2 586 4-Cl-Thi (2) H NH _Two O 2 587 4-Cl-Thi (2) Cl NH _Two O 2 588 4-Cl-Thi (2) Me NH _Two O 2 589 4-Cl-Thi (2) Et NH _Two O 2 590 4-Cl-Thi (2) Pr NH _Two O 2 591 4-Cl-Thi (2) Pr ⁱ NH _Two O 2 592 5-Cl-Thi (2) H NH _Two O 2 593 5-Cl-Thi (2) Cl NH _Two O 2 594 5-Cl-Thi (2) Me NH _Two O 2 596 5-Cl-Thi (2) Pr NH _Two O
2 597 5-Cl-Thi (2) Pr ⁱ NH _Two O 2 598 3-Br-Thi (2) H NH _Two O 2 599 3-Br-Thi (2) Cl NH _Two O 2 600 3-Br-Thi (2) Me NH _Two O 2 601 3-Br-Thi (2) Et NH _Two O 2 602 3-Br-Thi (2) Pr NH _Two O 2 603 3-Br-Thi (2) Pr ⁱ NH _Two O 2 604 3-Me-Thi (2) H NH _Two O 2 605 3-Me-Thi (2) Cl NH _Two O 2 606 3-Me-Thi (2) Me NH _Two O 2 607 3-Me-Thi (2) Et NH _Two O 2 608 3-Me-Thi (2) Pr NH _Two O 2 609 3-Me-Thi (2) Pr ⁱ NH _Two O 2 610 4-Me-Thi (2) H NH _Two O 2 611 4-Me-Thi (2) Cl NH _Two O 2 612 4-Me-Thi (2) Me NH _Two O 2 613 4-Me-Thi (2) Et NH _Two O 2 614 4-Me-Thi (2) Pr NH _Two O 2 615 4-Me-Thi (2) Pr ⁱ NH _Two O 2 616 4-Et-Thi (2) H NH _Two O 2 617 4-Et-Thi (2) Cl NH _Two O 2 618 4-Et-Thi (2) Me NH _Two O 2 619 4-Et-Thi (2) Et NH _Two O 2 620 4-Et-Thi (2) Pr NH _Two O 2 621 4-Et-Thi (2) Pr ⁱ NH _Two O 2 622 4-CF _Three -Thi (2) H NH _Two O 2 623 4-CF _Three -Thi (2) Cl NH _Two O 2 625 4-CF _Three -Thi (2) Et NH _Two O
2 626 4-CF _Three -Thi (2) Pr NH _Two O 2 627 4-CF _Three -Thi (2) Pr ⁱ NH _Two O 2 628 4-MeO-Thi (2) H NH _Two O 2 629 4-MeO-Thi (2) Cl NH _Two O 2 630 4-MeO-Thi (2) Me NH _Two O 2 631 4-MeO-Thi (2) Et NH _Two O 2 632 4-MeO-Thi (2) Pr NH _Two O 2 633 4-MeO-Thi (2) Pr ⁱ NH _Two O 2 634 3-Ph-Thi (2) H NH _Two O 2 635 3-Ph-Thi (2) Cl NH _Two O 2 636 3-Ph-Thi (2) Me NH _Two O 2 637 3-Ph-Thi (2) Et NH _Two O 2 638 3-Ph-Thi (2) Pr NH _Two O 2 639 3-Ph-Thi (2) Pr ⁱ NH _Two O 2 640 4-Ph-Thi (2) H NH _Two O 2 641 4-Ph-Thi (2) Cl NH _Two O 2 642 4-Ph-Thi (2) Me NH _Two O 2 643 4-Ph-Thi (2) Et NH _Two O 2 644 4-Ph-Thi (2) Pr NH _Two O 2 645 4-Ph-Thi (2) Pr ⁱ NH _Two O 2 646 5-Ph-Thi (2) H NH _Two O 2 647 5-Ph-Thi (2) Cl NH _Two O 2 648 5-Ph-Thi (2) Me NH _Two O 2 649 5-Ph-Thi (2) Et NH _Two O 2 650 5-Ph-Thi (2) Pr NH _Two O 2 651 5-Ph-Thi (2) Pr ⁱ NH _Two O 2 652 3-MeOCO-Thi (2) H NH _Two O 2 653 3-MeOCO-Thi (2) Cl NH _Two O 2 654 3-MeOCO-Thi (2) Me NH _Two O 2 655 3-MeOCO-Thi (2) Et NH _Two O 2 656 3-MeOCO-Thi (2) Pr NH _Two O 2 657 3-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 658 4-MeOCO-Thi (2) H NH _Two O 2 659 4-MeOCO-Thi (2) Cl NH _Two O 2 660 4-MeOCO-Thi (2) Me NH _Two O 2 661 4-MeOCO-Thi (2) Et NH _Two O 2 662 4-MeOCO-Thi (2) Pr NH _Two O 2 663 4-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 664 5-MeOCO-Thi (2) H NH _Two O 2 665 5-MeOCO-Thi (2) Cl NH _Two O 2 666 5-MeOCO-Thi (2) Me NH _Two O 2 667 5-MeOCO-Thi (2) Et NH _Two O 2 668 5-MeOCO-Thi (2) Pr NH _Two O 2 669 5-MeOCO-Thi (2) Pr ⁱ NH _Two O 2 670 3-H _Two NCO-Thi (2) H NH _Two O 2 671 3-H _Two NCO-Thi (2) Cl NH _Two O 2 672 3-H _Two NCO-Thi (2) Me NH _Two O 2 673 3-H _Two NCO-Thi (2) Et NH _Two O 2 674 3-H _Two NCO-Thi (2) Pr NH _Two O 2 675 3-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 676 4-H _Two NCO-Thi (2) H NH _Two O 2 677 4-H _Two NCO-Thi (2) Cl NH _Two O 2 678 4-H _Two NCO-Thi (2) Me NH _Two O 2 679 4-H _Two NCO-Thi (2) Et NH _Two O 2 680 4-H _Two NCO-Thi (2) Pr NH _Two O 2 681 4-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 682 5-H _Two NCO-Thi (2) H NH _Two O 2 683 5-H _Two NCO-Thi (2) Cl NH _Two O 2 684 5-H _Two NCO-Thi (2) Me NH _Two O 2 685 5-H _Two NCO-Thi (2) Et NH _Two O 2 686 5-H _Two NCO-Thi (2) Pr NH _Two O 2 687 5-H _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 688 3-MeNHCO-Thi (2) H NH _Two O 2 689 3-MeNHCO-Thi (2) Cl NH _Two O 2 690 3-MeNHCO-Thi (2) Me NH _Two O 2 691 3-MeNHCO-Thi (2) Et NH _Two O 2 692 3-MeNHCO-Thi (2) Pr NH _Two O 2 693 3-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 694 4-MeNHCO-Thi (2) H NH _Two O 2 695 4-MeNHCO-Thi (2) Cl NH _Two O 2 696 4-MeNHCO-Thi (2) Me NH _Two O 2 697 4-MeNHCO-Thi (2) Et NH _Two O 2 698 4-MeNHCO-Thi (2) Pr NH _Two O 2 699 4-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 700 5-MeNHCO-Thi (2) H NH _Two O 2 701 5-MeNHCO-Thi (2) Cl NH _Two O 2 702 5-MeNHCO-Thi (2) Me NH _Two O 2 703 5-MeNHCO-Thi (2) Et NH _Two O 2 704 5-MeNHCO-Thi (2) Pr NH _Two O 2 705 5-MeNHCO-Thi (2) Pr ⁱ NH _Two O 2 706 3- (Me) _Two NCO-Thi (2) H NH _Two O 2 707 3- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 708 3- (Me) _Two NCO-Thi (2) Me NH _Two O 2 709 3- (Me) _Two NCO-Thi (2) Et NH _Two O 2 710 3- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 711 3- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 712 4- (Me) _Two NCO-Thi (2) H NH _Two O 2 713 4- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 714 4- (Me) _Two NCO-Thi (2) Me NH _Two O 2 715 4- (Me) _Two NCO-Thi (2) Et NH _Two O 2 716 4- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 717 4- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 718 5- (Me) _Two NCO-Thi (2) H NH _Two O 2 719 5- (Me) _Two NCO-Thi (2) Cl NH _Two O 2 720 5- (Me) _Two NCO-Thi (2) Me NH _Two O 2 721 5- (Me) _Two NCO-Thi (2) Et NH _Two O 2 722 5- (Me) _Two NCO-Thi (2) Pr NH _Two O 2 723 5- (Me) _Two NCO-Thi (2) Pr ⁱ NH _Two O 2 724 Thi (3) H NH _Two O 2 725 Thi (3) H NH _Two O 3 726 Thi (3) H NH _Two O 4 727 Thi (3) H NH _Two O 5 728 Thi (3) F NH _Two O 2 729 Thi (3) Cl NH _Two O 2 730 Thi (3) Me NH _Two O 2 731 Thi (3) Et NH _Two O 2 732 Thi (3) Pr NH _Two O 2 733 Thi (3) Pr ⁱ NH _Two O 2 734 Thi (3) Bu NH _Two O 2 735 Thi (3) Bu ⁱ NH _Two O 2 736 Thi (3) Bu ^s NH _Two O 2 737 Thi (3) Bu ^t NH _Two O 2 738 Thi (3) H NH _Two S 2 739 Thi (3) H NH _Two S 3 740 Thi (3) H NH _Two S 4 741 Thi (3) F NH _Two S 2 742 Thi (3) Cl NH _Two S 2 743 Thi (3) Me NH _Two S 2 744 Thi (3) Et NH _Two S 2 745 Thi (3) Pr NH _Two S 2 746 Thi (3) Pr ⁱ NH _Two S 2 747 Thi (3) H NHMe O 2 748 Thi (3) H NHEt O 2 749 Thi (3) HN (Me) _Two O 2 750 Thi (3) H Pip (1) O 2 751 Thi (3) H Mor (4) O 2 752 2-F-Thi (3) H NH _Two O 2 753 2-F-Thi (3) Cl NH _Two O 2 754 2-F-Thi (3) Me NH _Two O 2 755 2-F-Thi (3) Et NH _Two O 2 756 2-F-Thi (3) Pr NH _Two O 2 757 2-F-Thi (3) Pr ⁱ NH _Two O 2 758 2-F-Thi (3) H NH _Two S 2 759 2-F-Thi (3) Cl NH _Two S 2 760 2-F-Thi (3) Me NH _Two S 2 761 2-F-Thi (3) Et NH _Two S 2 762 2-F-Thi (3) Pr NH _Two S 2 763 2-F-Thi (3) Pr ⁱ NH _Two S 2 764 4-F-Thi (3) H NH _Two O 2 765 4-F-Thi (3) Cl NH _Two O 2 766 4-F-Thi (3) Me NH _Two O 2 767 4-F-Thi (3) Et NH _Two O 2 768 4-F-Thi (3) Pr NH _Two O 2 769 4-F-Thi (3) Pr ⁱ NH _Two O 2 770 4-F-Thi (3) H NH _Two S 2 771 4-F-Thi (3) Cl NH _Two S 2 772 4-F-Thi (3) Me NH _Two S 2 773 4-F-Thi (3) Et NH _Two S 2 774 4-F-Thi (3) Pr NH _Two S 2 775 4-F-Thi (3) Pr ⁱ NH _Two S 2 776 5-F-Thi (3) H NH _Two O 2 777 5-F-Thi (3) Cl NH _Two O 2 778 5-F-Thi (3) Me NH _Two O 2 779 5-F-Thi (3) Et NH _Two O 2 780 5-F-Thi (3) Pr NH _Two O 2 781 5-F-Thi (3) Pr ⁱ NH _Two O 2 782 5-F-Thi (3) H NH _Two S 2 783 5-F-Thi (3) Cl NH _Two S 2 784 5-F-Thi (3) Me NH _Two S 2 785 5-F-Thi (3) Et NH _Two S 2 786 5-F-Thi (3) Pr NH _Two S 2 787 5-F-Thi (3) Pr ⁱ NH _Two S 2 788 2-Cl-Thi (3) H NH _Two O 2 789 2-Cl-Thi (3) Cl NH _Two O 2 790 2-Cl-Thi (3) Me NH _Two O 2 791 2-Cl-Thi (3) Et NH _Two O 2 792 2-Cl-Thi (3) Pr NH _Two O 2 793 2-Cl-Thi (3) Pr ⁱ NH _Two O 2 794 4-Cl-Thi (3) H NH _Two O 2 795 4-Cl-Thi (3) Cl NH _Two O 2 796 4-Cl-Thi (3) Me NH _Two O 2 797 4-Cl-Thi (3) Et NH _Two O 2 798 4-Cl-Thi (3) Pr NH _Two O 2 799 4-Cl-Thi (3) Pr ⁱ NH _Two O 2 800 5-Cl-Thi (3) H NH _Two O 2 801 5-Cl-Thi (3) Cl NH _Two O 2 802 5-Cl-Thi (3) Me NH _Two O 2 803 5-Cl-Thi (3) Et NH _Two O 2 804 5-Cl-Thi (3) Pr NH _Two O 2 805 5-Cl-Thi (3) Pr ⁱ NH _Two O 2 806 4-Me-Thi (3) H NH _Two O 2 807 4-Me-Thi (3) Cl NH _Two O 2 808 4-Me-Thi (3) Me NH _Two O 2 809 4-Me-Thi (3) Et NH _Two O 2 810 4-Me-Thi (3) Pr NH _Two O 2 811 4-Me-Thi (3) Pr ⁱ NH _Two O 2 812 4-Et-Thi (3) H NH _Two O 2 813 4-Et-Thi (3) Cl NH _Two O 2 814 4-Et-Thi (3) Me NH _Two O 2 815 4-Et-Thi (3) Et NH _Two O 2 816 4-Et-Thi (3) Pr NH _Two O 2 817 4-Et-Thi (3) Pr ⁱ NH _Two O 2 818 4-CF _Three -Thi (3) H NH _Two O 2 819 4-CF _Three -Thi (3) Cl NH _Two O 2 820 4-CF _Three -Thi (3) Me NH _Two O 2 821 4-CF _Three -Thi (3) Et NH _Two O 2 822 4-CF _Three -Thi (3) Pr NH _Two O 2 823 4-CF _Three -Thi (3) Pr ⁱ NH _Two O 2 824 4-MeO-Thi (3) H NH _Two O 2 825 4-MeO-Thi (3) Cl NH _Two O 2 826 4-MeO-Thi (3) Me NH _Two O 2 827 4-MeO-Thi (3) Et NH _Two O 2 828 4-MeO-Thi (3) Pr NH _Two O 2 829 4-MeO-Thi (3) Pr ⁱ NH _Two O 2 830 2-Ph-Thi (3) H NH _Two O 2 831 2-Ph-Thi (3) Cl NH _Two O 2 832 2-Ph-Thi (3) Me NH _Two O 2 833 2-Ph-Thi (3) Et NH _Two O 2 834 2-Ph-Thi (3) Pr NH _Two O 2 835 2-Ph-Thi (3) Pr ⁱ NH _Two O 2 836 4-Ph-Thi (3) H NH _Two O 2 837 4-Ph-Thi (3) Cl NH _Two O 2 838 4-Ph-Thi (3) Me NH _Two O 2 839 4-Ph-Thi (3) Et NH _Two O 2 840 4-Ph-Thi (3) Pr NH _Two O 2 841 4-Ph-Thi (3) Pr ⁱ NH _Two O 2 842 5-Ph-Thi (3) H NH _Two O 2 843 5-Ph-Thi (3) Cl NH _Two O 2 844 5-Ph-Thi (3) Me NH _Two O 2 845 5-Ph-Thi (3) Et NH _Two O 2 846 5-Ph-Thi (3) Pr NH _Two O 2 847 5-Ph-Thi (3) Pr ⁱ NH _Two O 2 848 2-MeOCO-Thi (3) H NH _Two O 2 849 2-MeOCO-Thi (3) Cl NH _Two O 2 850 2-MeOCO-Thi (3) Me NH _Two O 2 851 2-MeOCO-Thi (3) Et NH _Two O 2 852 2-MeOCO-Thi (3) Pr NH _Two O 2 853 2-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 854 4-MeOCO-Thi (3) H NH _Two O 2 855 4-MeOCO-Thi (3) Cl NH _Two O 2 856 4-MeOCO-Thi (3) Me NH _Two O 2 857 4-MeOCO-Thi (3) Et NH _Two O 2 858 4-MeOCO-Thi (3) Pr NH _Two O 2 859 4-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 860 5-MeOCO-Thi (3) H NH _Two O 2 861 5-MeOCO-Thi (3) Cl NH _Two O 2 862 5-MeOCO-Thi (3) Me NH _Two O 2 863 5-MeOCO-Thi (3) Et NH _Two O 2 864 5-MeOCO-Thi (3) Pr NH _Two O 2 865 5-MeOCO-Thi (3) Pr ⁱ NH _Two O 2 866 2-H _Two NCO-Thi (3) H NH _Two O 2 867 2-H _Two NCO-Thi (3) Cl NH _Two O 2 868 2-H _Two NCO-Thi (3) Me NH _Two O 2 869 2-H _Two NCO-Thi (3) Et NH _Two O 2 870 2-H _Two NCO-Thi (3) Pr NH _Two O 2 871 2-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 872 4-H _Two NCO-Thi (3) H NH _Two O 2 873 4-H _Two NCO-Thi (3) Cl NH _Two O 2 874 4-H _Two NCO-Thi (3) Me NH _Two O 2 875 4-H _Two NCO-Thi (3) Et NH _Two O 2 876 4-H _Two NCO-Thi (3) Pr NH _Two O 2 877 4-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 878 5-H _Two NCO-Thi (3) H NH _Two O 2 879 5-H _Two NCO-Thi (3) Cl NH _Two O 2 880 5-H _Two NCO-Thi (3) Me NH _Two O 2 881 5-H _Two NCO-Thi (3) Et NH _Two O 2 882 5-H _Two NCO-Thi (3) Pr NH _Two O 2 883 5-H _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 884 2-MeNHCO-Thi (3) H NH _Two O 2 885 2-MeNHCO-Thi (3) Cl NH _Two O 2 886 2-MeNHCO-Thi (3) Me NH _Two O 2 887 2-MeNHCO-Thi (3) Et NH _Two O 2 888 2-MeNHCO-Thi (3) Pr NH _Two O 2 889 2-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 890 4-MeNHCO-Thi (3) H NH _Two O 2 891 4-MeNHCO-Thi (3) Cl NH _Two O 2 892 4-MeNHCO-Thi (3) Me NH _Two O 2 893 4-MeNHCO-Thi (3) Et NH _Two O 2 894 4-MeNHCO-Thi (3) Pr NH _Two O 2 895 4-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 896 5-MeNHCO-Thi (3) H NH _Two O 2 897 5-MeNHCO-Thi (3) Cl NH _Two O 2 898 5-MeNHCO-Thi (3) Me NH _Two O 2 899 5-MeNHCO-Thi (3) Et NH _Two O 2 900 5-MeNHCO-Thi (3) Pr NH _Two O 2 901 5-MeNHCO-Thi (3) Pr ⁱ NH _Two O 2 902 2- (Me) _Two NCO-Thi (3) H NH _Two O 2 903 2- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 904 2- (Me) _Two NCO-Thi (3) Me NH _Two O 2 905 2- (Me) _Two NCO-Thi (3) Et NH _Two O 2 906 2- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 907 2- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 908 4- (Me) _Two NCO-Thi (3) H NH _Two O 2 909 4- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 910 4- (Me) _Two NCO-Thi (3) Me NH _Two O 2 911 4- (Me) _Two NCO-Thi (3) Et NH _Two O 2 912 4- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 913 4- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 914 5- (Me) _Two NCO-Thi (3) H NH _Two O 2 915 5- (Me) _Two NCO-Thi (3) Cl NH _Two O 2 916 5- (Me) _Two NCO-Thi (3) Me NH _Two O 2 917 5- (Me) _Two NCO-Thi (3) Et NH _Two O 2 918 5- (Me) _Two NCO-Thi (3) Pr NH _Two O 2 919 5- (Me) _Two NCO-Thi (3) Pr ⁱ NH _Two O 2 (Continued from Table 1) Compound number R ¹ R ^Two R ^Three X n 920 Pyr (2) H NH _Two O 2 921 Pyr (2) H NH _Two O 2 922 Pyr (2) H NH _Two O 3 923 Pyr (2) H NH _Two O 4 924 Pyr (2) F NH _Two O 2 925 Pyr (2) Cl NH _Two O 2 926 Pyr (2) Me NH _Two O 2 927 Pyr (2) Et NH _Two O 2 928 Pyr (2) Pr NH _Two O 2 929 Pyr (2) Pr ⁱ NH _Two O 2 930 Pyr (2) Bu NH _Two O 2 931 Pyr (2) Bu ⁱ NH _Two O 2 932 Pyr (2) Bu ^s NH _Two O 2 933 Pyr (2) Bu ^t NH _Two O 2 934 Pyr (2) H NH _Two S 2 935 Pyr (2) H NH _Two S 3 936 Pyr (2) H NH _Two S 4 937 Pyr (2) F NH _Two S 2 938 Pyr (2) Cl NH _Two S 2 939 Pyr (2) Me NH _Two S 2 940 Pyr (2) Et NH _Two S 2 941 Pyr (2) Pr NH _Two S 2 942 Pyr (2) Pr ⁱ NH _Two S 2 943 Pyr (2) H NHMe O 2 944 Pyr (2) H NHEt O 2 945 Pyr (2) HN (Me) _Two O 2 946 Pyr (2) H Pip (1) O 2 947 Pyr (2) H Mor (4) O 2 948 3-F-Pyr (2) H NH _Two O 2 949 3-F-Pyr (2) Cl NH _Two O 2 950 3-F-Pyr (2) Me NH _Two O 2 951 3-F-Pyr (2) Et NH _Two O 2 952 3-F-Pyr (2) Pr NH _Two O 2 953 3-F-Pyr (2) Pr ⁱ NH _Two O 2 954 4-F-Pyr (2) H NH _Two O 2 955 4-F-Pyr (2) Cl NH _Two O 2 956 4-F-Pyr (2) Me NH _Two O 2 957 4-F-Pyr (2) Et NH _Two O 2 958 4-F-Pyr (2) Pr NH _Two O 2 959 4-F-Pyr (2) Pr ⁱ NH _Two O 2 960 3-Cl-Pyr (2) H NH _Two O 2 961 3-Cl-Pyr (2) Cl NH _Two O 2 962 3-Cl-Pyr (2) Me NH _Two O 2 963 3-Cl-Pyr (2) Et NH _Two O 2 964 3-Cl-Pyr (2) Pr NH _Two O 2 965 3-Cl-Pyr (2) Pr ⁱ NH _Two O 2 966 4-Cl-Pyr (2) H NH _Two O 2 967 4-Cl-Pyr (2) Cl NH _Two O 2 968 4-Cl-Pyr (2) Me NH _Two O 2 969 4-Cl-Pyr (2) Et NH _Two O 2 970 4-Cl-Pyr (2) Pr NH _Two O 2 971 4-Cl-Pyr (2) Pr ⁱ NH _Two O 2 972 4-Me-Pyr (2) H NH _Two O 2 973 4-Me-Pyr (2) Cl NH _Two O 2 974 4-Me-Pyr (2) Me NH _Two O 2 975 4-Me-Pyr (2) Et NH _Two O 2 976 4-Me-Pyr (2) Pr NH _Two O 2 977 4-Me-Pyr (2) Pr ⁱ NH _Two O 2 978 4-Et-Pyr (2) H NH _Two O 2 979 4-Et-Pyr (2) Cl NH _Two O 2 980 4-Et-Pyr (2) Me NH _Two O 2 981 4-Et-Pyr (2) Et NH _Two O 2 982 4-Et-Pyr (2) Pr NH _Two O 2 983 4-Et-Pyr (2) Pr ⁱ NH _Two O 2 984 4-CF _Three -Pyr (2) H NH _Two O 2 985 4-CF _Three -Pyr (2) Cl NH _Two O 2 986 4-CF _Three -Pyr (2) Me NH _Two O 2 987 4-CF _Three -Pyr (2) Et NH _Two O 2 988 4-CF _Three -Pyr (2) Pr NH _Two O 2 989 4-CF _Three -Pyr (2) Pr ⁱ NH _Two O 2 990 4-MeO-Pyr (2) H NH _Two O 2 991 4-MeO-Pyr (2) Cl NH _Two O 2 992 4-MeO-Pyr (2) Me NH _Two O 2 993 4-MeO-Pyr (2) Et NH _Two O 2 994 4-MeO-Pyr (2) Pr NH _Two O 2 995 4-MeO-Pyr (2) Pr ⁱ NH _Two O 2 996 3-Ph-Pyr (2) H NH _Two O 2 997 3-Ph-Pyr (2) Cl NH _Two O 2 998 3-Ph-Pyr (2) Me NH _Two O 2 999 3-Ph-Pyr (2) Et NH _Two O 2 1000 3-Ph-Pyr (2) Pr NH _Two O 2 1001 3-Ph-Pyr (2) Pr ⁱ NH _Two O 2 1002 4-Ph-Pyr (2) H NH _Two O 2 1003 4-Ph-Pyr (2) Cl NH _Two O 2 1004 4-Ph-Pyr (2) Me NH _Two O 2 1005 4-Ph-Pyr (2) Et NH _Two O 2 1006 4-Ph-Pyr (2) Pr NH _Two O 2 1007 4-Ph-Pyr (2) Pr ⁱ NH _Two O 2 1008 3-MeOCO-Pyr (2) H NH _Two O 2 1009 3-MeOCO-Pyr (2) Cl NH _Two O 2 1010 3-MeOCO-Pyr (2) Me NH _Two O 2 1011 3-MeOCO-Pyr (2) Et NH _Two O 2 1012 3-MeOCO-Pyr (2) Pr NH _Two O 2 1013 3-MeOCO-Pyr (2) Pr ⁱ NH _Two O 2 1014 4-MeOCO-Pyr (2) H NH _Two O 2 1015 4-MeOCO-Pyr (2) Cl NH _Two O 2 1016 4-MeOCO-Pyr (2) Me NH _Two O 2 1017 4-MeOCO-Pyr (2) Et NH _Two O 2 1018 4-MeOCO-Pyr (2) Pr NH _Two O 2 1019 4-MeOCO-Pyr (2) Pr ⁱ NH _Two O 2 1020 3-H _Two NCO-Pyr (2) H NH _Two O 2 1021 3-H _Two NCO-Pyr (2) Cl NH _Two O 2 1022 3-H _Two NCO-Pyr (2) Me NH _Two O 2 1023 3-H _Two NCO-Pyr (2) Et NH _Two O 2 1024 3-H _Two NCO-Pyr (2) Pr NH _Two O 2 1025 3-H _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1026 4-H _Two NCO-Pyr (2) H NH _Two O 2 1027 4-H _Two NCO-Pyr (2) Cl NH _Two O 2 1028 4-H _Two NCO-Pyr (2) Me NH _Two O 2 1029 4-H _Two NCO-Pyr (2) Et NH _Two O 2 1030 4-H _Two NCO-Pyr (2) Pr NH _Two O 2 1031 4-H _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1032 3-MeNHCO-Pyr (2) H NH _Two O 2 1033 3-MeNHCO-Pyr (2) Cl NH _Two O 2 1034 3-MeNHCO-Pyr (2) Me NH _Two O 2 1035 3-MeNHCO-Pyr (2) Et NH _Two O 2 1036 3-MeNHCO-Pyr (2) Pr NH _Two O 2 1037 3-MeNHCO-Pyr (2) Pr ⁱ NH _Two O 2 1038 4-MeNHCO-Pyr (2) H NH _Two O 2 1039 4-MeNHCO-Pyr (2) Cl NH _Two O 2 1040 4-MeNHCO-Pyr (2) Me NH _Two O 2 1041 4-MeNHCO-Pyr (2) Et NH _Two O 2 1042 4-MeNHCO-Pyr (2) Pr NH _Two O 2 1043 4-MeNHCO-Pyr (2) Pr ⁱ NH _Two O 2 1044 3- (Me) _Two NCO-Pyr (2) H NH _Two O 2 1045 3- (Me) _Two NCO-Pyr (2) Cl NH _Two O 2 1046 3- (Me) _Two NCO-Pyr (2) Me NH _Two O 2 1047 3- (Me) _Two NCO-Pyr (2) Et NH _Two O 2 1048 3- (Me) _Two NCO-Pyr (2) Pr NH _Two O 2 1049 3- (Me) _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1050 4- (Me) _Two NCO-Pyr (2) H NH _Two O 2 1051 4- (Me) _Two NCO-Pyr (2) Cl NH _Two O 2 1052 4- (Me) _Two NCO-Pyr (2) Me NH _Two O 2 1053 4- (Me) _Two NCO-Pyr (2) Et NH _Two O 2 1054 4- (Me) _Two NCO-Pyr (2) Pr NH _Two O 2 1055 4- (Me) _Two NCO-Pyr (2) Pr ⁱ NH _Two O 2 1056 Pyr (3) H NH _Two O 2 1057 Pyr (3) H NH _Two O 2 1058 Pyr (3) H NH _Two O 3 1059 Pyr (3) H NH _Two O 4 1060 Pyr (3) F NH _Two O 2 1061 Pyr (3) Cl NH _Two O 2 1062 Pyr (3) Me NH _Two O 2 1063 Pyr (3) Et NH _Two O 2 1064 Pyr (3) Pr NH _Two O 2 1065 Pyr (3) Pr ⁱ NH _Two O 2 1066 Pyr (3) Bu NH _Two O 2 1067 Pyr (3) Bu ⁱ NH _Two O 2 1068 Pyr (3) Bu ^s NH _Two O 2 1069 Pyr (3) Bu ^t NH _Two O 2 1070 Pyr (3) H NH _Two S 2 1071 Pyr (3) H NH _Two S 3 1072 Pyr (3) H NH _Two S 4 1073 Pyr (3) F NH _Two S 2 1074 Pyr (3) Cl NH _Two S 2 1075 Pyr (3) Me NH _Two S 2 1076 Pyr (3) Et NH _Two S 2 1077 Pyr (3) Pr NH _Two S 2 1078 Pyr (3) Pr ⁱ NH _Two S 2 1079 Pyr (3) H NHMe O 2 1080 Pyr (3) H NHEt O 2 1081 Pyr (3) HN (Me) _Two O 2 1082 Pyr (3) H Pip (1) O 2 1083 Pyr (3) H Mor (4) O 2 1084 2-F-Pyr (3) H NH _Two O 2 1085 2-F-Pyr (3) Cl NH _Two O 2 1086 2-F-Pyr (3) Me NH _Two O 2 1087 2-F-Pyr (3) Et NH _Two O 2 1088 2-F-Pyr (3) Pr NH _Two O 2 1089 2-F-Pyr (3) Pr ⁱ NH _Two O 2 1090 4-F-Pyr (3) H NH _Two O 2 1091 4-F-Pyr (3) Cl NH _Two O 2 1092 4-F-Pyr (3) Me NH _Two O 2 1093 4-F-Pyr (3) Et NH _Two O 2 1094 4-F-Pyr (3) Pr NH _Two O 2 1095 4-F-Pyr (3) Pr ⁱ NH _Two O 2 1096 2-Cl-Pyr (3) H NH _Two O 2 1097 2-Cl-Pyr (3) Cl NH _Two O 2 1098 2-Cl-Pyr (3) Me NH _Two O 2 1099 2-Cl-Pyr (3) Et NH _Two O 2 1100 2-Cl-Pyr (3) Pr NH _Two O 2 1101 2-Cl-Pyr (3) Pr ⁱ NH _Two O 2 1102 4-Cl-Pyr (3) H NH _Two O 2 1103 4-Cl-Pyr (3) Cl NH _Two O 2 1104 4-Cl-Pyr (3) Me NH _Two O 2 1105 4-Cl-Pyr (3) Et NH _Two O 2 1106 4-Cl-Pyr (3) Pr NH _Two O 2 1107 4-Cl-Pyr (3) Pr ⁱ NH _Two O 2 1108 4-Me-Pyr (3) H NH _Two O 2 1109 4-Me-Pyr (3) Cl NH _Two O 2 1110 4-Me-Pyr (3) Me NH _Two O 2 1111 4-Me-Pyr (3) Et NH _Two O 2 1112 4-Me-Pyr (3) Pr NH _Two O 2 1113 4-Me-Pyr (3) Pr ⁱ NH _Two O 2 1114 4-Et-Pyr (3) H NH _Two O 2 1115 4-Et-Pyr (3) Cl NH _Two O 2 1116 4-Et-Pyr (3) Me NH _Two O 2 1117 4-Et-Pyr (3) Et NH _Two O 2 1118 4-Et-Pyr (3) Pr NH _Two O 2 1119 4-Et-Pyr (3) Pr ⁱ NH _Two O 2 1120 4-CF _Three -Pyr (3) H NH _Two O 2 1121 4-CF _Three -Pyr (3) Cl NH _Two O 2 1122 4-CF _Three -Pyr (3) Me NH _Two O 2 1123 4-CF _Three -Pyr (3) Et NH _Two O 2 1124 4-CF _Three -Pyr (3) Pr NH _Two O 2 1125 4-CF _Three -Pyr (3) Pr ⁱ NH _Two O 2 1126 4-MeO-Pyr (3) H NH _Two O 2 1127 4-MeO-Pyr (3) Cl NH _Two O 2 1128 4-MeO-Pyr (3) Me NH _Two O 2 1129 4-MeO-Pyr (3) Et NH _Two O 2 1130 4-MeO-Pyr (3) Pr NH _Two O 2 1131 4-MeO-Pyr (3) Pr ⁱ NH _Two O 2 1132 2-Ph-Pyr (3) H NH _Two O 2 1133 2-Ph-Pyr (3) Cl NH _Two O 2 1134 2-Ph-Pyr (3) Me NH _Two O 2 1135 2-Ph-Pyr (3) Et NH _Two O 2 1136 2-Ph-Pyr (3) Pr NH _Two O 2 1137 2-Ph-Pyr (3) Pr ⁱ NH _Two O 2 1138 4-Ph-Pyr (3) H NH _Two O 2 1139 4-Ph-Pyr (3) Cl NH _Two O 2 1140 4-Ph-Pyr (3) Me NH _Two O 2 1141 4-Ph-Pyr (3) Et NH _Two O 2 1142 4-Ph-Pyr (3) Pr NH _Two O 2 1143 4-Ph-Pyr (3) Pr ⁱ NH _Two O 2 1144 2-MeOCO-Pyr (3) H NH _Two O 2 1145 2-MeOCO-Pyr (3) Cl NH _Two O 2 1146 2-MeOCO-Pyr (3) Me NH _Two O 2 1147 2-MeOCO-Pyr (3) Et NH _Two O 2 1148 2-MeOCO-Pyr (3) Pr NH _Two O 2 1149 2-MeOCO-Pyr (3) Pr ⁱ NH _Two O 2 1150 4-MeOCO-Pyr (3) H NH _Two O 2 1151 4-MeOCO-Pyr (3) Cl NH _Two O 2 1152 4-MeOCO-Pyr (3) Me NH _Two O 2 1153 4-MeOCO-Pyr (3) Et NH _Two O 2 1154 4-MeOCO-Pyr (3) Pr NH _Two O 2 1155 4-MeOCO-Pyr (3) Pr ⁱ NH _Two O 2 1156 2-H _Two NCO-Pyr (3) H NH _Two O 2 1157 2-H _Two NCO-Pyr (3) Cl NH _Two O 2 1158 2-H _Two NCO-Pyr (3) Me NH _Two O 2 1159 2-H _Two NCO-Pyr (3) Et NH _Two O 2 1160 2-H _Two NCO-Pyr (3) Pr NH _Two O 2 1161 2-H _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1162 4-H _Two NCO-Pyr (3) H NH _Two O 2 1163 4-H _Two NCO-Pyr (3) Cl NH _Two O 2 1164 4-H _Two NCO-Pyr (3) Me NH _Two O 2 1165 4-H _Two NCO-Pyr (3) Et NH _Two O 2 1166 4-H _Two NCO-Pyr (3) Pr NH _Two O 2 1167 4-H _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1168 2-MeNHCO-Pyr (3) H NH _Two O 2 1169 2-MeNHCO-Pyr (3) Cl NH _Two O 2 1170 2-MeNHCO-Pyr (3) Me NH _Two O 2 1171 2-MeNHCO-Pyr (3) Et NH _Two O 2 1172 2-MeNHCO-Pyr (3) Pr NH _Two O 2 1173 2-MeNHCO-Pyr (3) Pr ⁱ NH _Two O 2 1174 4-MeNHCO-Pyr (3) H NH _Two O 2 1175 4-MeNHCO-Pyr (3) Cl NH _Two O 2 1176 4-MeNHCO-Pyr (3) Me NH _Two O 2 1177 4-MeNHCO-Pyr (3) Et NH _Two O 2 1178 4-MeNHCO-Pyr (3) Pr NH _Two O 2 1179 4-MeNHCO-Pyr (3) Pr ⁱ NH _Two O 2 1180 2- (Me) _Two NCO-Pyr (3) H NH _Two O 2 1181 2- (Me) _Two NCO-Pyr (3) Cl NH _Two O 2 1182 2- (Me) _Two NCO-Pyr (3) Me NH _Two O 2 1183 2- (Me) _Two NCO-Pyr (3) Et NH _Two O 2 1184 2- (Me) _Two NCO-Pyr (3) Pr NH _Two O 2 1185 2- (Me) _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1186 4- (Me) _Two NCO-Pyr (3) H NH _Two O 2 1187 4- (Me) _Two NCO-Pyr (3) Cl NH _Two O 2 1188 4- (Me) _Two NCO-Pyr (3) Me NH _Two O 2 1189 4- (Me) _Two NCO-Pyr (3) Et NH _Two O 2 1190 4- (Me) _Two NCO-Pyr (3) Pr NH _Two O 2 1191 4- (Me) _Two NCO-Pyr (3) Pr ⁱ NH _Two O 2 1192 Pyr (4) H NH _Two O 2 1193 Pyr (4) H NH _Two O 2 1194 Pyr (4) H NH _Two O 3 1195 Pyr (4) H NH _Two O 4 1196 Pyr (4) F NH _Two O 2 1197 Pyr (4) Cl NH _Two O 2 1198 Pyr (4) Me NH _Two O 2 1199 Pyr (4) Et NH _Two O 2 1200 Pyr (4) Pr NH _Two O 2 1201 Pyr (4) Pr ⁱ NH _Two O 2 1202 Pyr (4) Bu NH _Two O 2 1203 Pyr (4) Bu ⁱ NH _Two O 2 1204 Pyr (4) Bu ^s NH _Two O 2 1206 Pyr (4) Bu ^t NH _Two O 2 1207 Pyr (4) H NH _Two S 2 1208 Pyr (4) H NH _Two S 3 1209 Pyr (4) H NH _Two S 4 1210 Pyr (4) F NH _Two S 2 1211 Pyr (4) Cl NH _Two S 2 1212 Pyr (4) Me NH _Two S 2 1213 Pyr (4) Et NH _Two S 2 1214 Pyr (4) Pr NH _Two S 2 1215 Pyr (4) Pr ⁱ NH _Two S 2 1216 Pyr (4) H NHMe O 2 1217 Pyr (4) H NHEt O 2 1218 Pyr (4) HN (Me) _Two O 2 1219 Pyr (4) H Pip (1) O 2 1220 Pyr (4) H Mor (4) O 2 1221 2-F-Pyr (4) H NH _Two O 2 1222 2-F-Pyr (4) Cl NH _Two O 2 1223 2-F-Pyr (4) Me NH _Two O 2 1224 2-F-Pyr (4) Et NH _Two O 2 1225 2-F-Pyr (4) Pr NH _Two O 2 1226 2-F-Pyr (4) Pr ⁱ NH _Two O 2 1227 3-F-Pyr (4) H NH _Two O 2 1228 3-F-Pyr (4) Cl NH _Two O 2 1229 3-F-Pyr (4) Me NH _Two O 2 1230 3-F-Pyr (4) Et NH _Two O 2 1231 3-F-Pyr (4) Pr NH _Two O 2 1232 3-F-Pyr (4) Pr ⁱ NH _Two O 2 1233 2-Cl-Pyr (4) H NH _Two O 2 1234 2-Cl-Pyr (4) Cl NH _Two O 2 1235 2-Cl-Pyr (4) Me NH _Two O 2 1236 2-Cl-Pyr (4) Et NH _Two O 2 1237 2-Cl-Pyr (4) Pr NH _Two O 2 1238 2-Cl-Pyr (4) Pr ⁱ NH _Two O 2 1239 3-Cl-Pyr (4) H NH _Two O 2 1240 3-Cl-Pyr (4) Cl NH _Two O 2 1241 3-Cl-Pyr (4) Me NH _Two O 2 1242 3-Cl-Pyr (4) Et NH _Two O 2 1243 3-Cl-Pyr (4) Pr NH _Two O 2 1244 3-Cl-Pyr (4) Pr ⁱ NH _Two O 2 1245 3-Me-Pyr (4) H NH _Two O 2 1246 3-Me-Pyr (4) Cl NH _Two O 2 1247 3-Me-Pyr (4) Me NH _Two O 2 1248 3-Me-Pyr (4) Et NH _Two O 2 1249 3-Me-Pyr (4) Pr NH _Two O 2 1250 3-Me-Pyr (4) Pr ⁱ NH _Two O 2 1251 3-Et-Pyr (4) H NH _Two O 2 1252 3-Et-Pyr (4) Cl NH _Two O 2 1253 3-Et-Pyr (4) Me NH _Two O 2 1254 3-Et-Pyr (4) Et NH _Two O 2 1255 3-Et-Pyr (4) Pr NH _Two O 2 1256 3-Et-Pyr (4) Pr ⁱ NH _Two O 2 1257 3-CF _Three -Pyr (4) H NH _Two O 2 1258 3-CF _Three -Pyr (4) Cl NH _Two O 2 1259 3-CF _Three -Pyr (4) Me NH _Two O 2 1260 3-CF _Three -Pyr (4) Et NH _Two O 2 1261 3-CF _Three -Pyr (4) Pr NH _Two O 2 1262 3-CF _Three -Pyr (4) Pr ⁱ NH _Two O 2 1263 3-MeO-Pyr (4) H NH _Two O 2 1264 3-MeO-Pyr (4) Cl NH _Two O 2 1265 3-MeO-Pyr (4) Me NH _Two O 2 1266 3-MeO-Pyr (4) Et NH _Two O 2 1267 3-MeO-Pyr (4) Pr NH _Two O 2 1268 3-MeO-Pyr (4) Pr ⁱ NH _Two O 2 1269 2-Ph-Pyr (4) H NH _Two O 2 1270 2-Ph-Pyr (4) Cl NH _Two O 2 1271 2-Ph-Pyr (4) Me NH _Two O 2 1272 2-Ph-Pyr (4) Et NH _Two O 2 1273 2-Ph-Pyr (4) Pr NH _Two O 2 1274 2-Ph-Pyr (4) Pr ⁱ NH _Two O 2 1275 3-Ph-Pyr (4) H NH _Two O 2 1276 3-Ph-Pyr (4) Cl NH _Two O 2 1277 3-Ph-Pyr (4) Me NH _Two O 2 1278 3-Ph-Pyr (4) Et NH _Two O 2 1280 3-Ph-Pyr (4) Pr ⁱ NH _Two O
2 1281 2-MeOCO-Pyr (4) H NH _Two O 2 1282 2-MeOCO-Pyr (4) Cl NH _Two O 2 1283 2-MeOCO-Pyr (4) Me NH _Two O 2 1284 2-MeOCO-Pyr (4) Et NH _Two O 2 1285 2-MeOCO-Pyr (4) Pr NH _Two O 2 1286 2-MeOCO-Pyr (4) Pr ⁱ NH _Two O 2 1287 3-MeOCO-Pyr (4) H NH _Two O 2 1288 3-MeOCO-Pyr (4) Cl NH _Two O 2 1289 3-MeOCO-Pyr (4) Me NH _Two O 2 1290 3-MeOCO-Pyr (4) Et NH _Two O 2 1291 3-MeOCO-Pyr (4) Pr NH _Two O 2 1292 3-MeOCO-Pyr (4) Pr ⁱ NH _Two O 2 1293 2-H _Two NCO-Pyr (4) H NH _Two O 2 1294 2-H _Two NCO-Pyr (4) Cl NH _Two O 2 1295 2-H _Two NCO-Pyr (4) Me NH _Two O 2 1296 2-H _Two NCO-Pyr (4) Et NH _Two O 2 1297 2-H _Two NCO-Pyr (4) Pr NH _Two O 2 1298 2-H _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1299 3-H _Two NCO-Pyr (4) H NH _Two O 2 1300 3-H _Two NCO-Pyr (4) Cl NH _Two O 2 1301 3-H _Two NCO-Pyr (4) Me NH _Two O 2 1302 3-H _Two NCO-Pyr (4) Et NH _Two O 2 1303 3-H _Two NCO-Pyr (4) Pr NH _Two O 2 1304 3-H _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1305 2-MeNHCO-Pyr (4) H NH _Two O 2 1306 2-MeNHCO-Pyr (4) Cl NH _Two O 2 1307 2-MeNHCO-Pyr (4) Me NH _Two O 2 1308 2-MeNHCO-Pyr (4) Et NH _Two O 2 1309 2-MeNHCO-Pyr (4) Pr NH _Two O 2 1310 2-MeNHCO-Pyr (4) Pr ⁱ NH _Two O 2 1311 3-MeNHCO-Pyr (4) H NH _Two O 2 1312 3-MeNHCO-Pyr (4) Cl NH _Two O 2 1313 3-MeNHCO-Pyr (4) Me NH _Two O 2 1314 3-MeNHCO-Pyr (4) Et NH _Two O 2 1315 3-MeNHCO-Pyr (4) Pr NH _Two O 2 1316 3-MeNHCO-Pyr (4) Pr ⁱ NH _Two O 2 1317 2- (Me) _Two NCO-Pyr (4) H NH _Two O 2 1318 2- (Me) _Two NCO-Pyr (4) Cl NH _Two O 2 1319 2- (Me) _Two NCO-Pyr (4) Me NH _Two O 2 1320 2- (Me) _Two NCO-Pyr (4) Et NH _Two O 2 1321 2- (Me) _Two NCO-Pyr (4) Pr NH _Two O 2 1322 2- (Me) _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1323 3- (Me) _Two NCO-Pyr (4) H NH _Two O 2 1324 3- (Me) _Two NCO-Pyr (4) Cl NH _Two O 2 1325 3- (Me) _Two NCO-Pyr (4) Me NH _Two O 2 1326 3- (Me) _Two NCO-Pyr (4) Et NH _Two O 2 1327 3- (Me) _Two NCO-Pyr (4) Pr NH _Two O 2 1328 3- (Me) _Two NCO-Pyr (4) Pr ⁱ NH _Two O 2 1329 Pyrazinyl (2) H NH _Two O 2 1330 Pyrazinyl (2) Cl NH _Two O 2 1331 Pyrazinyl (2) Me NH _Two O 2 1332 Pyrazinyl (2) Et NH _Two O 2 1333 Pyrazinyl (2) Pr NH _Two O 2 1334 Pyrazinyl (2) Pr ⁱ NH _Two O 2 1335 Pyrimidinyl (2) H NH _Two O 2 1336 Pyrimidinyl (2) Cl NH _Two O 2 1337 Pyrimidinyl (2) Me NH _Two O 2 1338 Pyrimidinyl (2) Et NH _Two O 2 1339 Pyrimidinyl (2) Pr NH _Two O 2 1340 Pyrimidinyl (2) Pr ⁱ NH _Two O 2 1341 Pyridazinyl (3) H NH _Two O 2 1342 Pyridazinyl (3) Cl NH _Two O 2 1343 Pyridazinyl (3) Me NH _Two O 2 1344 Pyridazinyl (3) Et NH _Two O 2 1345 Pyridazinyl (3) Pr NH _Two O 2 1346 Pyridazinyl (3) Pr ⁱ NH _Two O 2 (Continued from Table 1) Compound number R ¹ R ^Two R ^Three X n 1347 Ph H NHAc O 2 1348 Ph H NHMoc O 2 1349 Ph H NHBz O 2 1350 Ph H Pyrd (1) O 2 1351 Ph H Piz (1) O 2 1352 Ph Cl NHAc O 2 1353 Ph Cl NHMoc O 2 1354 Ph Cl NHBz O 2 1355 Ph Cl Pyrd (1) O 2 1356 Ph Cl Piz (1) O 2 1357 Ph Br NH _Two O 2 1358 Ph Br NH _Two S 2 1359 Ph I NH _Two O 2 1360 Ph I NH _Two S 2 1361 Ph Et NHAc O 2 1362 Ph Et NHMoc O 2 1363 Ph Et NHBz O
2 1364 Ph Et Pyrd (1) O 2 1365 Ph Et Piz (1) O 2 1366 Ph Pr NHAc O 2 1367 Ph Pr NHMoc O 2 1368 Ph Pr NHBz O 2 1369 Ph Pr Pyrd (1) O 2 1370 Ph Pr Piz (1) O 2 1371 Ph Pr ⁱ NHAc O 2 1372 Ph Pr ⁱ NHMoc O 2 1373 Ph Pr ⁱ NHBz O 2 1374 Ph Pr ⁱ Pyrd (1) O 2 1375 Ph Pr ⁱ Piz (1) O 2 1376 Ph Bu ⁱ NHAc O 2 1377 Ph Bu ⁱ NHMoc O 2 1378 Ph Bu ⁱ NHBz O 2 1379 Ph Bu ⁱ Pyrd (1) O 2 1380 Ph Bu ⁱ Piz (1) O 2 1381 Ph Bu ^t NHAc O 2 1382 Ph Bu ^t NHMoc O 2 1383 Ph Bu ^t NHBz O 2 1384 Ph Bu ^t Pyrd (1) O 2 1385 Ph Bu ^t Piz (1) O 2 1386 Ph Pn NH _Two O 2 1387 Ph Pn NH _Two S 2 1388 Ph Hex NH _Two O 2 1389 Ph Hex NH _Two S 2 1390 Ph 1-Cl-Et NH _Two O 2 1391 Ph 1-Cl-Et NH _Two S 2 1392 Ph All NH _Two O 2 1393 Ph All NH _Two S 2 1394 Ph Pre ⁱ NH _Two O 2 1395 Ph Pre ⁱ NH _Two S 2 1396 Ph Bun (2) NH _Two O 2 1397 Ph Bun (2) NH _Two S 2 1398 Ph Prg NH _Two O 2 1399 Ph Prg NH _Two S 2 1400 Ph Pr ^c NH _Two O 2 1401 Ph Pr ^c NH _Two S 2 1402 Ph Pn ^c NH _Two O 2 1403 Ph Pn ^c NH _Two S 2 1404 Ph Pen ^c (2) NH _Two O 2 1405 Ph Pen ^c (2) NH _Two S 2 1406 Ph CN NH _Two O 2 1407 Ph CN NH _Two S 2 1408 Ph COOH NH _Two O 2 1409 Ph COOH NH _Two S 2 1410 Ph Ac NH _Two O 2 1411 Ph Ac NH _Two S 2 1412 Ph COOMe NH _Two O 2 1413 Ph COOMe NH _Two S 2 1414 Ph CONH _Two NH _Two O 2 1415 Ph CONH _Two NH _Two S 2 1416 Ph CONHMe NH _Two O 2 1417 Ph CONHMe NH _Two S 2 1418 2,4-diF-Ph Br NH _Two O 2 1419 2,4-diF-Ph I NH _Two O 2 1420 2,4-diF-Ph Pn NH _Two O 2 1421 2,4-diF-Ph Hex NH _Two O 2 1422 2,4-diF-Ph 1-Cl-Et NH _Two O 2 1423 2,4-diF-Ph All NH _Two O 2 1424 2,4-diF-Ph Pre ⁱ NH _Two O 2 1425 2,4-diF-Ph Bun (2) NH _Two O 2 1426 2,4-diF-Ph Prg NH _Two O 2 1427 2,4-diF-Ph Pr ^c NH _Two O 2 1428 2,4-diF-Ph Pn ^c NH _Two O 2 1429 2,4-diF-Ph Pen ^c (2) NH _Two O 2 1430 2,4-diF-Ph CN NH _Two O 2 1431 2,4-diF-Ph COOH NH _Two O 2 1432 2,4-diF-Ph Ac NH _Two O 2 1433 2,4-diF-Ph COOMe NH _Two O 2 1434 2,4-diF-Ph CONH _Two NH _Two O 2 1435 2,4-diF-Ph CONHMe NH _Two O 2 1436 2,4-diF-Ph Br NH _Two S 2 1437 2,4-diF-Ph I NH _Two S 2 1438 2,4-diF-Ph Pn NH _Two S 2 1439 2,4-diF-Ph Hex NH _Two S 2 1440 2,4-diF-Ph 1-Cl-Et NH _Two S 2 1441 2,4-diF-Ph All NH _Two S 2 1442 2,4-diF-Ph Pre ⁱ NH _Two S 2 1443 2,4-diF-Ph Bun (2) NH _Two S 2 1444 2,4-diF-Ph Prg NH _Two S 2 1445 2,4-diF-Ph Pr ^c NH _Two S 2 1446 2,4-diF-Ph Pn ^c NH _Two S 2 1447 2,4-diF-Ph Pen ^c (2) NH _Two S 2 1448 2,4-diF-Ph CN NH _Two S 2 1449 2,4-diF-Ph COOH NH _Two S 2 1450 2,4-diF-Ph Ac NH _Two S
2 1451 2,4-diF-Ph COOMe NH _Two S 2 1452 2,4-diF-Ph CONH _Two NH _Two S 2 1453 2,4-diF-Ph CONHMe NH _Two S 2 1454 2-Cl-Ph Br NH _Two O 2 1455 2-Cl-Ph I NH _Two O 2 1456 2-Cl-Ph Pn NH _Two O 2 1457 2-Cl-Ph Hex NH _Two O 2 1458 2-Cl-Ph 1-Cl-Et NH _Two O 2 1459 2-Cl-Ph All NH _Two O 2 1460 2-Cl-Ph Bun (2) NH _Two O 2 1461 2-Cl-Ph Pre ⁱ NH _Two O 2 1462 2-Cl-Ph Prg NH _Two O 2 1463 2-Cl-Ph Pr ^c NH _Two O 2 1464 2-Cl-Ph Pn ^c NH _Two O 2 1465 2-Cl-Ph Pen ^c (2) NH _Two O 2 1466 2-Cl-Ph CN NH _Two O 2 1467 2-Cl-Ph COOH NH _Two O 2 1468 2-Cl-Ph Ac NH _Two O 2 1469 2-Cl-Ph COOMe NH _Two O 2 1470 2-Cl-Ph CONH _Two NH _Two O 2 1471 2-Cl-Ph CONHMe NH _Two O 2 1472 2-Cl-Ph Br NH _Two S 2 1473 2-Cl-Ph I NH _Two S 2 1474 2-Cl-Ph Pn NH _Two S 2 1475 2-Cl-Ph Hex NH _Two S 2 1476 2-Cl-Ph 1-Cl-Et NH _Two S 2 1477 2-Cl-Ph All NH _Two S 2 1478 2-Cl-Ph Bun (2) NH _Two S 2 1479 2-Cl-Ph Pre ⁱ NH _Two S 2 1480 2-Cl-Ph Prg NH _Two S 2 1481 2-Cl-Ph Pr ^c NH _Two S 2 1482 2-Cl-Ph Pn ^c NH _Two S 2 1483 2-Cl-Ph Pen ^c (2) NH _Two S 2 1484 2-Cl-Ph CN NH _Two S 2 1485 2-Cl-Ph COOH NH _Two S 2 1486 2-Cl-Ph Ac NH _Two S 2 1487 2-Cl-Ph COOMe NH _Two S 2 1488 2-Cl-Ph CONH _Two NH _Two S 2 1489 2-Cl-Ph CONHMe NH _Two S 2 1490 4-Cl-Ph Br NH _Two O 2 1491 4-Cl-Ph I NH _Two O 2 1492 4-Cl-Ph Pn NH _Two O 2 1493 4-Cl-Ph Hex NH _Two O 2 1494 4-Cl-Ph 1-Cl-Et NH _Two O 2 1495 4-Cl-Ph All NH _Two O 2 1496 4-Cl-Ph Bun (2) NH _Two O 2 1497 4-Cl-Ph Pre ⁱ NH _Two O 2 1498 4-Cl-Ph Prg NH _Two O 2 1499 4-Cl-Ph Pr ^c NH _Two O 2 1500 4-Cl-Ph Pn ^c NH _Two O 2 1501 4-Cl-Ph Pen ^c (2) NH _Two O 2 1502 4-Cl-Ph CN NH _Two O 2 1503 4-Cl-Ph COOH NH _Two O 2 1504 4-Cl-Ph Ac NH _Two O 2 1505 4-Cl-Ph COOMe NH _Two O 2 1506 4-Cl-Ph CONH _Two NH _Two O 2 1507 4-Cl-Ph CONHMe NH _Two O 2 1508 4-Cl-Ph Br NH _Two S 2 1509 4-Cl-Ph I NH _Two S 2 1510 4-Cl-Ph Pn NH _Two S 2 1511 4-Cl-Ph Hex NH _Two S 2 1512 4-Cl-Ph 1-Cl-Et NH _Two S 2 1513 4-Cl-Ph All NH _Two S 2 1514 4-Cl-Ph Bun (2) NH _Two S 2 1515 4-Cl-Ph Pre ⁱ NH _Two S 2 1516 4-Cl-Ph Prg NH _Two S 2 1517 4-Cl-Ph Pr ^c NH _Two S 2 1518 4-Cl-Ph Pn ^c NH _Two S 2 1519 4-Cl-Ph Pen ^c (2) NH _Two S 2 1520 4-Cl-Ph CN NH _Two S 2 1521 4-Cl-Ph COOH NH _Two S 2 1522 4-Cl-Ph Ac NH _Two S 2 1523 4-Cl-Ph COOMe NH _Two S 2 1524 4-Cl-Ph CONH _Two NH _Two S 2 1525 4-Cl-Ph CONHMe NH _Two S 2 1526 2,3-diCl-Ph H NH _Two O 2 1527 2,3-diCl-Ph Cl NH _Two O 2 1528 2,3-diCl-Ph Et NH _Two O 2 1529 2,3-diCl-Ph Pr NH _Two O 2 1530 2,3-diCl-Ph Pr ⁱ NH _Two O 2 1531 2,3-diCl-Ph Bu ⁱ NH _Two O 2 1532 2,3-diCl-Ph Bu ^t NH _Two O 2 1533 2,3-diCl-Ph H NH _Two S 2 1534 2,3-diCl-Ph Cl NH _Two S 2 1535 2,3-diCl-Ph Et NH _Two S 2 1536 2,3-diCl-Ph Pr NH _Two S 2 1537 2,3-diCl-Ph Pr ⁱ NH _Two S 2 1538 2,3-diCl-Ph Bu ⁱ NH _Two S 2 1539 2,3-diCl-Ph Bu ^t NH _Two S 2 1540 2,4-diCl-Ph Br NH _Two O 2 1541 2,4-diCl-Ph I NH _Two O 2 1542 2,4-diCl-Ph Pn NH _Two O 2 1543 2,4-diCl-Ph Hex NH _Two O 2 1544 2,4-diCl-Ph 1-Cl-Et NH _Two O 2 1545 2,4-diCl-Ph All NH _Two O 2 1546 2,4-diCl-Ph Bun (2) NH _Two O 2 1547 2,4-diCl-Ph Pre ⁱ NH _Two O 2 1548 2,4-diCl-Ph Prg NH _Two O 2 1549 2,4-diCl-Ph Pr ^c NH _Two O 2 1550 2,4-diCl-Ph Pn ^c NH _Two O 2 1551 2,4-diCl-Ph Pen ^c (2) NH _Two O 2 1552 2,4-diCl-Ph CN NH _Two O 2 1553 2,4-diCl-Ph COOH NH _Two O 2 1554 2,4-diCl-Ph Ac NH _Two O 2 1555 2,4-diCl-Ph COOMe NH _Two O 2 1556 2,4-diCl-Ph CONH _Two NH _Two O 2 1557 2,4-diCl-Ph CONHMe NH _Two O 2 1558 2,4-diCl-Ph Br NH _Two S 2 1559 2,4-diCl-Ph I NH _Two S 2 1560 2,4-diCl-Ph Pn NH _Two S 2 1561 2,4-diCl-Ph Hex NH _Two S 2 1562 2,4-diCl-Ph 1-Cl-Et NH _Two S 2 1563 2,4-diCl-Ph All NH _Two S 2 1564 2,4-diCl-Ph Bun (2) NH _Two S 2 1565 2,4-diCl-Ph Pre ⁱ NH _Two S 2 1566 2,4-diCl-Ph Prg NH _Two S 2 1567 2,4-diCl-Ph Pr ^c NH _Two S 2 1568 2,4-diCl-Ph Pn ^c NH _Two S 2 1569 2,4-diCl-Ph Pen ^c (2) NH _Two S 2 1570 2,4-diCl-Ph CN NH _Two S 2 1571 2,4-diCl-Ph COOH NH _Two S 2 1572 2,4-diCl-Ph Ac NH _Two S 2 1573 2,4-diCl-Ph COOMe NH _Two S 2 1574 2,4-diCl-Ph CONH _Two NH _Two S 2 1575 2,4-diCl-Ph CONHMe NH _Two S 2 1576 2,4-diCl-3-Me-Ph H NH _Two O 2 1577 2,4-diCl-3-Me-Ph Cl NH _Two O 2 1578 2,4-diCl-3-Me-Ph Et NH _Two O 2 1579 2,4-diCl-3-Me-Ph Pr NH _Two O 2 1580 2,4-diCl-3-Me-Ph Pr ⁱ NH _Two O 2 1581 2,4-diCl-3-Me-Ph Bu ⁱ NH _Two O 2 1582 2,4-diCl-3-Me-Ph Bu ^t NH _Two O 2 1583 2,4-diCl-3-Me-Ph H NH _Two S 2 1584 2,4-diCl-3-Me-Ph Cl NH _Two S 2 1585 2,4-diCl-3-Me-Ph Et NH _Two S 2 1586 2,4-diCl-3-Me-Ph Pr NH _Two S 2 1587 2,4-diCl-3-Me-Ph Pr ⁱ NH _Two S 2 1588 2,4-diCl-3-Me-Ph Bu ⁱ NH _Two S 2 1589 2,4-diCl-3-Me-Ph Bu ^t NH _Two S 2 1590 2,4-diCl-3-Et-Ph H NH _Two O 2 1591 2,4-diCl-3-Et-Ph Cl NH _Two O 2 1592 2,4-diCl-3-Et-Ph Et NH _Two O 2 1593 2,4-diCl-3-Et-Ph Pr NH _Two O 2 1594 2,4-diCl-3-Et-Ph Pr ⁱ NH _Two O 2 1595 2,4-diCl-3-Et-Ph Bu ⁱ NH _Two O
2 1596 2,4-diCl-3-Et-Ph Bu ^t NH _Two O 2 1597 2,4-diCl-3-Et-Ph H NH _Two S 2 1598 2,4-diCl-3-Et-Ph Cl NH _Two S 2 1599 2,4-diCl-3-Et-Ph Et NH _Two S 2 1600 2,4-diCl-3-Et-Ph Pr NH _Two S 2 1601 2,4-diCl-3-Et-Ph Pr ⁱ NH _Two S 2 1602 2,4-diCl-3-Et-Ph Bu ⁱ NH _Two S 2 1603 2,4-diCl-3-Et-Ph Bu ^t NH _Two S 2 1604 3,4-diCl-Ph H NH _Two O 2 1605 3,4-diCl-Ph Cl NH _Two O 2 1606 3,4-diCl-Ph Et NH _Two O 2 1607 3,4-diCl-Ph Pr NH _Two O 2 1608 3,4-diCl-Ph Pr ⁱ NH _Two O 2 1609 3,4-diCl-Ph Bu ⁱ NH _Two O 2 1610 3,4-diCl-Ph Bu ^t NH _Two O 2 1611 3,4-diCl-Ph H NH _Two S 2 1612 3,4-diCl-Ph Cl NH _Two S 2 1613 3,4-diCl-Ph Et NH _Two S 2 1614 3,4-diCl-Ph Pr NH _Two S 2 1615 3,4-diCl-Ph Pr ⁱ NH _Two S 2 1616 3,4-diCl-Ph Bu ⁱ NH _Two S 2 1617 3,4-diCl-Ph Bu ^t NH _Two S 2 1618 4-Pr ⁱ -Ph H NH _Two O 2 1619 4-Pr ⁱ -Ph Cl NH _Two O 2 1620 4-Pr ⁱ -Ph Et NH _Two O 2 1621 4-Pr ⁱ -Ph Pr NH _Two O 2 1622 4-Pr ⁱ -Ph Pr ⁱ NH _Two O 2 1623 4-Pr ⁱ -Ph Bu ⁱ NH _Two O 2 1624 4-Pr ⁱ -Ph Bu ^t NH _Two O 2 1625 4-Pr ⁱ -Ph H NH _Two S 2 1626 4-Pr ⁱ -Ph Cl NH _Two S 2 1627 4-Pr ⁱ -Ph Et NH _Two S 2 1628 4-Pr ⁱ -Ph Pr NH _Two S 2 1629 4-Pr ⁱ -Ph Pr ⁱ NH _Two S 2 1630 4-Pr ⁱ -Ph Bu ⁱ NH _Two S 2 1631 4-Pr ⁱ -Ph Bu ^t NH _Two S 2 1632 4-PhO-Ph H NH _Two O 2 1633 4-PhO-Ph Cl NH _Two O 2 1634 4-PhO-Ph Et NH _Two O 2 1635 4-PhO-Ph Pr NH _Two O 2 1636 4-PhO-Ph Pr ⁱ NH _Two O 2 1637 4-PhO-Ph Bu ⁱ NH _Two O 2 1638 4-PhO-Ph Bu ^t NH _Two O 2 1639 4-PhO-Ph H NH _Two S 2 1640 4-PhO-Ph Cl NH _Two S 2 1641 4-PhO-Ph Et NH _Two S 2 1642 4-PhO-Ph Pr NH _Two S 2 1643 4-PhO-Ph Pr ⁱ NH _Two S 2 1644 4-PhO-Ph Bu ⁱ NH _Two S 2 1645 4-PhO-Ph Bu ^t NH _Two S 2 1646 4-BnO-Ph H NH _Two O 2 1647 4-BnO-Ph Cl NH _Two O 2 1648 4-BnO-Ph Et NH _Two O 2 1649 4-BnO-Ph Pr NH _Two O 2 1650 4-BnO-Ph Pr ⁱ NH _Two O 2 1651 4-BnO-Ph Bu ⁱ NH _Two O 2 1652 4-BnO-Ph Bu ^t NH _Two O 2 1653 4-BnO-Ph H NH _Two S 2 1654 4-BnO-Ph Cl NH _Two S 2 1655 4-BnO-Ph Et NH _Two S 2 1656 4-BnO-Ph Pr NH _Two S 2 1657 4-BnO-Ph Pr ⁱ NH _Two S 2 1658 4-BnO-Ph Bu ⁱ NH _Two S 2 1659 4-BnO-Ph Bu ^t NH _Two S 2 1660 4-NO _Two -Ph H NH _Two O 2 1661 4-NO _Two -Ph Cl NH _Two O 2 1662 4-NO _Two -Ph Et NH _Two O 2 1663 4-NO _Two -Ph Pr NH _Two O 2 1664 4-NO _Two -Ph Pr ⁱ NH _Two O 2 1665 4-NO _Two -Ph Bu ⁱ NH _Two O 2 1666 4-NO _Two -Ph Bu ^t NH _Two O 2 1667 4-NO _Two -Ph H NH _Two S 2 1668 4-NO _Two -Ph Cl NH _Two S 2 1669 4-NO _Two -Ph Et NH _Two S 2 1670 4-NO _Two -Ph Pr NH _Two S 2 1671 4-NO _Two -Ph Pr ⁱ NH _Two S 2 1672 4-NO _Two -Ph Bu ⁱ NH _Two S 2 1673 4-NO _Two -Ph Bu ^t NH _Two S 2 1674 4-OH-Ph H NH _Two O 2 1675 4-OH-Ph Cl NH _Two O 2 1676 4-OH-Ph Et NH _Two O 2 1677 4-OH-Ph Pr NH _Two O 2 1678 4-OH-Ph Pr ⁱ NH _Two O 2 1679 4-OH-Ph Bu ⁱ NH _Two O 2 1680 4-OH-Ph Bu ^t NH _Two O 2 1681 4-OH-Ph H NH _Two S 2 1682 4-OH-Ph Cl NH _Two S 2 1683 4-OH-Ph Et NH _Two S 2 1684 4-OH-Ph Pr NH _Two S 2 1685 4-OH-Ph Pr ⁱ NH _Two S 2 1686 4-OH-Ph Bu ⁱ NH _Two S 2 1687 4-OH-Ph Bu ^t NH _Two S 2 1688 4-AcO-Ph H NH _Two O 2 1689 4-AcO-Ph Cl NH _Two O 2 1690 4-AcO-Ph Et NH _Two O 2 1691 4-AcO-Ph Pr NH _Two O 2 1692 4-AcO-Ph Pr ⁱ NH _Two O 2 1693 4-AcO-Ph Bu ⁱ NH _Two O 2 1694 4-AcO-Ph Bu ^t NH _Two O 2 1695 4-AcO-Ph H NH _Two S 2 1696 4-AcO-Ph Cl NH _Two S 2 1697 4-AcO-Ph Et NH _Two S 2 1698 4-AcO-Ph Pr NH _Two S 2 1699 4-AcO-Ph Pr ⁱ NH _Two S 2 1700 4-AcO-Ph Bu ⁱ NH _Two S 2 1701 4-AcO-Ph Bu ^t NH _Two S 2 1702 4-NH _Two -Ph H NH _Two O 2 1703 4-NH _Two -Ph Cl NH _Two O 2 1704 4-NH _Two -Ph Et NH _Two O 2 1705 4-NH _Two -Ph Pr NH _Two O 2 1706 4-NH _Two -Ph Pr ⁱ NH _Two O 2 1707 4-NH _Two -Ph Bu ⁱ NH _Two O 2 1708 4-NH _Two -Ph Bu ^t NH _Two O 2 1709 4-NH _Two -Ph H NH _Two S 2 1711 4-NH _Two -Ph Et NH _Two S
2 1712 4-NH _Two -Ph Pr NH _Two S 2 1713 4-NH _Two -Ph Pr ⁱ NH _Two S 2 1714 4-NH _Two -Ph Bu ⁱ NH _Two S 2 1715 4-NH _Two -Ph Bu ^t NH _Two S 2 1716 4-BzHN-Ph H NH _Two O 2 1717 4-BzHN-Ph Cl NH _Two O 2 1718 4-BzHN-Ph Et NH _Two O 2 1719 4-BzHN-Ph Pr NH _Two O 2 1720 4-BzHN-Ph Pr ⁱ NH _Two O 2 1721 4-BzHN-Ph Bu ⁱ NH _Two O 2 1722 4-BzHN-Ph Bu ^t NH _Two O 2 1723 4-BzHN-Ph H NH _Two S 2 1724 4-BzHN-Ph Cl NH _Two S 2 1725 4-BzHN-Ph Et NH _Two S 2 1726 4-BzHN-Ph Pr NH _Two S 2 1727 4-BzHN-Ph Pr ⁱ NH _Two S 2 1728 4-BzHN-Ph Bu ⁱ NH _Two S 2 1729 4-BzHN-Ph Bu ^t NH _Two S 2 1730 Fur (2) Br NH _Two O 2 1731 Fur (2) I NH _Two O 2 1732 Fur (2) Pn NH _Two O 2 1733 Fur (2) Hex NH _Two O 2 1734 Fur (2) 1-Cl-Et NH _Two O 2 1735 Fur (2) All NH _Two O 2 1736 Fur (2) Pre ⁱ NH _Two O 2 1737 Fur (2) Bun (2) NH _Two O 2 1738 Fur (2) Prg NH _Two O 2 1740 Fur (2) Pn ^c NH _Two O 2 1741 Fur (2) Pen ^c (2) NH _Two O 2 1742 Fur (2) CN NH _Two O 2 1743 Fur (2) COOH NH _Two O 2 1744 Fur (2) Ac NH _Two O 2 1745 Fur (2) COOMe NH _Two O 2 1746 Fur (2) CONH _Two NH _Two O 2 1747 Fur (2) CONHMe NH _Two O 2 1748 Fur (2) Br NH _Two S 2 1749 Fur (2) I NH _Two S 2 1750 Fur (2) Pn NH _Two S 2 1751 Fur (2) Hex NH _Two S 2 1752 Fur (2) 1-Cl-Et NH _Two S 2 1753 Fur (2) All NH _Two S 2 1754 Fur (2) Pre ⁱ NH _Two S 2 1755 Fur (2) Bun (2) NH _Two S 2 1756 Fur (2) Prg NH _Two S 2 1757 Fur (2) Pr ^c NH _Two S 2 1758 Fur (2) Pn ^c NH _Two S 2 1759 Fur (2) Pen ^c (2) NH _Two S 2 1760 Fur (2) CN NH _Two S 2 1761 Fur (2) COOH NH _Two S 2 1762 Fur (2) Ac NH _Two S 2 1763 Fur (2) COOMe NH _Two S 2 1764 Fur (2) CONH _Two NH _Two S 2 1765 Fur (2) CONHMe NH _Two S 2 1766 Thi (2) Br NH _Two O 2 1767 Thi (2) I NH _Two O 2 1768 Thi (2) Pn NH _Two O 2 1769 Thi (2) Hex NH _Two O 2 1770 Thi (2) 1-Cl-Et NH _Two O 2 1771 Thi (2) All NH _Two O 2 1772 Thi (2) Pre ⁱ NH _Two O 2 1773 Thi (2) Bun (2) NH _Two O 2 1774 Thi (2) Prg NH _Two O 2 1775 Thi (2) Pr ^c NH _Two O 2 1776 Thi (2) Pn ^c NH _Two O 2 1777 Thi (2) Pen ^c (2) NH _Two O 2 1778 Thi (2) CN NH _Two O 2 1779 Thi (2) COOH NH _Two O 2 1780 Thi (2) Ac NH _Two O 2 1781 Thi (2) COOMe NH _Two O 2 1782 Thi (2) CONH _Two NH _Two O 2 1783 Thi (2) CONHMe NH _Two O 2 1784 Thi (2) Br NH _Two S 2 1785 Thi (2) I NH _Two S 2 1786 Thi (2) Pn NH _Two S 2 1787 Thi (2) Hex NH _Two S 2 1788 Thi (2) 1-Cl-Et NH _Two S 2 1789 Thi (2) All NH _Two S 2 1790 Thi (2) Pre ⁱ NH _Two S 2 1791 Thi (2) Bun (2) NH _Two S 2 1792 Thi (2) Prg NH _Two S 2 1793 Thi (2) Pr ^c NH _Two S 2 1794 Thi (2) Pn ^c NH _Two S 2 1795 Thi (2) Pen ^c (2) NH _Two S 2 1796 Thi (2) CN NH _Two S 2 1797 Thi (2) COOH NH _Two S 2 1798 Thi (2) Ac NH _Two S 2 1799 Thi (2) COOMe NH _Two S 2 1800 Thi (2) CONH _Two NH _Two S 2 1801 Thi (2) CONHMe NH _Two S 2 1802 Ph 1-Cl-Pr NH _Two O 2 1803 Ph 1-Cl-Pr NH _Two S 2 1804 Ph 1-Cl-Bu ⁱ NH _Two O 2 1805 Ph 1-Cl-Bu ⁱ NH _Two S 2 1806 Ph 1-Cl-Pn ⁱ NH _Two O 2 1807 Ph 1-Cl-Pn ⁱ NH _Two S 2 1808 2,4-diMe-Ph H NH _Two O 2 1809 2,4-diMe-Ph Pr ⁱ NH _Two O 2 1810 3,5-diMe-Ph H NH _Two O 2 1811 3,5-diMe-Ph Pr ⁱ NH _Two O 2 In the isoxazole derivative having the general formula (I) of the present invention,
Among them, preferable compounds are 1, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 25,
27, 28, 29, 30, 32, 36, 48, 50, 5
4, 66, 70, 74, 93, 95, 99, 111, 1
12, 113, 114, 115, 116, 117, 12
5, 127, 131, 143, 146, 147, 14
8, 149, 150, 151, 152, 153, 15
4, 155, 170, 171, 172, 173, 17
4, 175, 176, 177, 178, 179, 18
0, 188, 190, 194, 206, 208, 21
2, 224, 226, 230, 242, 244, 24
8, 260, 262, 263, 264, 266, 27
8, 296, 298, 314, 316, 332, 33
4, 350, 357, 363, 368, 379, 38
6, 397, 408, 469, 475, 481, 50
5, 510, 511, 517, 523, 535, 53
8, 539, 540, 541, 542, 543, 54
4,545,546,562,568,574,58
0, 586, 592, 598, 604, 610, 61
6, 622, 628, 724, 728, 729, 73
0, 731, 732, 733, 752, 764, 77
6, 788, 794, 800, 806, 812, 81
8, 824, 1056, 1061, 1347, 134
8, 1349, 1350, 1351, 1357, 135
9, 1386, 1388, 1390, 1392, 139
4, 1396, 1398, 1400, 1402, 140
4, 1406, 1408, 1410, 1412, 141
4, 1416, 1459, 1495, 1499, 150
0, 1526, 1545, 1549, 1550, 157
6, 1590, 1604, 1618, 1632, 164
6, 1660, 1674, 1688, 1702, 171
6, 1809 or 1811 may be mentioned.

Further preferred compounds are 1, 4, 5,
6, 7, 8, 9, 11, 13, 14, 15, 30, 3
2, 36, 48, 50, 54, 66, 70, 74, 9
3, 95, 99, 111, 113, 117, 125, 1
27, 131, 143, 147, 149, 150, 15
1, 170, 172, 176, 188, 190, 19
4, 206, 208, 212, 224, 226, 23
0, 242, 244, 248, 260, 262, 26
3, 264, 266, 278, 296, 298, 31
4, 316, 332, 334, 350, 357, 36
3, 368, 379, 386, 397, 408, 46
9, 475, 481, 505, 510, 511, 51
7, 523, 535, 538, 539, 540, 54
1, 542, 543, 544, 545, 546, 56
2,568,574,580,586,592,59
8, 604, 610, 616, 622, 628, 72
4,728,729,730,731,732,73
3, 752, 764, 776, 788, 794, 80
0, 806, 812, 818, 824, 1056, 10
61, 1392, 1394, 1398, 1809 or 1
811 can be mentioned.

More preferred compounds include 1, 4,
5, 6, 7, 8, 9, 11, 13, 14, 15, 30,
48, 66, 74, 93, 111, 117, 125, 1
43, 149, 150, 151, 170, 176, 18
8, 206, 224, 242, 260, 296, 31
4, 332, 350, 368, 386, 408, 46
9, 475, 481, 505, 510, 511, 51
7, 523, 535, 538, 539, 543, 56
8, 586, 598, 604, 622, 724, 73
3, 1392, 1394 or 1398 may be mentioned.

Particularly preferred compounds are 1, 4, 5,
6, 7, 8, 9, 11, 13, 66, 93, 111, 1
17, 125, 143, 149, 150, 151, 17
0, 176, 224, 260, 332, 386, 51
0, 535, 539, 543, 604, 1392, 13
94 or 1398 can be mentioned.

The most preferable compound is exemplified compound number-1: 3- (2-aminoethoxy)
-5-Phenylisoxazole, Exemplified Compound No.-5: 3- (2-aminoethoxy)
-4-chloro-5-phenylisoxazole, Exemplified Compound No.-7: 3- (2-aminoethoxy)
-4-Ethyl-5-phenylisoxazole, Exemplified Compound No. -8: 3- (2-aminoethoxy)
-5-phenyl-4-propylisoxazole, Exemplified compound number-9: 3- (2-aminoethoxy)
-4-Isopropyl-5-phenylisoxazole, Exemplified Compound No.-11: 3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole, Exemplified Compound No.-117: 3- (2-amino Ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole, Exemplified compound number-143: 3- (2-Aminoethoxy) -5- (4-chlorophenyl) isoxazole, Exemplified compound number-151: 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole, Exemplified Compound No.-176: 3- (2-Aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropyl Isoxazole, Exemplified Compound No. -510: 3- (2-aminoethoxy) -5- (2-furyl) -4- Sopropylisoxazole, Exemplified Compound No.-535: 3- (2-Aminoethoxy) -5- (2-thienyl) isoxazole, Exemplified Compound No.-539: 3- (2-Aminoethoxy) -4-chloro-5 -(2-thienyl) isoxazole, Exemplified Compound No.-543: 3- (2-aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole, Exemplified Compound No.-1392: 4-allyl-3- (2
-Aminoethoxy) -5-phenylisoxazole may be mentioned.

[0046]

BEST MODE FOR CARRYING OUT THE INVENTION A method for producing the compound of the present invention will be described below.

[0047]

Embedded image

[0048]

Embedded image

[0049]

[Chemical 6]

In the above formula, R ¹ , R ² , R ³ , X and n
Represents the same meaning as described above, and R ³ _a represents a protected amino group or a protected mono C, which is the amino group or mono C ₁ -C ₆ alkylamino group contained in R ³ , respectively.
Besides being ₁ -C ₆ alkylamino group, with R ³ the same meaning, Y represents a hydroxyl group or a leaving group, Z is a halogen atom.

The protecting group for the amino group or mono-C ₁ -C ₆ alkylamino group for R ³ _a can be used without particular limitation as long as it is a group generally used as a protecting group for an amino group. , Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group,
C ₁ -C ₆ alkanoyl group such as pivaloyl group, valeryl group, isovaleryl group or hexanoyl group; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluoropropionyl group, 4,4-dichloro group Halogen or C ₁ such as butyryl group, methoxyacetyl group, butoxyacetyl group, ethoxypropionyl group or propoxybutyryl group.
A C ₁ -C ₄ alkanoyl group substituted with -C ₄ alkoxy; an unsaturated C ₁ -C ₄ alkanoyl group such as an acryloyl group, a propioloyl group, a methacryloyl group, a crotonoyl group or an isocrotonoyl group; a benzoyl group,
α-naphthoyl group, β-naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro-α-naphthoyl group, 4-
Toluoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group, 2,4,6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group, 4-anisoyl group, 4-propoxybenzoyl group, 4-t -Butoxybenzoyl group, 6-ethoxy-α-naphthoyl group, 2-ethoxycarbonylbenzoyl group, 4-t-butoxycarbonylbenzoyl group, 6-methoxycarbonyl-α-naphthoyl group, 4-phenylbenzoyl group, 4-phenyl- α-naphthoyl group, 6-α-naphthylbenzoyl group,
Halogen, C, such as 4-nitrobenzoyl group, 2-nitrobenzoyl group or 6-nitro-α-naphthoyl group
₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄
Alkoxycarbonyl, C ₆ -C ₁₀ ants - may be substituted with Le or nitro, C ₆ -C ₁₀ Ari - nyl group; a methoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
-Butoxycarbonyl group, t-butoxycarbonyl group,
Chloromethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,
2-dibromo -t- butoxycarbonyl group, triethylsilyl methoxycarbonyl group, 2-trimethylsilyl ethoxycarbonyl group, a halogen or a tri-C ₁ -C such as 4 tripropylsilyl butoxycarbonyl group or t- butyldimethylsilyl propoxycarbonyl group C ₁ -C ₄ alkoxycarbonyl group which may be substituted with ₄ alkylsilyl; C such as vinyloxycarbonyl group, allyloxycarbonyl group, 1,3-butadienyloxycarbonyl group or 2-pentenyloxycarbonyl group
_2- C ₅ alkenyloxycarbonyl group; aryldicarbonyl group such as phthaloyl group; benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, α-naphthylmethyl group, β-naphthylmethyl group, diphenyl An aralkyl group such as a methyl group, a triphenylmethyl group, an α-naphthyldiphenylmethyl group or a 9-anthrylmethyl group; or a benzyloxycarbonyl group,
(1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group A C ₇ -C ₁₅ aralkyloxycarbonyl group optionally substituted with methoxy or nitro, preferably C ₁ -C
₄ Alkanoyl group; trifluoroacetyl group; methoxyacetyl group; benzoyl group; α-naphthoyl group; β-naphthoyl group; anisoyl group; nitrobenzoyl group; C ₁
-C ₄ alkoxycarbonyl group; methoxycarbonyl group; ethoxycarbonyl group; t-butoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group; triethylsilylmethoxycarbonyl group; 2-trimethylsilylethoxycarbonyl group; vinyloxycarbonyl group; Allyloxycarbonyl group; phthaloyl group; benzyl group; benzyloxycarbonyl group; or nitrobenzyloxycarbonyl group, more preferably formyl group, acetyl group, benzoyl group, 4-anisoyl group, 4
-Nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, phthaloyl group, benzyl group, benzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, particularly preferably t- It is a butoxycarbonyl group.

The leaving group of Y is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue. For example, a halogen atom such as chlorine atom, bromine atom or iodine atom; methanesulfonyloxy. group, ethanesulfonyloxy group, propanesulfonyl group, or C ₁ -C ₄ alkanesulfonyloxy group such as butane sulfonyloxy group; trifluoromethanesulfonyloxy group, 2,2,2-trichloroethane sulfonyloxy group, 3,3, 3, -tribromopropanesulfonyloxy group or 4,4,4
A halogeno C ₁ -C ₄ alkanesulfonyloxy group, such as a trifluorobutanesulfonyloxy group; or a benzenesulfonyloxy group, an α-naphthylsulfonyloxy group, a β-naphthylsulfonyloxy group, a p-toluenesulfonyloxy group, 4-t-butylbenzenesulfonyloxy group, mesitylenesulfonyloxy group or 6-
C, such as an ethyl-α-naphthylsulfonyloxy group
_It may be a C ₆ -C ₁₀ arylsulfonyloxy group which may have 1 to 3 C ₁ -C ₄ alkyl, preferably a chlorine atom, a bromine atom, an iodine atom; a methanesulfonyloxy group,
Ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, 2,2,2-trichloroethanesulfonyloxy group; benzenesulfonyloxy group, toluenesulfonyloxy group or mesitylenesulfonyloxy group, more preferably chlorine atom, bromine atom, Iodine atom,
It is a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a mesitylenesulfonyloxy group.

The halogen atom of Z is, for example, a fluorine atom,
It may be a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.

Method A is a method for producing compound (I).

The step A1 is carried out in the presence or absence of a base (preferably in the presence of a base) in an inert solvent or in the absence of a solvent (preferably in an inert solvent), compound (II). Is a step of reacting with a halogenating agent to produce a compound having the general formula (III). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether,
It may be an ether such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, and preferably,
Halogenated hydrocarbons (especially methylene chloride) or ethers (especially tetrahydrofuran or dioxane).

Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; triethylamine, triethylamine. Butylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-
Diazabicyclo [4.3.0] non-5-ene (DB
N), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] organic amines such as undec-7-ene (DBU), preferably alkali metal carbonates or organic amines, more preferably organic amines (especially triethylamine or pyridine). .. The halogenating agent used is, for example, phosphorus oxychloride, phosphorus oxybromide,
It may be phosphorus oxyiodide or phosphorus pentachloride or a mixture thereof, preferably phosphorus oxychloride, phosphorus pentachloride or a mixture thereof.

The reaction temperature will vary depending on the starting compounds, reagents, etc., but is usually 0 ° C. to 150 ° C., preferably 10 ° C.
C. to 100.degree.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. The target compound is obtained by distilling off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step A2 is a step for producing a compound having the general formula (V) by reacting the compound (III) with the compound having the general formula (IV) in the presence of a base in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, dimethylformamide,
Amides such as dimethylacetamide or hexamethylphosphoric triamide; or may be sulfoxides such as dimethylsulfoxide or sulfolane, preferably
Ethers, amides or sulfoxides, more preferably ethers (especially diethyl ether, tetrahydrofuran or dioxane) or amides (especially dimethylformamide).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride. , Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine , Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5.
-Ene (DBN), 1,4-diazabicyclo [2.2.
2] organic amines such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyl lithiums such as methyl lithium, ethyl lithium or butyl lithium; or May be lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines, more preferably alkali metal carbonates. (Especially sodium carbonate or potassium carbonate) or alkali metal hydrides (especially sodium hydride).

In order to effectively carry out the reaction, crown ethers such as dibenzo-18-crown-6 may be added.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 150 ° C, preferably 0 ° C to 80 ° C.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 30 hours, preferably 1 hour to 10 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, the reaction solution is appropriately neutralized, and if an insoluble matter is present, it is filtered off if necessary, the solvent is distilled off, water is poured into the reaction solution, and a solvent immiscible with water (for example, benzene or ether). , Ethyl acetate, etc.)
After extraction with water and washing with water, the organic layer containing the target compound is dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step A3 is a step for producing a compound (I) by optionally removing the protecting group of the amino group or the alkylamino group.

The removal of the amino-protecting group varies depending on its type, but is generally carried out as follows by a method well known in the art of organic synthetic chemistry.

The amino-protecting group is a C ₁ -C ₆ alkanoyl group (preferably a formyl group or an acetyl group); C _6-
A C ₁₀ arylcarbonyl group (preferably a benzoyl group);
C ₁ -C ₄ alkoxycarbonyl group which may be substituted with halogen or tri C ₁ -C ₄ alkylsilyl (preferably methoxycarbonyl group, ethoxycarbonyl group, t-
Butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group or 2,2-dibromo-t-butoxycarbonyl group);
C ₂ -C ₅ alkenyloxycarbonyl group (preferably a vinyloxycarbonyl group); or methoxy, or may be substituted with nitro C ₇ -C ₁₅ aralkyloxycarbonyl group (preferably a benzyloxycarbonyl group, (1 -Phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group) with an acid in an inert solvent or an aqueous solvent. It can be removed by treatment. At that time, the target compound can be obtained as a salt. The acid used can be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably
Hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; methanol, ethanol, propanol , Alcohols such as isopropanol or butanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or It may be water or a mixed solvent of water and the above solvent, and is preferably a halogenated hydrocarbon, an ether, an alcohol, a fatty acid or water and the above solvent. A mixed solvent of, even more preferably halogenated hydrocarbons (particularly methylene chloride), ethers (particularly tetrahydrofuran or dioxane),
It is a fatty acid (particularly acetic acid) or water or a mixed solvent of water and the above solvent.

The reaction temperature varies depending on the starting compound, the solvent or the acid used, but it is usually -10 ° C to 150 ° C, preferably 0 ° C to 60 ° C.

The reaction time varies depending on the starting compound, the solvent or the acid used, but is usually 5 minutes to 20 hours, preferably 10 minutes to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, and a solvent immiscible with water (for example, benzene, ether, acetic acid). The target compound is obtained by washing the organic layer containing the target compound with water, drying it over anhydrous magnesium sulfate, etc., and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an alkanoyl group, an arylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aryldicarbonyl group, an aralkyl group or an aralkyloxycarbonyl group, it is used in an inert solvent or an aqueous solvent. It can be removed by treatment with a base in.

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; like methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metals, preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides (especially sodium methoxy). , Sodium ethoxide or potassium t-butoxide) or organic amines (especially hydrazine or methylamine).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol or butanol; Amides such as dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent,
Preferred are halogenated hydrocarbons, ethers, alcohols, or a mixed solvent of water and the above solvent, more preferred ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol), Alternatively, it is a mixed solvent of water and the above solvent.

The reaction temperature will vary depending on the starting compounds, solvent and base used, but it is usually from -10 ° C to 150 ° C.
And preferably 0 ° C. to 50 ° C.

The reaction time varies depending on the raw material compound, the solvent or the base used, but is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or the solvent is distilled off,
Water is poured into the reaction solution, the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, and the organic layer containing the target compound is washed with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is a tertiary butoxycarbonyl group, it can be removed by treating with a silyl compound or an acid, particularly in an inert solvent.

The silyl compound used can be, for example, trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyl trifluoromethanesulfonate, and the acid used can be, for example, aluminum chloride,
Hydrochloric acid or trifluoroacetic acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; Ethers such as diethyl ether, tetrahydrofuran or dioxane; may be nitriles such as acetonitrile, preferably halogenated hydrocarbons (especially methylene chloride, chloroform) or nitriles (especially acetonitrile). .

The reaction temperature will vary depending on the starting compounds, reagents, solvents, etc., but is usually -20 ° C to 100 ° C,
Preferably it is 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reagent, the solvent, the reaction temperature and the like, but is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off and the precipitated target compound is collected by filtration, or water is poured into the reaction solution to make the aqueous layer alkaline and the precipitate is collected by filtration,
Or a solvent immiscible with water (eg benzene, ether,
Ethyl acetate etc.) is added for extraction, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an allyloxycarbonyl group, palladium and triphenylphosphine or nickel tetracarbonyl are used, and a solvent similar to the method for removing the aralkyl group by a catalytic reduction reaction is used. It can be removed using reaction conditions such as reaction temperature, reaction time and the like.

The amino-protecting group is an aralkyl group or C
_{When it is a 7-} C ₁₁ aralkyloxycarbonyl group, it is usually contacted with a reducing agent (preferably, in an inert solvent).
The protecting group can be preferably removed by a method of removing by catalytic reduction (in the presence of a catalyst) or a method of removing by using an oxidizing agent. In the case of the reaction of removing the protecting group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in this reaction, and examples thereof include aliphatic hydrocarbons such as hexane or cyclohexane; toluene, benzene. Or aromatic hydrocarbons such as xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; such as methanol, ethanol or isopropanol Alcohols; fatty acids such as formic acid or acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers , Esters, alcohols, fatty acids, or a mixed solvent of these organic solvents and water, more preferably alcohols (especially methanol or Ethanol - Le), fatty acids (particularly formic acid or acetic acid), or a mixed solvent of these organic solvents and water.

The catalyst to be used is not particularly limited as long as it is used in a usual catalytic reduction reaction, but for example,
It can be palladium black, palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulphate, preferably palladium-carbon or Raney-nickel.

The pressure of hydrogen is not particularly limited, but is usually 1
To 10 atm, preferably 1 atm.

The reaction temperature varies depending on the starting compounds, the solvent, the reducing agent used, etc., but it is usually 0 ° C. to 100 ° C.
And preferably 10 ° C to 50 ° C.

The reaction time varies depending on the raw material compound, solvent, reducing agent used, reaction temperature and the like, but is usually 15 minutes to 10 hours, and preferably 30 minutes to 3 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, the catalyst is filtered off, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.). ) Is added and extracted, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The solvent used in the removal method by oxidation is not particularly limited as long as it does not participate in this reaction, and examples thereof include ketones such as acetone; halogens such as methylene chloride, chloroform or carbon tetrachloride. Hydrocarbons; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide Or a mixed solvent of these organic solvents and water,
Preferably, ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides, or a mixed solvent of these organic solvents and water, more preferably,
Ketones (especially acetone), halogenated hydrocarbons (especially methylene chloride), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethylsulfoxide) or their organic solvents and water. It is a mixed solvent with.

The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Preferred is ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature varies depending on the raw material compounds, the solvent, the oxidizing agent used, etc., but it is usually 0 ° C. to 150 ° C.
And preferably 10 ° C to 50 ° C.

The reaction time varies depending on the compound, the solvent, the oxidizing agent used, etc., but is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, water is poured into the reaction solution to make the aqueous layer alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate). Etc.) and extracted, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is removed with an acid, the desired compound is usually obtained in the form of a salt.
Generally, the amino group of the target compound can be converted into a free base by removing an acid used by a method well known in the art of organic chemistry.

Method B is a method for separately producing the compound (Va) in which X is an oxygen atom in the intermediate (V) of method A.

In step B1, compound (II) and general formula (I
In this step, a compound having Va) is reacted to produce compound (Va).

When Y is a hydroxyl group, basically, Burtin Chemical Society Japan, Vol. 40,
2380 pages (1967) [ Bull.Chem.Soc.Jap. , 40 , 23
80 (1967).] In the presence of phosphines and an azo compound in an inert solvent according to the Mitsunobu reaction.
It is carried out by dehydration condensation reaction of I) with the corresponding compound (IVa).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy. It may be an ether such as ethane or diethylene glycol dimethyl ether, preferably an aliphatic hydrocarbon,
Aromatic hydrocarbons or ethers, more preferably ethers (particularly diethyl ether or tetrahydrofuran).

The phosphines used are, for example, triC ₁ -C such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine.
₆ alkyl phosphine; triphenylphosphine, tri C ₆ -C ₁₀ arylphosphine such as tri indenyl phosphine or trinaphthylphosphine; or tolyl diphenyl phosphine, tritolylphosphine, trimesitylphosphine phosphine, tributyl triphenylphosphine or tri -
C ₁ -C ₄ such as 6-ethyl-2-naphthylphosphine
It may be tri C ₆ -C ₁₀ arylphosphine optionally having alkyl as a substituent, preferably tri C ₁ -C ₆ alkylphosphine (particularly trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, tri indenyl phosphine or trinaphthylphosphine), and more preferably a tri-C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine).

The azo compound used is not particularly limited as long as it is a known azodicarboxylic acid derivative. For example, dimethyl azodicarboxylate, diethyl azodicarboxylate,
It can be a di-C ₁ -C ₄ alkyl azodicarboxylate such as dipropyl azodicarboxylate or dibutyl azodicarboxylate, preferably dimethyl azodicarboxylate or diethyl azodicarboxylate.

The reaction temperature will vary depending on the starting compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if insoluble matter is present, it is filtered off and the solvent is distilled off,
Alternatively, pour water into the residue obtained by distilling off the solvent, add a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) and extract, then wash with water and dry over anhydrous magnesium sulfate, etc., and distill off the solvent. The target compound is obtained by. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When Y is a leaving group, compound (IVa) corresponding to compound (II) in the presence of a base in an inert solvent is used.
Can be reacted to give compound (Va).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, dimethylformamide,
Amides such as dimethylacetamide or hexamethylphosphoric triamide; or may be sulfoxides such as dimethylsulfoxide or sulfolane, preferably
Amides or sulfoxides, more preferably amides (particularly dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide).

The bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metals such as: triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithium such as methyllithium, ethyllithium or butyllithium; lithium such as lithium diisopropylamide or lithium dicyclohexylamide. It may be an alkylamide, preferably an alkali metal carbonate, an alkali metal hydride or an alkali metal hydroxide,
Alkali metal hydrides (particularly sodium hydroxide) are more preferable.

In order to effectively carry out the reaction, crown ethers such as dibenzo-18-crown-6 can be added.

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 20 hours, and preferably 1 hour to 5 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the reaction solution is appropriately neutralized, insoluble matter is removed by filtration, the solvent is distilled off, water is poured into the reaction solution, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate). Etc.), and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If the desired compound obtained is necessary,
It can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Method C is a method for separately producing compound (I) in Method A.

Step C1 is an optional step. Reaction (a): Reaction of introducing an alkyl group, an alkoxy group or a carboxy group into an isoxazole ring, an aromatic ring contained in R ¹ or the like, Reaction (b): Reaction introducing hydroxyalkyl group into isoxazole ring or aromatic ring contained in R ¹ , reaction (c): reaction converting hydroxy group contained in hydroxyalkyl group produced by reaction (b) into halogen atom, reaction ( d): 1,2-elimination (β elimination) of the hydroxy group contained in the hydroxyalkyl group produced by reaction (b), Reaction (e): Carbonyl hydroxyalkyl group produced by reaction (b) Reaction for converting to a group, Reaction (f): Reaction for esterifying a carboxy group, Reaction (g): Conversion of an alkoxycarbonyl group to a carbamoyl group Conversion reaction, reaction (h): conversion of carboxy group to carbamoyl group, reaction (i): conversion of carbamoyl group to cyano group, reaction (j): conversion of alkoxy group on aromatic ring to hydroxyl group Reaction, reaction (k): reaction of acylating hydroxyl group or amino group, reaction (l): reaction of aralkylating hydroxyl group or amino group, reaction (m): reaction of converting nitro group to amino group, and reaction ( n): A reaction for removing the protective group for the amino group contained in R ³ a and the like is included, and the order is appropriately changed.

Reaction (a): The reaction for introducing an alkyl group, an alkoxy group or a carboxy group into the isoxazole ring or the aromatic ring contained in R ¹ in the reaction (a) is carried out by a method well known in synthetic organic chemistry. Be seen. For example, in an inert solvent, in the presence of a base, halogeno C ₁ -C ₆ alkane, di C
It is carried out by reacting _1- C ₆ alkyl carbonate or carbon dioxide gas (preferably halogeno C ₁ -C ₆ alkane or carbon dioxide gas).

The halogeno C ₁ -C ₆ alkanes used are, for example, methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl iodide, propyl bromide, butyl iodide, pentyl iodide or hexyl iodide. It is possible, preferably methyl bromide or methyl iodide, more preferably methyl iodide.

The diC ₁ -C ₆ alkyl carbonates used are, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, disecondary butyl carbonate, ditertiary butyl carbonate,
It can be dipentyl carbonate or dihexyl carbonate, preferably dimethyl carbonate or diethyl carbonate.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as N, N, N ', N'-tetramethylethylenediamine Diamines; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably,
Ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).

Bases used are, for example, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkyl lithiums such as methyl lithium, ethyl lithium, butyl lithium or secondary butyl lithium; It may be a lithium alkylamide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably alkyllithium (especially butyllithium). ) Or lithium alkylamides (particularly lithium diisopropylamide).

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100 ° C to 30 ° C, preferably -70 ° C to 0 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, and preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and the water layer is acidified if desired, and then a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) Is added to extract the target compound, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (b): The reaction for introducing a hydroxyalkyl group into the isoxazole ring or the aromatic ring contained in R ¹ in the reaction (b) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with an aldehyde or a ketone in the presence of a base in an inert solvent.

Aldehydes can be straight or branched chain alkanals having 2 to 6 carbon atoms, such as acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde or hexaaldehyde. , Preferably C ₂ −
C ₄ alkanal, more preferably acetaldehyde.

Examples of the ketones include acetone, 2-butanone, 2-pentanone, 3-pentanone and 3-methyl-2.
-C3-C6 straight-chain or branched such as butanone, 2-hexanone, 3-hexanone, 3-methyl-2-pentanone, 4-methyl-2-pentanone or 3,3-dimethyl-2-butanone It may be a branched chain alkanone, preferably acetone, 2-butanone or 3-butanone, more preferably acetone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as N, N, N ', N'-tetramethylethylenediamine Diamines; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably,
Ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).

Bases used are, for example, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkyllithiums such as methyllithium, ethyllithium, butyllithium or secondary butyllithium; It may be a lithium alkylamide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably alkyllithium (especially butyllithium). ) Or lithium alkylamides (particularly lithium diisopropylamide).

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100 ° C to 30 ° C, preferably -70 ° C to 0 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, and preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. After washing the organic layer with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. Reaction (c): In the reaction (c), the reaction of converting the hydroxy group contained in the hydroxyalkyl group produced by the reaction (b) into a halogen atom is performed by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with a hydrohalic acid in an inert solvent.

The hydrohalic acid used is, for example,
It may be hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, preferably hydrochloric acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; or water or water And a mixed solvent of the above solvent, and preferably an ether (particularly dioxane) or a mixed solvent of ether and water. The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -50 ° C to 80 ° C.
C., preferably 0 to 50.degree. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, and preferably 10 minutes to 5 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent,
The target compound is extracted by adding a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.), the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and the target compound is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (d): In the reaction (d), the reaction of 1,2-eliminating (β-eliminating) the hydroxy group contained in the hydroxyalkyl group produced by the reaction (b) is
It is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with an acid in an inert solvent.

The acids used are, for example, mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfone. A sulfonic acid such as an acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid;
Alternatively it may be a carboxylic acid such as trifluoroacetic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably a mineral acid (especially hydrochloric acid).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
May be halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or esters such as methyl acetate or ethyl acetate, Preferred are ethers and esters, and more preferred are ethers (particularly dioxane). The reaction temperature will vary depending on the raw material compounds, reagents, etc., but is usually 0 ° C. to 150 ° C., and preferably 50
C. to 130.degree. The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours. After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (e): In the reaction (e), the reaction of converting the hydroxyalkyl group produced in the reaction (b) into a carbonyl group is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with an oxidizing agent in an inert solvent.

The oxidizing agent to be used is not particularly limited as long as it is usually used in an oxidation reaction. For example, manganese oxides such as potassium permanganate and manganese dioxide; ruthenium tetroxide and the like. Ruthenium oxides; silver compounds such as silver oxide; potassium chromate, chromate-
Inorganic metal oxidizers such as sulfuric acid complexes, chromic acid compounds such as chromic acid-pyridine complexes, cerium compounds such as ammonium cerium nitrate (CAN); reagents used for DMSO oxidation (dimethyl sulfoxide and dicyclohexylcarbodiimide, A complex with zalyl chloride, acetic anhydride or phosphorus pentoxide or a pyridine-sulfuric acid anhydride complex; succinimides such as N-bromosuccinimide; or 2,3-dichloro-5,6-dicyano-p It may be an organic oxidant such as a quinone compound such as benzoquinone (DDQ), preferably an inorganic metal oxidant or D
Reagents used for MSO oxidation, more preferably inorganic metal oxidizing agents (especially chromic acid-pyridine complex).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone; esters such as methyl acetate or ethyl acetate Nitriles such as acetonitrile; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent of these organic solvents and water, preferably Are halogenated hydrocarbons, ethers, ketones, nitriles, amides or sulfoxides, and more preferably halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature will vary depending on the starting compounds, reagents, etc., but is usually 0 ° C. to 100 ° C., preferably 20
C. to 50.degree. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 30 minutes to 48 hours, and preferably 1 hour to 30 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to give the target compound. After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (f): The reaction for esterifying the carboxy group in the reaction (f) is carried out by a method well known in synthetic organic chemistry. For example, (1) reacting with an esterifying agent in an inert solvent, or (2) reacting with an active esterifying agent in an inert solvent to produce an active ester, and then reacting with an alcohol in an inert solvent. Or
(3) It is carried out by reacting with a halogenating agent in an inert solvent to produce an acid halide, and then reacting with an alcohol in an inert solvent. The esterifying agent used in the reaction (f1) is not particularly limited as long as it is generally used in the technique of synthetic organic chemistry, and may be, for example, a diazoalkane or a trialkylsilyldiazoalkane, Suitably it may be a C ₁ -C ₆ diazoalkane such as diazomethane, diazoethane, diazopropane, diazobutane, diazopentane or diazohexane or trimethylsilyldiazomethane, more preferably C ₁
-C ₄ diazoalkane or trimethylsilyldiazomethane, particularly preferably diazomethane.

The solvent used in the reaction using the diazo C ₁ -C ₆ alkane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane and heptane. , Aliphatic hydrocarbons such as ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as methyl acetate or ethyl acetate Esters;
Or a mixed solvent of the above solvents, preferably halogenated hydrocarbons, ethers, esters or a mixed solvent of the above solvents, more preferably ethers (particularly diethyl ether), esters (particularly acetic acid) Ethyl) or a mixed solvent of the above solvents.

The solvent used in the reaction using trimethylsilyldiazomethane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, propanol, isopropanol, Alcohols such as butanol, isobutanol, t-butanol, pentanol or hexanol.
Or an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbon such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Selected from the group consisting of halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; and esters such as methyl acetate or ethyl acetate The solvent may be a mixed solvent of the above-mentioned solvent and the above-mentioned alcohols, preferably an alcohol (especially methanol) or an aromatic hydrocarbon (especially benzene) and an alcohol (especially methanol). It is a solvent.

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 minutes.
Time, preferably 15 minutes to 2 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after the reaction is completed. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The active esterifying agent used in the reaction (f2) is not particularly limited as long as it is generally used in the technology of synthetic organic chemistry, and for example, ethyl chloroformate, N-hydroxy. The active esterification reaction may be an N-hydroxy compound such as succinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or a disulfide compound such as dipyridyl disulfide. It is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The solvent used in both reactions is
There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether. Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or nitrites such as acetonitrile, Preferably ethers (especially tetrahydrofuran)
Or amides (particularly dimethylformamide). The reaction temperature varies depending on the raw material compounds, reagents, etc., but usually in the active esterification reaction, -70 ° C to 150 ° C.
(Preferably -10 ° C to 100 ° C), and -20 ° C to 1 in the reaction between the active ester compound and the alcohol.
The temperature is 00 ° C (preferably 0 ° C to 50 ° C). The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature, but in both reactions, it is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.
For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The halogenating agent used in the reaction (f3) is not particularly limited as long as it is generally used in the technology of synthetic organic chemistry, and examples thereof include oxalyl chloride, thionyl chloride and oxy. It can be phosphorus chloride or phosphorus pentachloride, preferably thionyl chloride.

The solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and for example, an aromatic hydrocarbon such as benzene, toluene or xylene. Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether,
It may be an ether such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably an ether (particularly tetrahydrofuran). The reaction temperature varies depending on the raw material compounds, reagents, etc., but usually it is -7 in the acid halide reaction.
It is 0 ° C to 150 ° C (preferably -10 ° C to 100 ° C), and -20 ° C to 100 ° C (preferably 0 ° C to 50 ° C) in the reaction between the acid halide and alcohol. The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature, but in both reactions, it is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (g): The reaction of converting the alkoxycarbonyl group into a carbamoyl group in the reaction (g) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting ammonia gas or concentrated ammonia water in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol. Diamines such as N, N, N ′, N′-tetramethylethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; or dimethylsulfoxide Or sulfoxides such as sulfolane, preferably ethers or alcohols, more preferably ethers (especially Tiger is a hydro furan).

The reaction temperature will vary depending on the starting compounds, reagents, etc., but is usually −10 ° C. to 100 ° C., and preferably 0 ° C. to 50 ° C. The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. After washing the organic layer with water,
The target compound is obtained by drying over anhydrous magnesium sulfate and the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (h): The reaction for converting a carboxy group into a carbamoyl group in the reaction (h) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by condensing with ammonia in an inert solvent according to a conventional method in peptide synthesis such as azide method, active ester method, mixed acid anhydride method or condensation method (preferably mixed acid anhydride method). . In the above method, the azide method includes hydrazine in an inert solvent (for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably dimethylformamide), -10 ° C to 100 ° C. The amino acid hydrazide obtained by the reaction at 0 ° C. (preferably 0 ° C. to 50 ° C.) is reacted with a nitrite compound to convert into an azide compound, and then treated with ammonia. The nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent, the solvent used being, for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;
It may be a sulfoxide such as dimethyl sulfoxide or sulfolane; or a pyrrolidone such as N-methylpyrrolidone, preferably an amide (particularly dimethylformamide). The two steps of this reaction (reaction with azidation and ammonia) are usually carried out in one reaction solution. The reaction temperature varies depending on the starting compounds, reagents, etc., but usually the azidation step is -70 ° C to 50 ° C (preferably -50 ° C to 0 ° C), and the reaction with ammonia is -70 ° C to The temperature is 50 ° C (preferably -10 ° C to 10 ° C). The time required for the reaction varies depending on the raw material compound, the reagent and the reaction temperature, but usually the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia is 5 hours. To 7 days (preferably 10 hours to 5 days). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The active ester method is performed by reacting with an active esterifying agent in an inert solvent to produce an active ester, and then reacting with ammonia in an inert solvent. The solvent used in both reactions does not interfere with the reaction,
There is no particular limitation as long as it dissolves the starting material to some extent, but for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or nitrites such as acetonitrile, preferably ethers ( In particular tetrahydrofuran) or amides (especially dimethylformamide). Active esterifying agents used include, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or dipyridyl disulfides. Such a disulfide compound may be used, and the active esterification reaction is suitably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature varies depending on the raw material compounds, reagents and the like, but usually in the active esterification reaction, -70 ° C to 150 ° C (preferably -10 ° C).
C. to 100.degree. C.), and -20.degree. C. to 100.degree. C. (preferably 0.degree. C.) in the reaction between the active ester compound and ammonia.
To 50 ° C). The time required for the reaction is the raw material compound,
Although it varies depending on the reagent and the reaction temperature, it is usually 30 minutes to 80 hours (preferably 1 to 48 hours) for both reactions. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The mixed acid anhydride method involves reacting a mixed acid anhydride agent in the presence of a base in an inert solvent to produce a mixed acid anhydride, and then reacting the mixed acid anhydride and ammonia in an inert solvent. Done. The solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, methylene chloride, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric acid It may be an amide such as a triamide, preferably an ether (particularly tetrahydrofuran).
Mixed acid anhydride agents are, for example, C ₁ -C ₄ alkyl halogenoformates such as ethyl chloroformate or isobutyl chloroformate, C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride or diethyl cyanophosphate or diphenyl. It may be a C ₁ -C ₄ alkyl such as cyanophosphate or a di C ₆ -C ₁₄ aryl cyanophosphate, preferably
Harogenogi acid C ₁ -C ₄ alkyl (especially isobutyl chloroformate). Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino). ) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona
5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.
4.0] organic amines such as undec-7-ene (DBU), preferably organic amines (especially triethylamine). The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the starting compounds, reagents and the like, but is usually -50 ° C to 100 ° C (preferably -10 ° C to 50 ° C). The reaction time in the reaction for producing the mixed acid anhydride varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 1 hour).
0 hours). The solvent used in the reaction of the mixed acid anhydride and ammonia is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example,
It may be an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether or an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably ethers ( Especially tetrahydrofuran). The reaction temperature in the reaction of the mixed acid anhydride and ammonia varies depending on the starting compounds, reagents, etc., but is usually -30 ° C to 100 ° C (preferably 0 ° C to 8 ° C).
0 ° C). The reaction time in the reaction of the mixed acid anhydride and ammonia varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. The condensation method is carried out by reacting directly with ammonia in the presence of a condensing agent in an inert solvent. The condensing agent used is, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-
It may be chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide. This reaction can be carried out under the same conditions as the reaction for producing the above-mentioned active ester. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.
For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (i): The reaction for converting the carbamoyl group into the cyano group in the reaction (i) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with a dehydrating agent in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as; esters such as methyl acetate or ethyl acetate; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexame Amides such as triphosphorous acid triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably amides (especially dimethyl Formamide). The dehydrating agent used can be, for example, phosphorus oxychloride, trifluoroacetic anhydride, methanesulfonyl chloride, paratoluenesulfonyl chloride or phosphorus pentoxide, preferably phosphorus oxychloride. The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -30
C. to 100.degree. C., preferably 0.degree. C. to 50.degree. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, and preferably 10 minutes.
Minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. The target compound is obtained by distilling off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (j): The reaction for converting the alkoxy group on the aromatic ring into a hydroxyl group in the reaction (j) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with aluminum chloride in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
May be halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or esters such as methyl acetate or ethyl acetate, Preferred are halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10 ° C to 100 ° C, preferably 10 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents, reaction temperature, etc., but it is usually 1 hour to 7 hours.
It is 2 hours, preferably 2 to 30 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, neutralized if desired, and then a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer is washed with water, and then anhydrous sulfuric acid is added. After drying with magnesium or the like, the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (k): The reaction of acylating the hydroxyl group or amino group in the reaction (k) is carried out by a method well known in synthetic organic chemistry. For example, an acylating agent (preferably alkanoyl halide, mixed acid anhydride of formic acid and acetic acid, alkanecarboxylic acid anhydride, arylcarbonyl) in an inert solvent in the presence or absence (preferably in the presence) of a base. Halide or aryl carboxylic acid anhydride). The alkanoyl halide used is, for example, acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide, isobutyryl chloride, valeryl chloride, pivaloyl chloride or hexanoyl chloride having 2 to 6 carbon atoms. it is straight-chain or branched-chain alkanoyl halide, preferably a C ₂ -C ₄ alkanoyl chloride, more preferably acetyl chloride. The alkanecarboxylic acid anhydride used is, for example, a straight chain having 4 to 12 carbon atoms such as acetic anhydride, propionic anhydride, butanoic acid, valeric acid anhydride, pivalic acid anhydride, pentanoic acid anhydride or hexanoic acid anhydride. or branched alkanes carboxylic acid anhydride obtained, preferably a C ₄ -C ₈ alkanecarboxylic acid anhydride, more preferably acetic anhydride. The arylcarbonyl halide used is, for example, benzoyl chloride, benzoyl bromide, fluorobenzoyl chloride, chlorobenzoyl chloride, dichlorobenzoyl chloride, toluoyl chloride, anisoyl chloride, indenoyl chloride, indenoyl bromide, naphthoyl chloride, naphthoyl. bromide, it is a C ₆ -C ₁₀ aryl carboxylic acid halide such as phenanthrylethynyl thread noil chloride or anthracenyl noil chloride, preferably benzoyl chloride. The aryl carboxylic acid anhydrides used are, for example, C such as benzoic anhydride, fluorobenzoic anhydride, chlorobenzoic anhydride, methylbenzoic anhydride, methoxybenzoic anhydride, indenylcarboxylic anhydride or naphthylcarboxylic anhydride. _It may be a _6- C ₁₀ aryl carboxylic acid anhydride, preferably benzoic anhydride. Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
It may be an organic amine such as diazabicyclo [5.4.0] undec-7-ene (DBU), preferably an organic amine (especially triethylamine, diisopropylethylamine, pyridine or 4- (N, N-dimethyl). Amino) pyridine). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene;
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, etc. Ketones; or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably ethers (especially tetrahydrofuran).

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -50 ° C to 100 ° C (preferably 0 ° C).
To 50 ° C). The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours). After the reaction,
The target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (l): The reaction for aralkylating a hydroxyl group or an amino group in the reaction (l) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with an aralkyl halide in the presence or absence (preferably in the presence) of a base in an inert solvent. Examples of the C ₆ -C ₄₈ aralkyl halide used include benzyl chloride, benzyl bromide, 4-chlorobenzyl chloride, 4-chlorobenzyl bromide, 4-bromobenzyl chloride, 4-bromobenzyl bromide,
2,4-difluorobenzyl chloride, 2,4-dichlorobenzyl chloride, 2,4-dichlorobenzyl bromide, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, trityl chloride, trityl bromide, dimethoxytrityl chloride or α-
Such as naphthyl diphenylmethyl chloride, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ 1 to 3 optionally C ₆ -C have a substituent the same or different and are selected from the group consisting of alkoxy ₄₈ aralkyl halides, preferably halogen, C ₁ -C ₄ alkyl and C _1-.
It is benzyl chloride or benzyl bromide, which may have 1 to 3 substituents which are the same or different and selected from the group consisting of C ₄ alkoxy, and more preferably benzyl chloride or benzyl bromide.

Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride. Alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine , Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5.
-Ene (DBN), 1,4-diazabicyclo [2.2.
2] organic amines such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyl lithiums such as methyl lithium, ethyl lithium or butyl lithium; or May be lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines, more preferably alkali metal carbonates. (Especially sodium carbonate or potassium carbonate) or alkali metal hydrides (especially sodium hydride).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone; or formamide, dimethylformamide,
It may be an amide such as dimethylacetamide or hexamethylphosphoric triamide, preferably an amide, especially dimethylformamide.

The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -50 ° C to 100 ° C (preferably 0 ° C).
To 50 ° C). The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and after neutralization as desired, a solvent immiscible with water (for example, benzene, ether,
The target compound is extracted by adding (ethyl acetate etc.), the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (m): The reaction for converting a nitro group into an amino group in the reaction (m) is carried out by a method well known in synthetic organic chemistry. For example, it is carried out by reacting with zinc in the presence of acetic acid in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether. Ethers such as; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol;
Diamines such as N, N, N ', N'-tetramethylethylenediamine; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; dimethylsulfoxide or sulfolane Sulfoxides; or water or a mixed solvent of water and the above solvent, preferably water. The reaction temperature is the raw material compound,
It varies depending on the reagent etc., but it is usually -10 ℃ to 100 ℃
And preferably 0 ° C. to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 1
It is 0 minutes to 10 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent,
After neutralization, a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (n): The reaction for removing the amino-group-protecting group contained in R ³ a and the like in the reaction (n) is carried out according to the above-mentioned A.
It is carried out under the same conditions as the three steps.

The compound having the general formula (II), which is the starting material compound of the present invention, is a known compound or can be produced according to a known method [eg, chemical abstract, Volume 74, 1255
21 (1970) [ Chem. Abstr. , 74 , 125521 (197
0).], Sankyo Institute Annual Report, Vol. 22, p. 215 (19)
70), Agricultural and Biological Chemistry, 50, 1831 (1986).
Year) [ Agric.Biol.Chem., EN , 50 , 1831 (1986).], Canadian Journal of Chemistry, Volume 48,
P. 1371 (1970) [ Can. J. Chem. , 48 , 1371 (19
70).], JP-A-59-216881, JP-B-43.
No. 14704, etc.]. The compound having the general formula (IV) or the general formula (IVa) is a known compound, or can be produced according to a known method. [For example, Synthesis, p. 366 (1990)
[ Synthesis , 366 (1990).], Journal of Medicinal Chemistry, 34, 1258 (199).
1 year) [ J. Med. Chem. , 34 , 1258 (1991).] Etc.]. In addition, the compound (II), which is the starting material compound of the present invention, is a known compound or can be produced according to a known method and is represented by the general formula (VI), (X) or (XIII). It can also be produced separately by reacting the compound possessed by the method described below.

[0162]

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[0163]

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[0164]

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In the above formula, R ¹ , R ² and Z have the same meanings as described above, R ² _a represents a specific substituent group in R ² (the substituent group is a halogen atom, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkyl group substituted by halogen or C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl groups, C
₂ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl group,
C ₃ -C ₁₀ cycloalkenyl group, consisting of C ₂ -C ₆ alkanoyl and C ₁ -C ₆ alkoxycarbonyl group. ) And R ⁴ represents a C ₁ -C ₆ alkyl group.

The alkyl group for R ⁴ is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2- Methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2 1 to 6 carbon atoms such as dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group or 2-ethylbutyl group Which is a straight chain or branched chain alkyl group, is preferably a C ₁ -C ₄ alkyl group, and is more preferably a methyl group or an ethyl group.

Method D is a method for producing the compound (II) which is the starting material compound in Method A or Method B.

In the step D1, the compound having the general formula (VI) is reacted with the active esterifying agent in (a) an inert solvent to produce an active ester, and then the compound having the general formula (VII) is added in an inert solvent. ) Or a compound (b)
By reacting with a halogenating agent in an inert solvent and then reacting with compound (VII), or (c) reacting with compound (VII) in the presence of an acid in an inert solvent to give a compound of general formula ( VIII) is a step of producing a compound having The step D1 (a) and the step D1 (b) are respectively the reaction (f2) and the reaction (f
It is performed under the same conditions as 3).

The acid used in Step D1 (c) is
There is no particular limitation as long as it is one generally used in the technology of synthetic organic chemistry, and hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, phosphoric acid, etc. Mineral acids; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid. It may be a carboxylic acid such as an acid, preferably a mineral acid (especially sulfuric acid). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone and methyl ethyl ketone; methanol, ethanol, propanol, isopropanol , Butanol or isobutanol, or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably alcohols (especially methanol or ethanol). The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -5
The temperature is 0 ° C to 150 ° C (preferably 20 ° C to 100 ° C). The reaction time varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound,
The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step D2 is a reaction of the compound (V
III) is reacted with a halogen molecule to give a compound of the general formula (IX)
Is a step of producing a compound having The halogen molecule used can be, for example, a chlorine molecule or a bromine molecule,
Preferred is a bromine molecule. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene;
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; acetone, methyl ethyl ketone Ketones; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably halogenated Hydrocarbons (especially chloroform or carbon tetrachloride). The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -50 ° C to 100 ° C (preferably 0 ° C.
To 50 ° C). The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it is usually 5 minutes to 12 hours (preferably 10 minutes to 5 hours). After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then extraction is performed. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step D3 is carried out in the presence of a base or in the absence of a base (preferably in the presence of a base) in an inert solvent, to give compound (IX).
Is a step of reacting with hydroxylamine or a hydroxylamine mineral acid salt (preferably a hydroxylamine mineral acid salt) to produce a compound (II). The hydroxylamine mineral acid salts used are, for example, hydroxylamine hydrofluoride, hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxylamine hydroiodide, hydroxylamine nitrate, hydroxylamine perchlorate, hydroxylamine sulfate. It may be an amine or hydroxylamine phosphate, preferably hydroxylamine hydrochloride. Method E is a method for separately producing the compound (II) which is a starting material compound in Method A or Method B. E
Step 1 is a step of producing a compound having the general formula (XII) by reacting the compound (X) with a compound having the general formula (XI) in the presence of a base in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene. Or aromatic hydrocarbons such as xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or like dimethyl sulfoxide or sulfolane Sulfoxides, preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably aromatic hydrocarbons (especially benzene) or ethers (especially tetrahydrofuran or dioxane). ).

Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate;
Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl mercaptan sodium Mercaptan alkali metals such as: triethylamine, tributylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8
Organic amines such as diazabicyclo [5.4.0] undec-7-ene (DBU); alkyl lithiums such as methyllithium, ethyllithium or butyllithium; lithium such as lithium diisopropylamide or lithium dicyclohexylamide. It may be an alkylamide, preferably a lithium alkylamide (especially lithium diisopropylamide) or an organic amine (especially 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)). . The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100 ° C to 1
The temperature is 00 ° C, preferably -70 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 48 hours, and preferably 10 minutes to 24 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent and pouring water into the reaction solution to make the reaction solution weakly acidic,
A solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added for extraction, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step E2 is carried out in the presence of a base or in the absence of a base (preferably in the presence of a base) in an inert solvent, and
I) is a step of reacting hydroxylamine or a hydroxylamine mineral acid salt (preferably a hydroxyamine mineral acid salt) to produce a compound (II), which is carried out under the same conditions as in step D3. .

[0174] Method F is, in the intermediates of Method E (XII), R ² is a halogen atom, C ₁ -C ₆ alkyl group, C ₁ substituted with halogen or C ₁ -C ₆ alkoxy
-C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆
Alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -
A compound which is a C ₁₀ cycloalkenyl group, a C ₂ -C ₆ alkanoyl group or a C ₁ -C ₆ alkoxycarbonyl group (X
This is a method of separately producing IIa).

The step F1 is carried out by reacting the compound of the general formula (XIII) with the compound of the general formula (XIII) in the presence of a base in an inert solvent.
This is a step of producing compound (XIIa) by reacting with a compound having IV), and is carried out under the same conditions as in step E1.

The isoxazole derivative (I) of the present invention is
It has an excellent A-type monoamine oxidase inhibitory action and weak toxicity, so depression, Parkinson's disease, Alzheimer's dementia (such as cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognition based on cerebrovascular dementia) It is useful as a therapeutic agent or preventive agent (particularly therapeutic agent) for neurological diseases (particularly depression) such as disorders.

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned neurological diseases, itself or an appropriate pharmacologically acceptable salt is used. It can be mixed with a form, a diluent and the like, and orally administered by tablets, capsules, granules, powders, syrups and the like, or parenterally by injections, suppositories and the like.

These formulations include excipients such as lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, α-starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxy. Cellulose derivatives such as methyl cellulose, carboxymethyl cellulose calcium, internally crosslinked sodium carboxymethyl cellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicates, silicate derivatives such as magnesium aluminometasilicate; phosphoric acid such as calcium phosphate Salt derivatives; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (for example, the above-mentioned excipients) Gelatin; polyvinylpyrrolidone;
), Disintegrants (eg, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinylpyrrolidone, cellulose derivatives, etc.), lubricants (eg, Talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; luxes such as bee gum and gallow; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium benzoate Carboxylic acid sodium salts such as; Sulfate salts such as sodium sulfate; Leucine; Lauryl sulfate salts such as sodium lauryl sulfate, magnesium lauryl sulfate; Silicic acids such as silicic anhydride and silicic acid hydrate; Stabilization of starch derivatives, etc.) (For example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), diluents, injection solvents (eg, water, ethanol, glycerin, etc.) It is manufactured by a known method. The amount used depends on symptoms, age, etc.,
In the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 2000 mg (preferably 400) per day.
In the case of intravenous administration, the daily lower limit is 0.1 mg (preferably 1 mg), and the upper limit is 500 mg.
(Preferably 300 mg) for adults, 1 per day
It is desirable to administer 6 to 6 times depending on the symptoms. Hereinafter, the present invention will be described in more detail by showing Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

[0179]

【Example】

Example 1 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl Isoxazole Triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (10 ml), diethyl azodicarboxylate (0.57 g) was added dropwise with stirring under ice-cooling, and 10
Stirred for minutes. 3-Hydroxy-5-phenylisoxazole (0.48 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) were added, and the mixture was stirred under ice cooling for 10 minutes and then at room temperature for 24 hours. It was stirred. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: cyclohexane / ethyl acetate = 4/1) and crystallized from isopropyl ether to give the desired compound (0.6
3 g, 69%) was obtained as colorless crystals. Melting point: 125-126 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 332
2,1721,1710,1619; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
4 (1H, brs), 6.14 (1H, s), 7.43
-7.51 (3H, m), 7.71-7.74 (2H,
m).

(B) 3- (2-aminoethoxy) -5
-Phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.5
0 g) with 4N hydrochloric acid / 1,4-dioxane solution (4.0
ml) was added and the mixture was stirred at room temperature for 15 minutes. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the object compound (0.39 g, 99%) as colorless crystals. Melting point: 215-218 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 313
2,2963, 2810, 2756, 1620, 159
7,1579; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, t, J = 5.1Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.85 (1H, s),
7.51-7.57 (3H, m), 7.84-7.87
(2H, m), 8.25 (3H, brs).

Example 2 3- (2-Aminoethoxy) -4-chloro-5-phenylisoxazole Hydrochloride (Exemplary Compound No. 5) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-chloro-5-phenylisoxazole 4-chloro-3-hydroxy-5-phenylisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) ) Is reacted in the same manner as in Example 1 (a) and post-treated to give
The target compound (0.73 g, 72%) was obtained as colorless crystals. Melting point: 115-116 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
6,1720,1709,1616; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.61 (2H, q, J = 5.1H
z), 4.42 (2H, t, J = 5.1Hz), 4.9.
7 (1H, brs), 7.46-7.53 (3H,
m), 7.94-8.00 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Chloro-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5-phenylisoxazole (0.54 g) was prepared in Example 1 (b). The target compound (0.41 g,
93%) as colorless crystals. Melting point: 204-207 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
1,905,2848,2775,1606,157
5,1534; NMR spectrum (DMSO-d ₆ ) δppm:
3.31 (2H, t, J = 5.1Hz), 4.56 (2
H, t, J = 5.1 Hz), 7.59-7.67 (3
H, m), 7.92-7.97 (2H, m), 8.27.
(3H, brs). Example 3 3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole hydrochloride (Exemplary compound number: 14)
3) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
Isoxazole 5- (4-chlorophenyl) -3-hydroxyaminoisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g)
Was treated in the same manner as in Example 1 (a) and post-treated to obtain the target compound (0.69 g, 68%) as colorless crystals. Melting point: 128-129 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 337
8, 1683, 1622; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
3 (1H, brs), 6.14 (1H, s), 7.43
(2H, d, J = 8.7 Hz), 7.66 (2H, d,
J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.54 g) was reacted in the same manner as in Example 1 (b). And post-treatment to obtain the target compound (0.43 g,
98%) as colorless crystals. Melting point: 218-223 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 313
5,2998,2809,1618,1603,159
4,1575,1567; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, t, J = 5.1Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.91 (1H, s),
7.63 (2H, d, J = 8.7Hz), 7.89 (2
H, d, J = 8.7 Hz), 8.25 (3, brs).

Example 4 3- (2-Aminoethoxy) -4-isopropyl-5-
Phenylisoxazole hydrochloride (Exemplary compound number:
9) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole 3-hydroxy-4-isopropyl-5-phenylisoxazole (0.50 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was treated in the same manner as in Example 1 (a) and post-treated to obtain the target compound (0.60 g, 69%) as colorless crystals. Melting point: 98-99 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 338
6, 1686, 1642; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
9 (6H, d, J = 6.8), 1.46 (9H, s),
3.06 (1H, q, J = 6.8), 3.60 (2H,
q, J = 5.1 Hz), 4.38 (2H, t, J = 5.
1Hz), 4.85 (1H, brs), 7.42-7.
50 (3H, m), 7.55-7.60 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole (0.50 g) was prepared in Example 1 (b). The target compound (0.39
g, 95%) as colorless crystals. Melting point: 202-210 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
5,2939,1642,1599,1575; NMR Spectrum (DMSO-d ₆₎ δppm:
1.26 (6H, d, J = 6.8Hz), 3.04 (1
H, q, J = 6.8 Hz), 3.28 (2H, t, J =
5.1 Hz), 4.46 (2H, t, J = 5.1H)
z), 7.50-7.64 (5H, m), 8.26 (3)
H, brs).

Example 5 3- (2-Aminoethoxy) -5- (2-thienyl) isoxazole hydrochloride (Exemplary Compound No. 535) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (2-Thienyl) isoxazole 3-Hydroxy-5- (2-thienyl) isoxazole (0.42 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were used in Example 1.
The target compound (0.63 g, 82%) was obtained as colorless crystals by reacting in the same manner as in (a) and post-treating. Melting point: 129-130 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 332
3,1708,1694,1618; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.34 (2H, t, J = 5.1Hz), 4.9.
3 (1H, brs), 6.05 (1H, s), 7.11
(1H, dd, J = 5.1Hz, J = 3.7Hz),
7.43-7.48 (2H, m).

(B) 3- (2-aminoethoxy) -5
-(2-Thienyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-thienyl) isoxazole (0.05 g) was reacted in the same manner as in Example 1 (b). And post-treatment to obtain the target compound (0.37 g, 95
%) As colorless crystals. Melting point: 278-283 ° C. (decomposition); IR spectrum (KBr) v _max cm ⁻¹ : 310
8, 3086, 2993, 2978, 2913, 161
3,1596; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.1Hz), 4.44 (2
H, t, J = 5.1 Hz), 6.69 (1H, s),
7.25 (1H, dd, J = 5.5Hz, J = 3.7H
z), 7.71 (1H, d, J = 3.7 Hz), 7.8
4 (1H, d, J = 5.5Hz), 8.25 (3H, b
rs).

Example 6 3- (2-Aminoethoxy) -4-chloro-5- (2-
Thienyl) isoxazole hydrochloride (Exemplified compound number: 539) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-thienyl) isoxazole 4-chloro-3-hydroxy-5- (2-thienyl) isoxazole (0.50 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was treated in the same manner as in Example 1 (a) and post-treated to obtain the target compound (0.57 g, 66%) as colorless crystals. Melting point: 94-95 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 334
2, 1718, 1708, 1622; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.60 (2H, q, J = 5.1H
z), 4.40 (2h, t, J = 5.1Hz), 4.9.
6 (1H, brs), 7.19 (1H, dd, J = 5.
2Hz, J = 3.6Hz), 7.56 (1H, d, J =
5.2 Hz), 7.74 (1 H, d, 3.6 Hz).

(B) 3- (2-aminoethoxy) -4
-Chloro-5- (2-thienyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (2-thienyl) isoxazole (0.40 g) By reacting in the same manner as in 1 (b) and post-treating, the target compound (0.3
1 g, 95%) was obtained as colorless crystals. Melting point: 278-283 ° C. (decomposition); IR spectrum (KBr) v _max cm ⁻¹ : 310
9, 2960, 2897, 1626, 1596, 157
9; NMR spectrum (DMSO = d ₆ ) δppm:
3.30 (2H, t, J = 5.1Hz), 4.54 (2
H, t, J = 5.1 Hz), 7.34 (1H, dd, J
= 5.1 Hz, J = 3.6 Hz), 7.83 (1H,
d, J = 3.6 Hz), 8.01 (1H, d, J = 5.
1 Hz), 8.26 (3H, brs).

Example 7 3- (2-Aminoethoxy) -5- (3-pyridyl) isoxazole Hydrochloride (Exemplified Compound No. 1056) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (3-Pyridyl) isoxazole 3-hydroxy-5- (3-pyridyl) isoxazole (0.41 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were added to Example 1.
The target compound (0.50 g, 65%) was obtained as colorless crystals by reacting in the same manner as in (a) and post-treating. Melting point: 97-98 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 324
9, 3145, 1712, 1626; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.37 (2H, t, J = 5.1Hz), 4.9.
4 (1H, brs), 6.25 (1H, s), 7.42
(1H, dd, J = 8.0 Hz, J = 4.9 Hz),
8.04 (1H, d, J = 8.0 Hz), 8.64 (1
H, d, J = 4.9 Hz), 8.97 (1 H, s).

(B) 3- (2-aminoethoxy) -5
-(3-Pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-pyridyl) isoxazole (0.48 g) was prepared in the same manner as in Example 1 (b). By reacting and post-treating, the target compound (0.41 g, 92
%) As colorless crystals. Melting point: 222-227 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 309
6,3068,3043,2967,2886,281
3,1641,1597,1539; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, q, J = 5.1Hz), 4.48 (2
H, t, J = 5.1 Hz), 7.11 (1H, s),
7.77 (1H, dd, J = 8.0Hz, J = 5.1H
z), 8.38 (3H, brs), 8.46 (1H,
d, J = 8.0 Hz), 8.79 (1H, d, J = 5.
1 Hz), 9.21 (1 H, s).

Example 8 3- (2-Aminoethoxy) -4-chloro-5- (3-
Pyridyl) isoxazole hydrochloride (Exemplified compound number: 1061) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-pyridyl) isoxazole 4-chloro-3-hydroxy-5- (3-Pyridyl) isoxazole (0.49 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g)
Was treated in the same manner as in Example 1 (a) and post-treated to obtain the target compound (0.54 g, 63%) as colorless crystals. Melting point: 76-77 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 335
3,3248, 1754, 1721, 1709, 161
6; NMR spectrum (CDCl ₃ ) δppm: 1.4
7 (9H, s), 3.62 (2H, q, J = 5.1H
z), 4.43 (2H, t, J = 5.1Hz), 4.9
7 (1H, brs), 7.45 (1H, dd, J = 8.
0 Hz, J = 5.1 Hz), 8.24 (1H, ddd,
J = 8.0 Hz, J = 2.0 Hz, J = 1.5 Hz),
8.72 (1H, dd, J = 5.1Hz, J = 1.5H
z), 9.24 (1H, d, J = 2.0 Hz).

(B) 3- (2-aminoethoxy) -4
-Chloro-5- (3-pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (3-pyridyl) isoxazole (0.40 g) was carried out. The reaction was performed in the same manner as in Example 1 (b) and post-treatment was carried out to give the target compound (0.3
5 g, 96%) was obtained as colorless crystals. Melting point: 205-210 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 310
3,3053,2937,2899,2875,282
3,2800, 1634, 1607, 1590, 154
1; NMR spectrum (DMSO-d ₆ ) δppm:
3.31 (2H, q, J = 5.1Hz), 4.59 (2
H, t, J = 5.1 Hz), 7.74 (1H, dd, J
= 8.0 Hz, J = 5.1 Hz), 8.40 (1H, d
dd, J = 8.0 Hz, J = 2.0 Hz, J = 1.5H
z), 8.40 (3H, brs), 8.82 (1H, d
d, J = 5.1 Hz, J = 1.5 Hz), 9.15 (1
H, d, J = 2.0 Hz).

Example 9 3- (2-Aminoethoxy) -5- (2-methoxyphenyl) isoxazole hydrochloride (Exemplary Compound No .: 35)
7) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methoxyphenyl) isoxazole Triphenylphosphine (0.45 g) was dissolved in tetrahydrofuran (5 ml) and ice-cooled. Diethyl azodicarboxylate (0.27 ml) was added dropwise with stirring, and the mixture was stirred at the same temperature for 3
After stirring for 0 minutes, 2- (N-tertiary butoxycarbonylamino) ethanol (0.20 g) and 3-hydroxy-5- (2-methoxyphenyl) isoxazole (0.22 g) were added, and the mixture was cooled to 10 on ice. After stirring for 1 minute, the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (0.33 g, 86%) as a colorless compound. Obtained as a solid. Melting point: 131-133 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 330
9, 1712, 1620; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 3.95 (3H, s), 4.36 (2H, t, J
= 5.2 Hz), 4.96 (1H, brs), 6.43
(1H, s), 7.00 (1H, d, J = 7.8H
z), 7.06 (1H, t, J = 7.8Hz), 7.4
1 (1H, ddd, J = 7.8Hz, J = 7.8Hz,
J = 1.7 Hz), 7.91 (1H, dd, J = 7.8)
Hz, J = 1.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(2-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methoxyphenyl) isoxazole (0.31 g) was added to 4N hydrochloric acid / 1,4 -Dissolved in dioxane solution (2.3 ml) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized using a mixed solvent of ethanol and isopropanol to give the desired compound (0.21 g, 84%).
Was obtained as colorless crystals. Melting point: 160-162 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
0,2959,2837,1621,1614; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.1Hz), 3.94 (3
H, s), 4.45 (2H, t, J = 5.1Hz),
6.56 (1H, s), 7.11 (1H, t, J = 7.
8Hz), 7.23 (1H, d, J = 7.8Hz),
7.52 (1H, ddd, J = 7.8Hz, J = 7.8
Hz, J = 1.7 Hz), 7.81 (1H, dd, J =
7.8 Hz, J = 1.7 Hz), 8.25 (3H, br
s).

Example 10 3- (2-Aminoethoxy) -5- (3-methoxyphenyl) isoxazole Hydrochloride (Exemplary Compound No. 36)
3) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-methoxyphenyl) isoxazole 3-hydroxy-5- (3-methoxyphenyl) isoxazole (0.22 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g)
The target compound (0.31 g, 82%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in Example 9 (a). Melting point: 89-90 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 331
2,1710; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 3.86 (3H, s), 4.35 (2H, t, J
= 5.2 Hz), 4.93 (1H, brs), 6.13
(1H, s), 6.96-7.00 (1H, m), 7.
26-7.42 (3H, m).

(B) 3- (2-aminoethoxy) -5
-(3-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-methoxyphenyl) isoxazole (0.29 g) was used in the same manner as in Example 9 (b). And recrystallized with a mixed solvent of ethanol and isopropanol to give the target compound (0.19
g, 83%) as colorless crystals. Melting point: 180-182 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
5, 2976, 2914, 1591; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1Hz), 3.84 (3
H, s), 4.45 (2H, t, J = 5.1Hz),
6.88 (1H, s), 7.09-7.11 (1H,
m), 7.38-7.48 (3H, m), 8.28 (3
H, brs).

Example 11 3- (2-Aminoethoxy) -5- (4-methoxyphenyl) isoxazole Hydrochloride (Exemplary Compound No. 35)
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methoxyphenyl) isoxazole 3-hydroxy-5- (4-methoxyphenyl) isoxazole (0.22 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g)
The target compound (0.32 g, 84%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in Example 9 (a). Melting point: 117-118 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 334
4, 1719, 1623; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 3.86 (3H, s), 4.34 (2H, t, J
= 5.2 Hz), 4.95 (1H, brs), 6.02
(1H, s), 6.96 (2H, d, J = 8.9H
z), 7.66 (2H, d, J = 8.9Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Methoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methoxyphenyl) isoxazole (0.30 g) was used in the same manner as in Example 9 (b). And then recrystallized using a mixed solvent of ethanol and isopropanol to give the target compound (0.17
g, 71%) as colorless crystals. Melting point: 190-193 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
0,2969,2950,2900,1617; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.1Hz), 3.83 (3
H, s), 4.43 (2H, t, J = 5.1Hz),
6.69 (1H, s), 7.09 (2H, d, J = 8.
9Hz), 7.79 (2H, d, J = 8.9Hz),
8.25 (3H, brs).

Example 12 3- (2-Aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride (Exemplary Compound No. 11)
1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl)
Isoxazole 5- (2-chlorophenyl) -3-hydroxy-isoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) were reacted in the same manner as in Example 9 (a), The target compound (0.35 g, 88%) was obtained as a colorless powder by post-treatment. Melting point: 125-127 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 333
3,1710,1697,1618; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2Hz), 4.9.
6 (1H, brs), 6.59 (1H, s), 7.33
-7.43 (2H, m), 7.46-7.54 (1H,
m), 7.87-7.94 (1H, m). (B) 3- (2-aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) isoxazole (0. 33 g) was reacted in the same manner as in Example 9 (b) and then recrystallized using isopropanol to obtain the target compound (0.20 g, 74%) as colorless crystals. Melting point: 141-144 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
3,2965,1610; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.278 (2H, t, J = 5.1Hz), 4.48
(2H, t, J = 5.1Hz), 6.80 (1H,
s), 7.52-7.60 (2H, m), 7.68 (1
H, dd, J = 7.5 Hz, J = 1.9 Hz), 7.8
7 (1H, dd, J = 7.5Hz, J = 1.9Hz),
8.27 (3H, brs).

Example 13 3- (2-Aminoethoxy) -5- (3-chlorophenyl) isoxazole Hydrochloride (Exemplary Compound No. 12)
5) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-chlorophenyl)
Isoxazole 5- (3-chlorophenyl) -3-hydroxy-isoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) were reacted in the same manner as in Example 9 (a), The target compound (0.34 g, 85%) was obtained as a colorless powder by post-treatment. Melting point: 117-119 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 338
5, 1685; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.36 (2H, t, J = 5.2Hz), 4.9.
3 (1H, brs), 6.16 (1H, s), 7.36
-7.44 (2H, m), 7.57-7.67 (1H,
m), 7.70 (1H, s).

(B) 3- (2-aminoethoxy) -5
-(3-Chlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-chlorophenyl) isoxazole (0.33 g) was reacted in the same manner as in Example 9 (b). After that, recrystallization is performed using a mixed solvent of ethanol and isopropanol to give the target compound (0.2
1 g, 78%) was obtained as colorless crystals. Melting point: 204-208 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
6,2980,2920,1619; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 5.1Hz), 4.45 (2
H, t, J = 5.1 Hz), 6.98 (1H, s),
7.56-7.63 (2H, m), 7.80-7.84
(1H, m), 7.96 (1H, s), 8.22 (3
H, brs).

Example 14 3- (2-Aminoethoxy) -4-methyl-5-phenylisoxazole Hydrochloride (Exemplified Compound No. 6) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-methyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
0 g) was dissolved in tetrahydrofuran (10 ml),
N-Butyllithium / n- at -70 ° C under nitrogen atmosphere
Hexane solution (1.56M, 1.4 ml) was added dropwise 10
Stirred for minutes. Then, methyl iodide (0.09 ml) was added dropwise, and the mixture was stirred for 10 minutes, heated to 0 ° C., poured into ice water, and the pH of the solution was adjusted to 6 using an aqueous solution of monopotassium phosphate. After that, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, and then dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (0.29 g, 94%) as a colorless powder. Melting point: 118-120 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 333
4, 2974, 1719, 1708; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.12 (3H, s), 3.59 (2
H, q, J = 5.1 Hz), 4.38 (2H, t, J =
5.1 Hz), 4.94 (1H, brs), 7.40-
7.53 (3H, m), 7.69 (2H, d, J = 7.
9 Hz).

(B) 3- (2-aminoethoxy) -4
-Methyl-5-phenylisoxazole hydrochloride 3- (2- (N-tertiarybutoxycarbonylamino) ethoxy) -4-methyl-5-phenylisoxazole (0.29 g) was prepared in Example 9 (b). After reacting in the same manner as above, recrystallization was performed using a mixed solvent of methanol and ethanol to give the target compound (0.18 g, 7
8%) as colorless crystals. Melting point: 245-250 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
3,2892,1516; NMR Spectrum (DMSO-d ₆₎ δppm:
2.13 (3H, s), 3.28 (2H, t, J = 5.
1Hz), 4.46 (2H, t, J = 5.1Hz),
7.50-7.59 (3H, m), 7.73 (2H,
d, J = 7.2 Hz), 8.21 (3H, brs).

Example 15 3- (2-Aminoethoxy) -4-ethyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 7) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-ethyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and ethyl iodide (0.12 ml) in Example 14
The target compound (0.24 g, 73%) was obtained as a colorless oily substance by reacting in the same manner as in (a) and post-treating. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2980, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
1 (3H, t, J = 7.5Hz), 1.46 (9H,
s), 2.56 (2H, q, J = 7.5Hz), 3.5
9 (2H, q, J = 5.2Hz), 4.38 (2H,
t, J = 5.2 Hz), 4.90 (1H, brs),
7.37-7.51 (3H, m), 7.64-7.68
(2H, m).

(B) 3- (2-aminoethoxy) -4
-Ethyl-5-phenylisoxazole hydrochloride 3- (2- (N-tertiary-butoxycarbonylamino) ethoxy) -4-ethyl-5-phenylisoxazole (0.21 g) was prepared in Example 9 (b). The target compound (0.12 g,
71%) as colorless crystals. Melting point: 210-215 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 296
8,2886,1518; NMR spectrum (DMSO-d ₆ ) δppm:
1.15 (3H, t, J = 7.5Hz), 2.58 (2
H, q, J = 7.5 Hz), 3.29 (2H, t, J =
5.1 Hz), 4.46 (2H, t, J = 5.1H)
z), 7.51-7.59 (3H, m), 7.67-
7.70 (2H, m), 8.25 (3H, brs).

Example 16 3- (2-Aminoethoxy) -5-phenyl-4-propylisoxazole hydrochloride (Exemplary Compound No. 8) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5-phenyl-4-propylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and propyl iodide (0.29 ml) in Example 14
The target compound (0.22 g, 65%) was obtained as a colorless oily substance by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2966, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
7 (3H, t, J = 7.4Hz), 1.46 (9H,
s), 1.56-1.69 (2H, m), 2.51 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.2 Hz), 4.37 (2H, t, J = 5.2H)
z), 4.90 (1H, brs), 7.43-7.53.
(3H, m), 7.65-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -5
-Phenyl-4-propylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propylisoxazole (0.18 g) was added to Example 9 (b). The target compound (0.10 g,
71%) as colorless crystals. Melting point: 119-121 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
0,2933,2872,1518; NMR Spectrum (DMSO-d ₆₎ δppm:
0.91 (3H, t, J = 7.3Hz), 1.51-
1.61 (2H, m), 2.54 (2H, t, J = 7.
7Hz), 3.28 (2H, t, J = 5.1Hz),
4.45 (2H, t, J = 5.1Hz), 7.50-
7.59 (3H, m), 7.68-7.70 (2H,
m), 8.20 (3H, brs).

Example 17 3- (2-Aminoethoxy) -4-butyl-5-phenylisoxazole hydrochloride (Exemplary Compound No. 10) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-butyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3
g) and butyl iodide (0.17 ml) in Example 14
The target compound (0.23 g, 66%) was obtained as a colorless oily substance by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2962, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
3 (3H, t, J = 7.3 Hz), 1.31-1.63
(4H, m), 1.46 (9H, s), 2.53 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.3 Hz), 4.38 (2H, t, J = 5.3H)
z), 4.90 (1H, brs), 7.42-7.51.
(3H, m), 7.65-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Butyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-butyl-5-phenylisoxazole (0.20 g) was prepared in Example 9 (b). The target compound (0.12 g,
75%) as colorless crystals. Melting point: 104-106 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 300
6,2963,2951,2931,28969,151
6; NMR spectrum (DMSO-d ₆ ) δppm:
0.87 (3H, t, J = 7.3Hz), 1.27-
1.37 (2H, m), 1.47-1.55 (2H,
m), 2.57 (2H, t, J = 7.7Hz), 3.2
8 (2H, t, J = 5.1Hz), 4.46 (2H,
t, J = 5.1 Hz), 7.51-7.59 (3H,
m), 7.68-7.70 (2H, m), 8.23 (3
H, brs).

Example 18 3- (2-Aminoethoxy) -4-hexyl-5-phenylisoxazole hydrochloride (Exemplified compound number: 138)
8) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Phenylisoxazole (0.4
g) and hexyl iodide (0.23 ml) in Example 14
The target compound (0.31 g, 61%) was obtained as a colorless powder by reacting in the same manner as in (a) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 338
7,2936,1715; NMR spectrum (CDCl ₃ ) δppm: 0.8
8 (3H, t, J = 6.6Hz), 1.23-1.42
(6H, m), 1.46 (9H, s), 1.53-1.
70 (2H, m), 2.52 (2H, t, J = 7.7H
z), 3.58 (2H, q, J = 5.1Hz), 4.3
7 (2H, t, J = 5.1Hz), 4.90 (1H, b
rs), 7.40-7.51 (3H, m), 7.65-
7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Hexyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole (0.2g) was prepared in Example 9 (b). The target compound (0.13 g,
81%) as colorless crystals. Melting point: 99-101 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 295
4, 2930, 1515; NMR spectrum (DMSO-d ₆ ) δppm:
0.83 (3H, t, J = 6.9Hz), 1.18-
1.32 (6H, m), 1.48-1.55 (2H,
m), 2.56 (2H, t, J = 7.7Hz), 3.2
8 (2H, t, J = 5.1Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.50-7.59 (3H,
m), 7.67-7.69 (2H, m), 8.16 (3
H, brs).

Example 19 3- (2-Aminoethoxy) -4-carboxy-5-phenylisoxazole hydrochloride (Exemplary Compound No. 14)
08) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Phenylisoxazole (2.0
0 g) was dissolved in tetrahydrofuran (20 ml),
Butyllithium (1.56
M hexane solution, 9.3 ml) was added dropwise and stirred for 10 minutes. Next, after bubbling carbon dioxide gas for 10 minutes, the temperature was raised to 0 ° C. The reaction solution was poured into ice water, and the pH of the solution was adjusted to 6 with an aqueous solution of monopotassium phosphate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then with anhydrous magnesium sulfate. Dried. After filtering
The solvent was evaporated under reduced pressure, and the obtained residue was washed with ether to give the object compound (2.18 g, 95%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 298
2,1706; NMR spectrum (DMSO-d ₆ ) δppm:
1.38 (9H, s), 3.38 (2H, q, J = 5.
7Hz), 4.29 (2H, t, J = 5.7Hz),
7.01 (1H, brs), 7.51-7.62 (3
H, m), 7.84-7.91 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Carboxy-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.12 g) was prepared in Example 9 (b). The target compound (0.06
g, 60%) as colorless crystals. Melting point: 180-183 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 314
9, 2873, 2820, 1755, 1709; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.3Hz), 4.54 (2
H, t, J = 5.3 Hz), 7.54-7.65 (3
H, m), 7.85-7.87 (2H, m), 8.22
(3H, brs). Example 20 3- (2-Aminoethoxy) -4-carbamoyl-5-
Phenylisoxazole hydrochloride (Exemplary compound number:
1414) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -Carboxy-5-phenylisoxazole (0.6 g) in tetrahydrofuran (6 ml)
And carbonyldiimidazole (0.31 g) were added under ice-cooling stirring, and the mixture was stirred at room temperature for 30 minutes.
Aqueous ammonia (1 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
Stirred for hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the target compound (0.60 g, quantitative) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 343
9,3371,3149,1694,1680; NMR Spectrum (DMSO-d ₆₎ δppm:
1.39 (9H, s), 3.39 (2H, q, J = 5.
0Hz), 4.30 (2H, t, J = 5.0Hz),
7.38 (1H, brs), 7.51 to 7.57 (3
H, m), 7.71 (1H, brs), 7.91-7.
94 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Carbamoyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole (0.22g) was prepared in Example 9 (b). The target compound (0.13
g, 72%) as colorless crystals. Melting point: 225-230 ° C. (decomposition); IR spectrum (KBr) v _max cm ⁻¹ : 340
7, 3213, 2963, 2878, 1662; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.32 (2H, t, J = 4.9Hz), 4.54 (2
H, t, J = 4.9 Hz), 7.52-7.60 (4
H, m), 7.77 (1H, brs), 7.92-7.
94 (2H, m), 8.29 (3H, brs).

Example 21 3- (2-Aminoethoxy) -4-cyano-5-phenylisoxazole hydrochloride (Exemplary compound number: 140)
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -Carbamoyl-5-phenylisoxazole (0.38 g) was added to dimethylformamide (4
ml), phosphorus oxychloride (0.11 ml) was added dropwise at 5 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate,
The organic layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give the target compound (0.28 g, 7
8%) as a colorless solid. IR spectrum (KBr) ν _max cm ⁻¹ : 338
4,2237,1690,1680; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.2H
z), 4.43 (2H, t, J = 5.2Hz), 4.9
7 (1H, brs), 7.52-7.64 (3H,
m), 8.01-8.05 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyano-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole (0.25 g) was prepared in Example 9 (b). The target compound (0.13 g,
65%) as colorless crystals. Melting point: 200-205 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 296
7,2236,1611; NMR Spectrum (DMSO-d ₆₎ δppm:
3.32 (2H, t, J = 5.1Hz), 4.60 (2
H, t, J = 5.1 Hz), 7.68-7.76 (3
H, m), 7.98-8.01 (2H, m), 8.29.
(3H, brs). Example 22 3- (2-Aminoethoxy) -4-methoxycarbonyl-5-phenylisoxazole hydrochloride (Exemplary compound number: 1412) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -4-Methoxycarbonyl-5
-Phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) in a mixed solution of methanol and benzene (1: 5, 10 ml ), Trimethylsilyldiazomethane (0.6 ml, 2.0 M hexane solution) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give the target compound (0.17 g, 81 %) As a colorless solid. IR spectrum (KBr) ν _max cm ⁻¹ : 335
5, 1725, 1691; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.62 (2H, q, J = 5.1H
z), 3.85 (3H, s), 4.43 (3H, t, J
= 5.1 Hz), 5.03 (1H, brs), 7.46
-7.54 (3H, m), 7.87-7.91 (2H,
m).

(B) 3- (2-aminoethoxy) -4
-Methoxycarbonyl-5-phenylisoxazole
Hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-5-phenylisoxazole (0.16 g) was reacted in the same manner as in Example 9 (b) and post-treated. By doing so, the target compound (0.08 g, 62%) was obtained as colorless crystals. Melting point: 195-198 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 314
8, 2870, 2848, 2821, 1708; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.2Hz), 3.77 (3
H, s), 4.54 (2H, t, J = 5.2Hz),
7.56-7.66 (3H, m), 7.85-7.87
(2H, m), 8.24 (3H, brs).

Example 23 3- (2-Aminoethoxy) -4-methylaminocarbonyl-5-phenylisoxazole hydrochloride (Exemplified compound number: 1416) (a) 3- (2- (N-tert-butoxy) Carbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) And methylamine (30% methanol solution, 0.12 ml) were reacted in the same manner as in Example 20 (a) and post-treated to give the target compound (0.18
g, 87%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 340
5,3369,1677; NMR spectrum (CDCl ₃ ) δppm: 1.4
5 (9H, s), 2.97 (3H, d, J = 5.0H
z), 3.64 (2H, q, J = 5.1Hz), 4.4
4 (2H, t, J = 5.1Hz), 4.90 (1H, b
rs), 7.30 (1H, brs), 7.46-7.5
0 (3H, m), 8.05-8.09 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Methylaminocarbonyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole (0.17 g) 14
The target compound (0.08 g, 57%) was obtained as colorless crystals by reacting in the same manner as in (a) and post-treating. Melting point: 223-226 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 310
2,2935,2879,1646; NMR Spectrum (DMSO-d ₆₎ δppm:
2.78 (3H, d, J = 4.4Hz), 3.32 (2
H, t, J = 4.8 Hz), 4.53 (2H, t, J =
4.8 Hz), 7.51-7.60 (3 H, m), 7.
89-7.92 (2H, m), 8.18 (1H, d, J
= 4.4 Hz), 8.31 (3H, brs).

Example 24 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-methylisoxazole hydrochloride (Exemplary Compound No. 148) (a) 3- (2- (N-Tersia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Methylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.25 g) and methyl iodide (0.06 ml)
Was reacted in the same manner as in Example 14 (a) and post-treated to obtain the target compound (0.23 g, 89%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 334
4, 2980, 1682; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.10 (3H, s), 3.58 (2
H, q, J = 5.2 Hz), 4.37 (2H, t, J =
5.2 Hz), 4.90 (1H, brs), 7.45
(2H, d, J = 8.6 Hz), 7.63 (2H, d,
J = 8.6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-methylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-methylisoxazole (0.22 g Was treated in the same manner as in Example 9 (b) and post-treated to obtain the target compound (0.09 g, 50%) as colorless crystals. Melting point: 248-253 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 302
0, 2991, 2884, 1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.12 (3H, s), 3.27 (2H, t, J = 5.
1Hz), 4.45 (2H, t, J = 5.1Hz),
7.63 (2H, d, J = 8.6Hz), 7.75 (2
H, d, J = 8.6 Hz), 8.23 (3H, br
s).

Example 25 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole Hydrochloride (Exemplified Compound No. 149) (a) 3- (2- (N-Tersia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Ethylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and ethyl iodide (0.11 ml) were used in Example 14. The target compound (0.26 g, 61%) was obtained as a colorless oily substance by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2980, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
0 (3H, t, J = 7.4Hz), 1.46 (9H,
s), 2.54 (2H, q, J = 7.4Hz), 3.5
9 (2H, q, J = 5.2Hz), 4.37 (2H,
t, J = 5.2 Hz), 4.90 (1H, brs),
7.45 (2H, d, J = 8.5Hz), 7.59 (2
H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-ethylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole (0.22 g Was reacted in the same manner as in Example 9 (b) and post-treated to obtain the target compound (0.13 g, 72%) as colorless crystals. Melting point: 217-220 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
2,2892,1515; NMR Spectrum (DMSO-d ₆₎ δppm:
1.14 (3H, t, J = 7.5Hz), 2.58 (2
H, q, J = 7.5 Hz), 3.28 (2H, t, J =
5.2 Hz), 4.46 (2H, t, J = 5.2H)
z), 7.64 (2H, d, J = 8.6Hz), 7.7
1 (2H, d, J = 8.6Hz), 8.20 (3H, b
rs).

Example 26 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-propylisoxazole hydrochloride (Exemplary Compound No. 150) (a) 3- (2- (N-tertiary) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-Propylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and propyl iodide (0.14 ml)
Was treated in the same manner as in Example 14 (a) and post-treated to obtain the target compound (0.21 g, 47%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 339
2, 2963, 1685; NMR spectrum (CDCl ₃ ) δppm: 0.9
6 (3H, t, J = 7.4Hz), 1.46 (9H,
s), 1.57-1.69 (2H, m), 2.49 (2
H, t, J = 7.6 Hz), 3.58 (2H, q, J =
5.2 Hz), 4.37 (2H, t, J = 5.2H)
z), 4.87 (1H, brs), 7.45 (2H,
d, J = 8.6 Hz), 7.60 (2H, d, J = 8.
6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-propylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-propylisoxazole (0.19 g ) To Example 9 (b)
The target compound (0.13 g, 81%) was obtained as colorless crystals by reacting in the same manner as above and post-treating. Melting point: 146-149 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 295
8,2871,2829,1516; NMR Spectrum (DMSO-d ₆₎ δppm:
0.90 (3H, t, J = 7.3Hz), 1.50-
1.59 (2H, m), 2.54 (2H, t, J = 7.
3Hz), 3.28 (2H, t, J = 5.2Hz),
4.45 (2H, t, J = 5.2Hz), 7.63 (2
H, d, J = 8.7 Hz), 7.72 (2H, d, J =
8.7 Hz), 8.21 (3H, brs).

Example 27 3- (2-Aminoethoxy) -5- (4-methylphenyl) isoxazole Hydrochloride (Exemplified Compound No .: 26)
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl)
Isoxazole 3-hydroxy-5- (4-methylphenyl) isoxazole (1.5 g) and 2- (N-tert-butoxycarbonylamino) ethanol (1.5 g) were added in Example 9.
The target compound (2.2 g, 82%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (KBr) ν _max cm ⁻¹ : 337
5,3356,3332,1719,1684; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.40 (3H, s), 3.56 (2
H, q, J = 5.1 Hz), 4.35 (2H, t, J =
5.1 Hz), 4.94 (1H, brs), 6.09
(1H, s), 7.26 (2H, d, J = 8.1H
z), 7.61 (2H, d, J = 8.1Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl) isoxazole (0.3 g) was used in the same manner as in Example 9 (b). The target compound (0.16 g,
67%) as colorless crystals. Melting point: 215-220 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
3,2979,1622; NMR Spectrum (DMSO-d ₆₎ δppm:
2.37 (3H, s), 3.25 (2H, t, J = 5.
0Hz), 4.44 (2H, t, J = 5.0Hz),
6.76 (1H, s), 7.35 (2H, d, J = 8.
1Hz), 7.74 (2H, d, J = 8.1Hz),
8.26 (3H, brs).

Example 28 3- (2-Aminoethoxy) -5- (4-trifluoromethylphenyl) isoxazole hydrochloride (Exemplary compound No. 332) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (4-trifluoromethylphenyl) isoxazole 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol ( 0.15
g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.26 g, 81%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 337
6,1679,1608; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H
z), 4.37 (2H, t, J = 5.1Hz), 4.9.
2 (1H, brs), 6.25 (1H, s), 7.72
(2H, d, J = 8.2 Hz), 7.84 (2H, d,
J = 8.2 Hz).

(B) 3- (2-aminoethoxy) -5
Example 1 The target compound (0.14 g, 70%) was obtained as colorless crystals by reacting in the same manner as in b) and post-treating. Melting point: 226-232 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
3,2965,2914,1608; NMR spectrum (DMSO-d ₆ ) δppm:
3.27 (2H, t, J = 5.1Hz), 4.47 (2
H, t, J = 5.1 Hz), 7.07 (1H, s),
7.93 (2H, d, J = 8.3Hz), 8.09 (2
H, d, J = 8.3 Hz), 8.26 (3H, br
s).

Example 29 3- (2-Aminoethoxy) -5- (4-fluorophenyl) isoxazole hydrochloride (Exemplified compound No. 6)
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole 5- (4-fluorophenyl) -3-hydroxyisoxazole (0.06 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.06 g) were reacted in the same manner as in Example 9 (a) and post-treated to give the target compound (0.08 g, 74%) as a colorless compound. Was obtained as a powder of. IR spectrum (KBr) ν _max cm ⁻¹ : 337
5, 1682; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
3 (1H, brs), 6.09 (1H, s), 7.15
(2H, t, J = 8.6 Hz), 7.71 (2H, d
d, J = 8.6 Hz, J = 5.3 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Fluorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole (0.05 g) was used in the same manner as in Example 9 (b). The target compound (0.02
g, 56%) as colorless crystals. Melting point: 232-238 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
3,2978,2911,1621; NMR Spectrum (DMSO-d ₆₎ δppm:
3.26 (2H, t, J = 5.0Hz), 4.44 (2
H, t, J = 5.0 Hz), 6.84 (1H, s),
7.40 (2H, t, J = 8.8Hz), 7.93 (2
H, dd, J = 8.8 Hz, J = 5.3 Hz), 8.2
5 (3H, brs).

Example 30 3- (2-Aminoethoxy) -5- (1-naphthyl) isoxazole Hydrochloride (Exemplified Compound No. 475) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -5- (1-Naphthyl) isoxazole 3-hydroxy-5- (1-naphthyl) isoxazole (0.20 g) and 2- (N-tertiarybutoxycarbonylamino) ethanol (0.17 g) were used in Example 9.
The target compound (0.30 g, 89%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (KBr) ν _max cm ⁻¹ : 331
8,1712; NMR spectrum (CDCl ₃ ) δppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.3H
z), 4.42 (2H, t, J = 5.3Hz), 4.9
7 (1H, brs), 6.25 (1H, s), 7.52
-7.61 (3H, m), 7.77-7.79 (1H,
m), 7.90-7.99 (2H, m), 8.27-
8.31 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(1-Naphthyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (1-naphthyl) isoxazole (0.28 g) was reacted in the same manner as in Example 9 (b). And post-treatment to obtain the target compound (0.18 g, 78
%) As colorless crystals. Melting point: 201-205 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
2,2968,2913,1602; NMR Spectrum (DMSO-d ₆₎ δppm:
3.31 (2H, t, J = 5.1Hz), 4.52 (2
H, t, J = 5.1 Hz), 6.83 (1H, s),
7.63-7.70 (3H, m), 7.87-7.89
(1H, m), 8.07-8.25 (3H, m), 8.
30 (3H, brs).

Example 31 3- (2-aminoethoxy) -4-bromo-5-phenylisoxazole hydrochloride (Exemplary compound number: 135)
7) (a) 4-Bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 4-bromo-3-hydroxy-5-phenylisoxazole (0.2 g ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g).
The target compound (0.26 g, 81%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (KBr) ν _max cm ⁻¹ : 335
2, 2976, 1719, 1709; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.1H
z), 4.41 (2H, t, J = 5.1Hz), 4.9.
7 (1H, brs), 7.47-7.55 (3H,
m), 7.98-8.04 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Bromo-5-phenylisoxazole hydrochloride 4-Bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.24 g) was prepared in Example 9 (b). The target compound (0.13 g,
65%) as colorless crystals. Melting point: 192-198 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
1,292,1894,1614,1594,157
4; NMR spectrum (DMSO-d ₆ ) δppm:
3.32 (2H, t, J = 5.1Hz), 4.54 (2
H, t, J = 5.1 Hz), 7.60-7.66 (3
H, m), 7.95-7.98 (2H, m), 8.19.
(3H, brs). Example 32 3- (2-aminoethoxy) -4-iodo-5-phenylisoxazole hydrochloride (Exemplary compound number: 135)
9) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodo-5-phenylisoxazole 3-hydroxy-4-iodo-5-phenylisoxazole (0.2 g ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.12 g) were used in Example 9.
The target compound (0.22 g, 73%) was obtained as a colorless powder by performing a reaction and a post-treatment in the same manner as in (a). IR spectrum (KBr) ν _max cm ⁻¹ : 332
8, 2977, 1696; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.61 (2H, q, J = 5.2H
z), 4.41 (2H, t, J = 5.2Hz), 4.9.
7 (1H, brs), 7.47-7.55 (3H,
m), 7.99-8.06 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Iodo-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodo-5-phenylisoxazole (0.20 g) was prepared in Example 9 (b). The target compound (0.12 g,
71%) as colorless crystals. Melting point: 201-206 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
1,912,1591; NMR spectrum (DMSO-d ₆ ) δppm:
3.30 (2H, t, J = 5.3Hz), 4.51 (2
H, t, J = 5.3 Hz), 7.58-7.64 (3
H, m), 7.96-8.01 (2H, m), 8.22
(3H, brs). Example 33 3- (2-aminoethoxy) -5- (4-isopropylphenyl) isoxazole hydrochloride (Exemplary compound number: 1618) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy)- 5- (4-Isopropylphenyl) isoxazole 3-Hydroxy-5- (4-isopropylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g) were used in Example 9 ( The target compound (0.26 g, 77%) was obtained as a colorless powder by reacting in the same manner as in a) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 332
6, 2973, 1713, 1697, 1623; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
7 (6H, d, J = 6.9Hz), 1.46 (9H,
s), 2.95 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
4 (1H, brs), 6.09 (1H, s), 7.31
(2H, d, J = 8.3 Hz), 7.65 (2H, d,
J = 8.3 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Isopropylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-isopropylphenyl) isoxazole (0.25 g) was used in the same manner as in Example 9 (b). The target compound (0.1
1 g, 55%) was obtained as colorless crystals. Melting point: 162-166 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
0, 2959, 2924, 1623, 1604; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.23 (6H, d, J = 6.9Hz), 2.96 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.2
6 (2H, t, J = 5.1Hz), 4.44 (2H,
t, J = 5.1 Hz), 6.77 (1H, s), 7.4
1 (2H, d, J = 8.2Hz), 7.77 (2H,
d, J = 8.2 Hz), 8.20 (3H, brs).

Example 34 3- (2-Aminoethoxy) -5- (2-methylphenyl) isoxazole hydrochloride (Exemplary Compound No. 22)
4) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl)
Isoxazole 3-hydroxy-5- (2-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.2 g) were added in Example 9.
The target compound (0.31 g, 86%) was obtained as a colorless powder by reacting in the same manner as in (a) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 331
5,1710,1619; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.49 (3H, s), 3.57 (2
H, q, J = 5.2 Hz), 4.37 (2H, t, J =
5.2 Hz), 4.95 (1H, brs), 6.06
(1H, s), 7.19-7.39 (3H, m), 7.
65-7.69 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(2-Methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl) isoxazole (0.30 g) was used in the same manner as in Example 9 (b). The desired compound (0.18 g,
75%) as colorless crystals. Melting point: 165-167 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 299
6, 2976, 2911, 1613; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.46 (3H, s), 3.26 (2H, t, J = 5.
2Hz), 4.46 (2H, t, J = 5.2Hz),
6.59 (1H, s), 7.34-7.46 (3H,
m), 7.67-7.69 (1H, m), 8.21 (3
H, brs).

Example 35 3- (2-aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride (Exemplified compound No. 36)
8) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole 3-hydroxy-5- (4-phenylphenyl) isoxazole (0.2 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) was reacted in the same manner as in Example 9 (a) and post-treated to give
The target compound (0.22 g, 69%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 334
5, 1694; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H
z), 4.37 (2H, t, J = 5.1Hz), 4.9.
5 (1H, brs), 6.18 (1H, s), 7.37
-7.51 (3H, m), 7.61-7.70 (4H,
m), 7.79-7.82 (2H, m). (B) 3- (2-Aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole ( 0.2 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the target compound (0.1 g, 6
3%) as colorless crystals. Melting point: 212-218 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
6,2966,2909,1619,1602; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.1Hz), 4.46 (2
H, t, J = 5.1 Hz), 6.90 (1 H, s),
7.41-7.55 (3H, m), 7.74-7.76
(2H, m), 7.84-7.87 (2H, m), 7.
94-7.96 (2H, m), 8.18 (3H, br
s).

Example 36 3- (2-Aminoethoxy) -5- (4-phenoxyphenyl) isoxazole hydrochloride (Exemplary compound number:
1632) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole 3-hydroxy-5- (4-phenoxyphenyl) isoxazole (0.2 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.14 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the target compound (0.23 g, 74%) as a colorless powder. Got as. IR spectrum (KBr) ν _max cm ⁻¹ : 333
1,1720; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.2H
z), 4.34 (2H, t, J = 5.2Hz), 4.9.
5 (1H, brs), 6.06 (1H, s), 7.02
-7.08 (4H, m), 7.15-7.20 (1H,
m), 7.35-7.42 (2H, m), 7.65-
7.70 (2H, m).

(B) 3- (2-aminoethoxy) -5
-(4-phenoxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole (0.18 g) was used in the same manner as in Example 9 (b). The target compound (0.1
g, 67%) as colorless crystals. Melting point: 207-213 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
0,2959,2909,1625; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1Hz), 4.43 (2
H, t, J = 5.1 Hz), 6.76 (1H, s),
7.10-7.14 (4H, m), 7.21-7.25
(1H, m), 7.44-7.48 (2H, m), 7.
85-7.88 (2H, m), 8.18 (3H, br
s).

Example 37 3- (2-Aminoethoxy) -5- (2-trifluoromethylphenyl) isoxazole hydrochloride (Exemplary Compound No. 296) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol ( 0.23
g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.36 g, 74%) as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
57, 2983, 1712; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2Hz), 4.9.
6 (1H, brs), 6.21 (1H, s), 7.56
-7.69 (2H, m), 7.75-7.82 (2H,
m).

(B) 3- (2-aminoethoxy) -5
-(2-Trifluoromethylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole (0.35 g) was added to Example 9 ( The target compound (0.22 g, 76%) was obtained as colorless crystals by reacting in the same manner as in b) and post-treating. Melting point: 118-122 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
6,2917,1622; NMR Spectrum (DMSO-d ₆₎ δppm:
3.28 (2H, t, J = 5.1Hz), 4.46 (2
H, t, J = 5.1 Hz), 6.63 (1H, s),
7.79-7.89 (3H, m), 7.96-7.98
(1H, m), 8.22 (3H, brs).

Example 38 3- (2-Aminoethoxy) -5- (4-hydroxyphenyl) isoxazole hydrochloride (Exemplary compound number:
1674) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole 3-hydroxy-5- (4-hydroxyphenyl) isoxazole (0.1 g) 2- (N-tert-butoxycarbonylamino) ethanol (0.1 g) was reacted in the same manner as in Example 9 (a) and post-treated to give
The target compound (0.12 g, 67%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 333
1,3247,1698,1666,1645,161
9; NMR spectrum (DMSO-d ₆ ) δppm:
1.38 (9H, s), 3.32 (2H, q, J = 5.
6Hz), 4.17 (2H, t, J = 5.6Hz),
6.53 (1H, s), 6.87 (2H, d, J = 8.
8Hz), 7.05 (1H, brs), 7.63 (2
H, d, J = 8.8 Hz), 8.98 (1H, br
s).

(B) 3- (2-aminoethoxy) -5
-(4-Hydroxyphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.12 g) was used as in Example 9 (b). The desired compound (0.05
g, 56%) as colorless crystals. Melting point: 240-245 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 314
5,3056,1620; NMR Spectrum (DMSO-d ₆₎ δppm:
3.24 (2H, t, J = 5.1Hz), 4.41 (2
H, t, J = 5.1 Hz), 6.58 (1 H, s),
6.90 (2H, d, J = 8.7Hz), 7.67 (2
H, d, J = 8.7 Hz), 8.13 (3H, br
s).

Example 39 3- (2-Aminoethoxy) -5- (2,4-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No. 170) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,4-dichlorophenyl) isoxazole 5- (2,4-dichlorophenyl) -3-hydroxyisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .17 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.26 g, 81%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
6,1681,1606; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.37 (2H, t, J = 5.2Hz), 4.9.
4 (1H, brs), 6.58 (1H, s), 7.38
(1H, dd, J = 8.5Hz, J = 2.1Hz),
7.53 (1H, d, J = 2.1Hz), 7.85 (1
H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.24 g) was prepared in Example 9 (b). The target compound (0.1
2 g, 60%) was obtained as colorless crystals. Melting point: 192-195 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 306
9,3005,2967,1611; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.1Hz), 4.47 (2
H, t, J = 5.1 Hz), 6.84 (1H, s),
7.64 (1H, dd, J = 8.7Hz, J = 2.1H
z), 7.89 (1H, d, J = 2.1 Hz), 7.9
0 (1H, d, J = 8.7 Hz), 8.20 (3H, b
rs).

Example 40 3- (2-Aminoethoxy) -5- (3,4-dichlorophenyl) isoxazole Hydrochloride (Exemplified Compound No. 1604) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (3,4-dichlorophenyl) isoxazole 5- (3,4-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.41 g, 85%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 336
9, 1687; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
1 (1H, brs), 6.16 (1H, s), 7.54
(2H, s), 7.80 (1H, s).

(B) 3- (2-aminoethoxy) -5
-(3,4-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3,4-dichlorophenyl) isoxazole (0.4 g) was added to Example 9 (b). The target compound (0.22
g, 67%) as colorless crystals. Melting point: 202-210 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
3,2977,2915,1617; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 5.1Hz), 4.45 (2
H, t, J = 5.1 Hz), 7.02 (1H, s),
7.84 (1H, d, J = 8.9Hz), 7.85 (1
H, d, J = 8.9 Hz), 8.17 (4H, br
s).

Example 41 3- (2-Aminoethoxy) -5- (2,3-dichlorophenyl) isoxazole Hydrochloride (Exemplified Compound No. 1526) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,3-dichlorophenyl) isoxazole 5- (2,3-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.37 g, 77%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
1, 1688, 1607; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H
z), 4.37 (2H, t, J = 5.1Hz), 4.9.
5 (1H, brs), 6.60 (1H, s), 7.34
(1H, t, J = 7.9 Hz), 7.58 (1H, d
d, J = 7.9 Hz, J = 1.4 Hz), 7.81 (1
H, dd, J = 7.9 Hz, J = 1.4 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,3-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,3-dichlorophenyl) isoxazole (0.36 g) was prepared in Example 9 (b). The target compound (0.2
0 g, 67%) was obtained as colorless crystals. Melting point: 183-186 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 301
0,2979,2908,1604; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.1Hz), 4.48 (2
H, t, J = 5.1 Hz), 6.87 (1H, s),
7.57 (1H, t, J = 7.8Hz), 7.82-
7.87 (2H, m), 8.19 (3H, brs).

Example 42 3- (2-Aminoethoxy) -5- (2,6-dichlorophenyl) isoxazole hydrochloride (Exemplary Compound No. 188) (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5- (2,6-dichlorophenyl) isoxazole 5- (2,6-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0 .23 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.31 g, 65%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 335
8, 1703, 1626; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.58 (2H, q, J = 5.1H
z), 4.39 (2H, t, J = 5.1Hz), 4.9.
6 (1H, brs), 6.11 (1H, s), 7.32
-7.44 (3H, m).

(B) 3- (2-aminoethoxy) -5
-(2,6-Dichlorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,6-dichlorophenyl) isoxazole (0.16 g) was used in Example 9 (b). The target compound (0.0
7 g, 54%) was obtained as colorless crystals. Melting point: 148-151 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
5,2966,2935,1631; NMR Spectrum (DMSO-d ₆₎ δppm:
3.27 (2H, t, J = 5.0Hz), 4.47 (2
H, t, J = 5.0 Hz), 6.69 (1H, s),
7.61-7.71 (3H, m), 8.15 (3H, b
rs).

Example 43 3- (2-Aminoethoxy) -5- (2,4-difluorophenyl) isoxazole Hydrochloride (Exemplified Compound No. 93) (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5- (2,4-difluorophenyl) isoxazole 5- (2,4-difluorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) Ethanol (0.27g)
Was treated in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.44 g, 85%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
2, 1694; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.36 (2H, t, J = 5.1Hz), 4.9.
3 (1H, brs), 6.30 (1H, s), 6.90
-7.05 (2H, m), 7.85-7.94 (1H,
m).

(B) 3- (2-aminoethoxy) -5
-(2,4-Difluorophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl)
Isoxazole (0.42 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the desired compound (0.
32 g, 94%) was obtained as colorless crystals. Melting point: 226-232 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
7, 2980, 2922, 1626; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1Hz), 4.47 (2
H, t, J = 5.1 Hz), 6.63 (1H, s),
7.29-7.34 (1H, m), 7.53-7.59
(1H, m), 7.94-8.00 (1H, m), 8.
21 (3H, brs).

Example 44 3- (2-Aminoethoxy) -4- (1-chloroethyl) -5-phenylisoxazole Hydrochloride (Exemplified Compound No. 1390) (a) 3- (2- (N-Tersia) Libutoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-phenylisoxazole 3- (2- (N-tertiarybutoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8
g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6 M hexane solution, 3.7 ml) was added dropwise at -70 ° C. under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. After adding acetaldehyde (0.22 ml) dropwise,
After stirring for 10 minutes and raising the temperature to 0 ° C., the reaction solution was poured into ice water, and the pH of the solution was adjusted using a phosphoric acid-potassium aqueous solution.
Was adjusted to 6. After extraction with ethyl acetate, the organic layer was washed with saturated brine, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent:
The target compound (0.90 g, 98%) was obtained as a colorless oily substance by purification using hexane / ethyl acetate = 2/1). IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 36
02,3459,2982,2936,1712; NMR spectrum (CDCl ₃ ) δppm: 1.4
5 (9H, s), 1.60 (3H, d, J = 6.7H
z), 2.64 (1H, brs), 3.58 (2H,
q, J = 5.0 Hz), 4.39 (2H, t, J = 5.
0 Hz), 4.90-5.10 (2H, m), 7.45
-7.50 (3H, m), 7.64-7.69 (2H,
m).

(B) 3- (2-aminoethoxy) -4
-(1-Chloroethyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-
Phenylisoxazole (0.2 g) was added to Example 1 (b).
The target compound (0.13 g, 75%) was obtained as colorless crystals by reacting in the same manner as above and post-treating. Melting point: 200-204 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
5,1640; NMR Spectrum (DMSO-d ₆₎ δppm:
1.86 (3H, d, J = 7.0Hz), 3.27 (2
H, t, J = 5.2 Hz), 4.52 (2H, t, J =
5.2 Hz), 5.46 (1H, q, J = 7.0H
z), 7.60-7.68 (3H, m), 7.71-
7.77 (2H, m), 8.20 (3H, brs).

Example 45 4-Acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary compound number: 141
0) (a) 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -(1-hydroxyethyl) -5-
Phenylisoxazole (0.3 g) was dissolved in methylene chloride (3 ml), pyridinium dichromate (0.49 g) was added at room temperature, and the mixture was stirred at the same temperature for 24 hours.
After completion of the reaction, the insoluble material was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to obtain the desired compound. The compound (0.26 g, 87%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 335
9,1685; NMR spectrum (CDCl ₃ ) δppm: 1.4
7 (9H, s), 2.51 (3H, s), 3.65 (2
H, q, J = 5.2 Hz), 4.48 (2H, t, J =
5.2 Hz), 4.87 (1H, brs), 7.40-
7.63 (3H, m), 7.93-7.96 (2H,
m).

(B) 4-acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- Phenylisoxazole (0.2 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the target compound (0.12 g,
75%) as colorless crystals. Melting point: 150-152 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
6,2909,1682; NMR Spectrum (DMSO-d ₆₎ δppm:
2.52 (3H, s), 3.35 (2H, t, J = 5.
0Hz), 4.59 (2H, t, J = 5.0Hz),
7.54-7.64 (3H, m), 7.85-7.88
(2H, m), 8.30 (3H, brs).

Example 46 3- (2-Aminoethoxy) -4-isopropenyl-5
-Phenylisoxazole hydrochloride (Exemplified compound number: 1394) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4- (1-hydroxyisopropyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8
g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6 M hexane solution, 3.7 ml) was added dropwise at -70 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. Then acetone (0.3 ml) was added dropwise,
After stirring for 10 minutes, the temperature was raised to 0 ° C. The reaction solution was poured into ice water, and a solution of p
After adjusting H to 6, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane / acetic acid). The desired compound (0.42 g, 44%) was obtained as a colorless oily substance by purification using ethyl = 3/1). IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2982, 2936, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.50 (6H, s), 2.52 (1
H, brs), 3.60 (2H, q, J = 5.3H
z), 4.41 (2H, t, J = 5.3Hz), 4.8
7 (1H, brs), 7.41-7.49 (3H,
m), 7.52-7.56 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isopropenyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4- (1-hydroxyisopropyl)-
5-phenylisoxazole (0.13 g) was dissolved in 4N hydrochloric acid / 1,4-dioxane solution (10 ml),
The mixture was stirred at 100 ° C for 1 hour. After completion of the reaction, the reaction solution was allowed to cool, the solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the target compound (0.10
g, 83%) as colorless crystals. Melting point: 130-133 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
4,1591,1572; NMR Spectrum (DMSO-d ₆₎ δppm:
1.95 (3H, s), 3.28 (2H, t, J = 5.
2Hz), 4.48 (2H, t, J = 5.2Hz),
5.23 (1H, s), 5.33 (1H, s), 7.5
3-7.58 (3H, m), 7.62-7.71 (2
H, m), 8.20 (3H, brs).

Example 47 3- (2-Aminoethoxy) -5- (4-nitrophenyl) isoxazole hydrochloride (Exemplary compound number: 166)
0) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-nitrophenyl) isoxazole 3-hydroxy-5- (4-nitrophenyl) isoxazole (0.64 g) and 2 -(N-tert-butoxycarbonylamino) ethanol (0.55 g) was reacted in the same manner as in Example 9 (a) and post-treated,
The target compound (0.86 g, 80%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
5, 1681; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.2H
z), 4.38 (2H, t, J = 5.2Hz), 4.9.
0 (1H, brs), 6.33 (1H, s), 7.90
(2H, d, J = 8.6 Hz), 8.33 (2H, d,
J = 8.6 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Nitrophenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-nitrophenyl) isoxazole (0.28 g) was prepared in the same manner as in Example 9 (b). By reacting and post-treating, the target compound (0.12 g,
52%) was obtained as colorless crystals. Melting point: 216-220 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
4, 2977, 2913, 1620, 1608; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.28 (2H, t, J = 5.1Hz), 4.47 (2
H, t, J = 5.1 Hz), 7.16 (1H, s),
8.15 (2H, d, J = 8.9Hz), 8.22 (3
H, brs), 8.39 (2H, d, J = 8.9H
z).

Example 48 3- (2-Aminoethoxy) -5- (4-aminophenyl) isoxazole dihydrochloride (Exemplified compound No. 17)
02) (a) 5- (4-aminophenyl) -3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
Isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-nitrophenyl) isoxazole (0.55 g) was mixed with acetic acid and water in a mixed solvent (9:
1, 5.5 ml) and dissolve at room temperature in zinc dust (0.5
After adding 5 g), the mixture was stirred at the same temperature for 2 hours. After the reaction was completed, the zinc powder was filtered off and the filtrate was extracted with ethyl acetate,
The organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give the target compound (0.45 g, 90
%) As a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 339
1,3378,3300,1712,1615; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.55 (2H, q, J = 5.1H
z), 4.00 (2H, brs), 4.33 (2H,
t, J = 5.1 Hz), 4.96 (1H, brs),
5.94 (1H, s), 6.70 (2H, d, J = 8.
7 Hz), 7.52 (2H, d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Aminophenyl) isoxazole dihydrochloride 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.25 g) as Example 9 (b). By reacting in the same manner and post-treating, the target compound (0.15 g,
65%) as colorless crystals. Melting point: 242-248 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 303
9, 2939, 2584, 1625, 1597; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 5.0Hz), 4.21 (2
H, brs), 4.42 (2H, t, J = 5.0H
z), 6.56 (1H, s), 6.94 (2H, d, J
= 8.3 Hz), 7.65 (2H, d, J = 8.3H)
z), 8.25 (3H, brs).

Example 49 3- (2-Aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride (Exemplified Compound No. 1716) (a) 5- (4-benzoylaminophenyl) -3-
(2- (N-tert-butoxycarbonylamino))
Ethoxy) isoxazole 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) was dissolved in tetrahydrofuran (1 ml), and the mixture was heated to 5 ° C. under a nitrogen atmosphere. Triethylamine (0.05 ml), then benzoyl chloride (0.
(04 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give the object compound (0.08 g, 62
%) As a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 337
5,1712; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 3.57 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
6 (1H, brs), 6.12 (1H, s), 7.52
-7.61 (3H, m), 7.72-7.80 (4H,
m), 7.87-7.95 (3H, m). (B) 3- (2-aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride 5- (4-benzoylaminophenyl) -3- (2-
(N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.07 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the desired compound (0.04 g, 68%) as colorless crystals. Got as. Melting point: 242-248 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 332
2, 2959, 2910, 1645, 1621; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 5.1Hz), 4.44 (2
H, t, J = 5.1 Hz), 6.75 (1H, s),
7.53-7.65 (3H, m), 7.83-8.00
(6H, m), 8.20 (3H, brs), 10.55
(1H, s).

Example 50 3- (2-Aminoethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole hydrochloride (Exemplified compound number: 1576) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3
-Methylphenyl) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3 g) and methyl iodide (0.08 m)
l) was reacted in the same manner as in Example 14 (a) and post-treated to obtain the target compound (0.14 g, 45%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 334
2,1710; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.56 (3H, s), 3.58 (2
H, q, J = 5.1 Hz), 4.38 (2H, t, J =
5.1 Hz), 4.95 (1H, brs), 6.54
(1H, s), 7.39 (1H, d, J = 8.5H
z), 7.76 (1 H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichloro-3-methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole (0 .13 g) in Example 9
The target compound (0.06 g, 55%) was obtained as colorless crystals by performing a reaction and a post-treatment in the same manner as in (b). Melting point: 197-200 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 313
0,2969,2897,1607; NMR Spectrum (DMSO-d ₆₎ δppm:
2.52 (3H, s), 3.27 (2H, t, J = 5.
1Hz), 4.47 (2H, t, J = 5.1Hz),
6.82 (1H, s), 7.65 (1H, d, J = 8.
5Hz), 7.71 (1H, d, J = 8.5Hz),
8.17 (3H, brs).

Example 51 3- (2-Aminoethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole hydrochloride (Exemplified compound number: 1590) (a) 3- (2- (N- Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3
-Ethylphenyl) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3g) and ethyl iodide (0.1m).
l) was reacted in the same manner as in Example 14 (a) and post-treated to obtain the target compound (0.25 g, 78%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 334
2,1702; NMR spectrum (CDCl ₃ ) δppm: 1.2
1 (3H, t, J = 7.5Hz), 1.46 (9H,
s), 3.05 (2H, q, J = 7.5Hz), 3.5
7 (2H, q, J = 5.1Hz), 4.36 (2H,
t, J = 5.1 Hz), 4.94 (1H, brs),
6.54 (1H, s), 7.40 (1H, d, J = 8.
5 Hz), 7.65 (1 H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichloro-3-ethylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole (0 .23 g) in Example 9
The target compound (0.14 g, 74%) was obtained as colorless crystals by performing a reaction and a post-treatment in the same manner as in (b). Melting point: 173-176 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 297
0,2935,2876,1608; NMR Spectrum (DMSO-d ₆₎ δppm:
1.16 (3H, t, J = 7.4Hz), 3.00 (2
H, q, J = 7.4 Hz), 3.27 (2H, t, J =
5.1 Hz), 4.47 (2H, t, J = 5.1H)
z), 6.82 (1H, s), 7.65 (1H, d, J
= 8.4 Hz), 7.70 (1H, d, J = 8.4H)
z), 8.21 (3H, brs).

Example 52 5- (4-acetoxyphenyl) -3- (2-aminoethoxy) isoxazole hydrochloride (Exemplary compound number:
1688) (a) 5- (4-acetoxyphenyl) -3- (2-
(N-tert-butoxycarbonylamino) ethoxy) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.15 g) was added to tetrahydrofuran (1.
5 ml) and triethylamine (0.07 ml) at 5 ° C. under a nitrogen atmosphere, and then acetyl chloride (0.
(04 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give the target compound (0.12 g, 71 %) As a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 334
5,1696; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.33 (3H, s), 3.56 (2
H, q, J = 5.2 Hz), 4.35 (2H, t, J =
5.2 Hz), 4.94 (1H, brs), 6.12
(1H, s), 7.20 (2H, d, J = 8.8H
z), 7.74 (2H, d, J = 8.8Hz).

(B) 5- (4-acetoxyphenyl)
-3- (2-Aminoethoxy) isoxazole hydrochloride 5- (4-acetoxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) was prepared in Example 9 (b). The target compound (0.05
g, 63%) as colorless crystals. Melting point: 202-212 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
6,2977,2912,1755,1621; NMR Spectrum (DMSO-d ₆₎ δppm:
2.30 (3H, s), 3.26 (2H, t, J = 5.
1Hz), 4.45 (2H, t, J = 5.1Hz),
6.84 (1H, s), 7.32 (2H, d, J = 8.
6Hz), 7.91 (2H, d, J = 8.6Hz),
8.22 (3H, brs).

Example 53 3- (2-Aminoethoxy) -5- (4-benzyloxyphenyl) isoxazole hydrochloride (Exemplified Compound No. 1646) (a) 5- (4-benzyloxyphenyl) -3-
(2- (N-tert-butoxycarbonylamino))
Ethoxy) isoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.2 g) was added to dimethylformamide (2 m).
l), 55% sodium hydride (oiliness, 0.03 g) was added at 5 ° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10
Stirred for minutes. Then, benzyl bromide (0.08 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate.
After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1),
The target compound (0.14 g, 54%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 333
8, 1698; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.56 (2H, q, J = 5.0H
z), 4.34 (2H, t, J = 5.0 Hz), 4.9.
4 (1H, brs), 5.12 (2H, s), 6.02
(1H, s), 7.04 (2H, d, J = 8.7H
z), 7.28-7.47 (5H, m), 7.66 (2
H, d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Benzyloxyphenyl) isoxazole hydrochloride 5- (4-benzyloxyphenyl) -3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
Isoxazole (0.13 g) was reacted in the same manner as in Example 9 (b) and post-treated to give the desired compound (0.
07 g, 64%) was obtained as colorless crystals. Melting point: 205-210 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
7,2966,2912,1621,1604; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25 (2H, t, J = 5.1Hz), 4.43 (2
H, t, J = 5.1 Hz), 5.19 (2H, s),
6.69 (1H, s), 7.17 (2H, d, J = 9.
0 Hz), 7.33-7.48 (5H, m), 7.79
(2H, d, J = 9.0 Hz), 8.21 (3H, br
s).

Example 54 3- (2-Aminoethoxy) -5- (2-furyl) -4
-Isopropylisoxazole hydrochloride (Exemplified compound number: 510) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole 5- (2-furyl) -3-hydroxy-4-isopropylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18
g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.29 g, 83%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 331
7,2985,1690; NMR spectrum (CDCl ₃ ) δppm: 1.2
8 (6H, d, J = 7.2Hz), 1.46 (9H,
s), 3.33 (1H, qq, J = 7.2 Hz, J =
7.2 Hz), 3.58 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.8.
4 (1H, brs), 6.52 (1H, dd, J = 3.
4 Hz, J = 1.8 Hz), 6.80 (1 H, d, J =
3.4 Hz), 7.55 (1H, d, J = 1.8H
z).

(B) 3- (2-aminoethoxy) -5
-(2-furyl) -4-isopropylisoxazole
Hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole (0.27 g) was reacted in the same manner as in Example 1 (b). The target compound (0.17 g, 77%) was obtained as colorless crystals by post-treatment. Melting point: 137-139 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
2, 2898, 1560, 1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.26 (6H, d, J = 7.0Hz), 3.24 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
8 (2H, t, J = 5.2Hz), 4.44 (2H,
t, J = 5.2 Hz), 6.73 (1H, dd, J =
3.4 Hz, J = 1.8 Hz), 7.01 (1H, d,
J = 3.4 Hz), 7.97 (1H, d, J = 1.8H)
z), 8.21 (3H, brs).

Example 55 3- (2-Aminoethoxy) -4- (tert-butyl) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 13) (a) 3- (2- (N-tert-tert-hydroxy) Leavebutoxycarbonylamino) ethoxy) -4- (tertiarybutyl)
-5-Phenylisoxazole 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole (0.15 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.
12 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.16 g, 64%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 337
4, 2974, 1683; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
8 (9H, s), 1.46 (9H, s), 3.60 (2
H, q, J = 5.2 Hz), 4.38 (2H, t, J =
5.2 Hz), 4.85 (1H, brs), 7.36-
7.55 (5H, m).

(B) 3- (2-aminoethoxy) -4
-(Tertiarybutyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (tert-butyl) -5-phenylisoxazole (0.14 g ) In Example 1 (b)
The target compound (0.09 g, 82%) was obtained as colorless crystals by reacting in the same manner as above and post-treating. Melting point: 230-234 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
1,290,2890,1516; NMR spectrum (DMSO-d ₆ ) δppm:
1.16 (9H, s), 3.30 (2H, t, J = 5.
3Hz), 4.46 (2H, t, J = 5.3Hz),
7.44-7.57 (5H, m), 8.20 (3H, b
rs).

Example 56 3- (2-Aminoethoxy) -4-cyclopropyl-5
-Phenylisoxazole hydrochloride (Exemplified compound number: 1400) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole 4-cyclopropyl- 3-hydroxy-5-phenylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18 g) are reacted in the same manner as in Example 9 (a) and post-treated. Thus, the target compound (0.25 g, 74%) was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 336
9, 1692, 1536, 1520; NMR spectrum (CDCl ₃ ) δ ppm: 0.6
6-0.75 (2H, m), 0.88-0.95 (2
H, m), 1.46 (9H, s), 1.67-1.73.
(1H, m), 3.58 (2H, q, J = 5.1H
z), 4.35 (2H, t, J = 5.1Hz), 4.9.
0 (1H, brs), 7.40-7.51 (3H,
m), 7.84-7.87 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyclopropyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole (0.15 g) was prepared in Example 1 ( By reacting in the same manner as in b) and post-treating, the target compound (0.0
6 g, 49%) was obtained as colorless crystals. Melting point: 180-182 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 291
9,2851,1713,1519; NMR Spectrum (DMSO-d ₆₎ δppm:
0.68-0.76 (2H, m), 0.83-0.92
(2H, m), 1.71-1.78 (1H, m), 3.
27 (2H, t, J = 5.2Hz), 4.44 (2H,
t, J = 5.2 Hz), 7.51-7.60 (3H,
m), 7.83-7.86 (2H, m), 8.20 (3
H, brs).

Example 57 3- (2-aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplified compound No. 176) (a) 3- (2- (N -Tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole 5- (2,4-dichlorophenyl) -3-hydroxy-
4-isopropylisoxazole (0.06 g) and 2-
(N-tert-butoxycarbonylamino) ethanol (0.04 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the target compound (0.078).
g, 86%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 34
60, 2975, 2936, 1713; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
8 (6H, d, J = 7.0Hz), 1.46 (9H,
s), 2.69 (1H, qq, J = 7.0 Hz, J =
7.0 Hz), 3.59 (2H, q, J = 5.2H
z), 4.38 (2H, t, J = 5.2Hz), 4.8.
5 (1H, brs), 7.30 (1H, d, J = 8.3)
Hz), 7.35 (1H, dd, J = 8.3 Hz, J =
1.9 Hz), 7.52 (1H, d, J = 1.9H
z).

(B) 3- (2-aminoethoxy) -5
-(2,4-Dichlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl)-
4-Isopropylisoxazole (0.07 g) was reacted in the same manner as in Example 1 (b) and post-treated to give
The target compound (0.04 g, 68%) was obtained as colorless crystals. Melting point: 171-173 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 296
8,2934,2875,1514; NMR spectrum (DMSO-d ₆ ) δppm:
1.13 (6H, d, J = 7.0Hz), 2.69 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.3Hz), 4.46 (2H,
t, J = 5.3 Hz), 7.56 (1H, d, J = 8.
5Hz), 7.62 (1H, dd, J = 8.5Hz, J
= 2.0 Hz), 7.89 (1H, d, J = 2.0H
z), 8.18 (3H, brs).

Example 58 3- (2-Aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No. 117) (a) 3- (2- (N-Tersia) Libutoxycarbonylamino) ethoxy) -5- (2-chlorophenyl)
-4-isopropylisoxazole 5- (2-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.13 g) and 2- (N-
Tertiary butoxycarbonylamino) ethanol (0.1 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the desired compound (0.15 g, 72%).
Was obtained as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
2, 2974, 1691; NMR spectrum (CDCl ₃ ) δppm: 1.1
8 (6H, d, J = 6.9Hz), 1.46 (9H,
s), 2.71 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.60 (2H, q, J = 5.2H
z), 4.39 (2H, t, J = 5.2Hz), 4.8.
7 (1H, brs), 7.34-7.51 (4H,
m).

(B) 3- (2-aminoethoxy) -5
-(2-Chlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole (0.13 g ) Example 1
The target compound (0.08 g, 73%) was obtained as colorless crystals by reacting in the same manner as in (b) and post-treating. Melting point: 143-145 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
0,2937,2896,2879,1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.13 (6H, d, J = 7.0Hz), 2.69 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.2Hz), 4.47 (2H,
t, J = 5.2 Hz), 7.50-7.68 (4H,
m), 8.24 (3H, brs).

Example 59 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole hydrochloride (Exemplary Compound No. 151) (a) 3- (2- (N-Tersia) Libutoxycarbonylamino) ethoxy) -5- (4-chlorophenyl)
-4-isopropylisoxazole 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.15 g) and 2- (N-
Tertiary butoxycarbonylamino) ethanol (0.11 g) was reacted in the same manner as in Example 9 (a) and post-treated to give the desired compound (0.19 g, 79).
%) As a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
2, 2966, 1685; NMR spectrum (CDCl ₃ ) δppm: 1.2
9 (6H, d, J = 7.0Hz), 1.46 (9H,
s), 3.03 (1H, qq, J = 7.0 Hz, J =
7.0 Hz), 3.59 (2H, q, J = 5.1H
z), 4.36 (2H, t, J = 5.1Hz), 7.4
4 (2H, d, J = 8.7 Hz), 7.52 (2H,
d, J = 8.7 Hz).

(B) 3- (2-aminoethoxy) -5
-(4-Chlorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole (0.18 g ) Example 1
The target compound (0.12 g, 80%) was obtained as colorless crystals by reacting in the same manner as in (b) and post-treating. Melting point: 224-227 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
1, 219, 2851, 1639; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.26 (6H, d, J = 7.0Hz), 3.02 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
8 (2H, t, J = 5.3Hz), 4.45 (2H,
t, J = 5.3 Hz), 7.62 (2H, d, J = 9.
0 Hz), 7.63 (2H, d, J = 9.0 Hz),
8.18 (3H, brs).

Example 60 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary compound number: 139)
2) (a) 4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole 4-allyl-3-hydroxy-5-phenylisoxazole (1.00 g ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) were reacted in the same manner as in Example 1 (a) and post-treated to give
The target compound (1.57 g, 91%) was obtained as colorless crystals. Melting point: 78-79 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 332
7,1708,1644,1526,1518; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.27-3.29 (2H, m),
3.57 (2H, q, J = 5.1Hz), 4.38 (2
H, t, J = 5.1 Hz), 4.90 (1H, br
s), 5.05-5.15 (2H, m), 5.91-
6.01 (1H, m), 7.41-7.49 (3H,
m), 7.63-7.68 (2H, m).

(B) 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride 4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- Phenylisoxazole (200 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (160 mg,
98%) as colorless crystals. Melting point: 95-96 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 296
7,2912,2885,2817,2694,164
3,1601,1577,1514,1495; NMR Spectrum (DMSO-d ₆₎ δppm:
3.25-3.30 (2H, m), 3.35 (2H, m)
t, J = 5.1 Hz), 4.46 (2H, t, J = 5.
1 Hz), 5.03-5.09 (2H, m), 5.91
-6.00 (1H, m), 7.52-7.58 (3H,
m), 7.67-7.70 (2H, m), 8.20 (3
H, brs).

Example 61 3- (2-Aminoethoxy) -5-phenyl-4-propargylisoxazole hydrochloride (Exemplified compound number:
1398) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargylisoxazole 3-hydroxy-5-phenyl-4-propargylisoxazole (1.00 g) ) And 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) are reacted in the same manner as in Example 1 (a) and post-treated to give the target compound (1.44 g, 84%) as a colorless compound. Was obtained as an oily substance. IR spectrum (KBr) ν _max cm ⁻¹ : 335
2,3302,1711,1643,1600,157
7,1520,1499; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.09 (1H, t, J = 2.8H
z), 3.43 (2H, d, J = 2.8 Hz), 3.6
0 (2H, q, J = 5.1Hz), 4.41 (2H,
t, J = 5.1 Hz), 5.02 (1H, brs),
7.45-7.55 (3H, m), 7.74-7.76
(2H, m).

(B) 3- (2-aminoethoxy) -5
-Phenyl-4-propargylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargylisoxazole (200 mg) was used as in Example 1 (b). The target compound (152 m
g, 94%) as colorless crystals. Melting point: 210-212 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 325
8,2959,2899,2830,1632,160
1,1577,1523; NMR spectrum (DMSO-d ₆ ) δppm:
2.97 (1H, t, J = 2.8Hz), 3.30 (1
H, t, J = 5.1 Hz), 3.59 (2H, d, J =
2.8 Hz), 4.47 (2H, t, J = 5.1H
z), 7.56-7.62 (3H, m), 7.79-
7.82 (2H, m), 8.13 (3H, brs).

Example 62 3- (2-Aminoethoxy) -4-isobutyl-5-phenylisoxazole hydrochloride (Exemplary compound No. 1)
1) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole 3-hydroxy-4-isobutyl-5-phenylisoxazole (217 mg) 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) was reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (303 mg, 84%) as colorless crystals. Melting point: 80-81 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 337
7, 1683, 1637, 1516, 1498; NMR spectrum (CDCl ₃ ) δ ppm: 0.9
3 (6H, d, J = 6.8Hz), 1.46 (9H,
s), 1.89-1.96 (1H, m), 2.42 (2
H, d, J = 7.3 Hz), 3.58 (2H, q, J =
5.1 Hz), 4.37 (2H, t, J = 5.1H)
z), 4.88 (1H, brs), 7.40-7.49.
(3H, m), 7.66-7.70 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Isobutyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole (200 mg) was used as in Example 1 (b). The target compound (160 m
g, 98%) as colorless crystals. Melting point: 202-210 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 300
5,2957,2869,1629,1601,157
6,1514,1495; NMR spectrum (DMSO-d ₆ ) δppm:
0.86 (6H, d, J = 6.8Hz), 2.47 (2
H, d, J = 7.3 Hz), 3.27 (2H, t, J =
5.1 Hz), 4.45 (2H, t, J = 5.1H)
z), 7.49-7.58 (3H, m), 7.70-
7.74 (2H, m), 8.19 (3H, brs).

Example 63 3- (2-Aminoethoxy) -4-cyclopentyl-5
-Phenylisoxazole hydrochloride (Exemplary compound number: 1402) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole 3-hydroxy-4- Cyclopentyl-5-phenylisoxazole (229 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg)
Was reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (308 mg, 83%) as colorless crystals. Melting point: 112-113 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 339
1,1691, 1655, 1643, 1531, 151
5; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 1.56 to 1.67 (2H, m),
1.71-1.92 (6H, m), 3.03-3.12.
(1H, m), 3.58 (2H, q, J = 5.1H
z), 4.38 (2H, t, J = 5.1Hz), 4.8.
2 (1H, brs), 7.41-7.49 (3H,
m), 7.55-7.61 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Cyclopentyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole (200 mg) was used in the same manner as in Example 1 (b). The target compound (161
mg, 97%) as colorless crystals. Melting point: 197-199 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 295
4,2869,1637,1599,1576,151
1,1490; NMR spectrum (DMSO-d ₆ ) δppm:
1.57-1.63 (2H, m), 1.72-1.91
(6H, m), 2.98-3.07 (1H, m), 3.
27 (2H, t, J = 5.1Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.51-7.61 (5H,
m), 8.07 (3H, brs).

Example 64 3- (2-Aminoethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole hydrochloride (Exemplified Compound No. 1404) (a) 3- (2- (N- Tertiary butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole 3-hydroxy-4- (2-cyclopentenyl) -5-
Phenylisoxazole (227 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (1
93 mg) was reacted in the same manner as in Example 1 (a) and post-treated to give the target compound (295 mg, 80%).
Was obtained as colorless crystals. Melting point: 81-82 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 339
4, 1690, 1636, 1515, 1495; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.88-1.98 (1H, m),
2.24-2.34 (1H, m), 2.39-2.49
(1H, m), 2.52-2.61 (1H, m), 3.
47-3.59 (2H, m), 4.01-4.06 (1
H, m), 4.30-4.36 (2H, m), 4.86.
(1H, brs), 5.63-5.67 (1H, m),
5.89-5.92 (1H, m), 7.42-7.49
(3H, m), 7.60-7.63 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(2-Cyclopentenyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-
Phenylisoxazole (200 mg) in Example 1
The target compound (156 mg, 94%) was obtained as colorless crystals by performing a reaction and a post-treatment in the same manner as in (b). Melting point: 157-160 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 305
1,954,2901,852,1635,159
9,1575,1516,1492; NMR Spectrum (DMSO-d ₆₎ δppm:
1.79-1.99 (1H, m), 2.21-2.41
(2H, m), 2.44-2.53 (1H, m), 3.
25 (2H, brs), 3.95-4.02 (1H,
m), 4.38-4.48 (2H, m), 5.56-
5.71 (1H, m), 5.85-5.89 (1H,
m), 7.51-7.57 (3H, m), 7.59-
7.63 (2H, m), 8.12 (3H, brs).

Example 65 3- (2-aminoethoxy) -4-pentyl-5-phenylisoxazole hydrochloride (Exemplified compound number: 138)
6) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole 3-hydroxy-4-pentyl-5-phenylisoxazole (231 mg) 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) was reacted in the same manner as in Example 1 (a) and post-treated to give
The target compound (305 mg, 82%) was obtained as a colorless oily substance. IR spectrum (KBr) ν _max cm ⁻¹ : 346
1,1713,1640,1510,1496; NMR spectrum (CDCl ₃ ) δppm: 0.8
9 (3H, t, J = 7.0Hz), 1.26-1.38
(2H, m), 1.46 (9H, s), 1.49-1.
61 (2H, m), 2.52 (2H, t, J = 7.7H
z), 3.59 (2H, q, J = 5.1Hz), 4.3
7 (2H, t, J = 5.1Hz), 4.89 (1H, b
rs), 7.40-7.49 (3H, m), 7.64-
7.69 (2H, m).

(B) 3- (2-aminoethoxy) -4
-Pentyl-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole (100 mg) was used as in Example 1 (b). The target compound (80 mg, 9
5%) as colorless crystals. Melting point: 107-109 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 300
8,2955,2930,2869,1641,160
1,1576,1566,1516,1496; NMR spectrum (DMSO-d ₆ ) δppm:
0.83 (3H, t, J = 7.0Hz), 1.25-
1.30 (4H, m), 1.48-1.56 (2H,
m), 2.55 (2H, t, J = 7.7Hz), 3.2
8 (2H, t, J = 5.1Hz), 4.45 (2H,
t, J = 5.1 Hz), 7.51-7.59 (3H,
m), 7.66-7.69 (2H, m), 8.10 (3
H, brs).

Example 66 3- (2-Aminoethoxy) -4- (2-butenyl)-
5-Phenylisoxazole hydrochloride (Exemplary Compound No. 1396) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-
Phenylisoxazole 3-hydroxy-4- (2-butenyl) -5-phenylisoxazole (215 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 m
g) was reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (292 mg, 82%) as colorless crystals. Melting point: 62-63 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 337
8, 1682, 1634, 1514, 1497; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 1.68-1.74 (3H, m),
3.19-3.21 (2H, m), 3.57 (2H, m
q, J = 5.1 Hz), 4.37 (2H, t, J = 5.
1 Hz), 4.89 (1H, brs), 5.46-5.
60 (2H, m), 7.40-7.52 (3H, m),
7.64-7.68 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(2-Butenyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-phenylisoxazole (200 mg) By reacting in the same manner as in Example 1 (b) and post-treating, the target compound (16
2 mg, 98%) was obtained as colorless crystals. Melting point: 123-125 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 302
8,2961,934,2916,2855,164
1,1601,1577,1570,1515,149
4; NMR spectrum (DMSO-d ₆ ) δppm:
1.60-1.70 (3H, m), 3.26-3.28
(2H, m), 3.33 (2H, t, J = 5.1H
z), 4.45 (2H, t, J = 5.1Hz), 5.4
3-5.59 (2H, m), 7.50-7.58 (3
H, m), 7.65-7.70 (2H, m), 8.10
(3H, brs).

Example 67 3- (2-aminoethoxy) -4-isopropyl-5-
(2-thienyl) isoxazole hydrochloride (Exemplified compound number: 543) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (2
-Thienyl) isoxazole 3-hydroxy-4-isopropyl-5- (2-thienyl) isoxazole (209 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193
mg) was reacted in the same manner as in Example 1 (a) and post-treated to obtain the target compound (301 mg, 86%) as colorless crystals. Melting point: 94-95 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 332
5,1711,1693,1635,1542,152
8,1508; NMR spectrum (CDCl ₃ ) δppm: 1.2
9 (6H, d, J = 7.1Hz), 1.46 (9H,
s), 3.19 (1H, m), 3.58 (2H, q, J
= 5.1 Hz), 4.36 (2H, t, J = 5.1H)
z), 4.83 (1H, brs), 7.14 (1H, d
d, J = 5.3 Hz, J = 3.7 Hz), 7.42 (1
H, dd, J = 3.4 Hz, J = 1.4 Hz), 7.4
6 (1H, d, J = 5.3 Hz).

(B) 3- (2-aminoethoxy) -4
Example 1 The target compound (150 mg, 93%) was obtained as colorless crystals by reacting in the same manner as in b) and post-treating. Melting point: 192-194 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
5,3087, 2973, 1644, 1579, 152
7,1498; NMR Spectrum (DMSO-d ₆₎ δppm:
1.27 (6H, d, J = 7.2Hz), 3.16 (1
H, m), 3.28 (2H, t, J = 5.1Hz),
4.44 (2H, t, J = 5.1Hz), 7.26 (1
H, dd, J = 5.2 Hz, J = 1.4 Hz), 7.5
4 (1H, dd, J = 4.7Hz, J = 1.0Hz),
7.87 (1H, d, J = 5.2Hz), 8.13 (3
H, brs).

Example 68 3- (2-Aminoethoxy) -4-fluoro-5-phenylisoxazole hydrochloride (Exemplified compound number: 4) (a) 3-methoxymethoxy-5-phenylisoxazole 3- Hydroxy-5-phenylisoxazole (8.0
5 g) was dissolved in dimethylformamide (80 ml) and sodium methoxide (28% methanol solution,
After adding 3.24 g), the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 5 ° C. and chloromethyl methyl ether (4.
83 g) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water (200 ml) and extracted with ether (200 ml).
x2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (6.30 g, 61 %) As a colorless oil. IR spectrum (KBr) ν _max cm ⁻¹ : 162
1, 1596, 1577, 1512; NMR spectrum (CDCl ₃ ) δ ppm: 3.5
8 (3H, s), 5.37 (2H, s), 7.40-
7.48 (3H, m), 7.71-7.95 (2H,
m).

(B) 4-Fluoro-3-methoxymethoxy-5-phenylisoxazole 3-methoxymethoxy-5-phenylisoxazole (2.05 g) was added to anhydrous tetrahydrafuran (30 ml).
Was dissolved in and cooled to -78 ° C, butyllithium (1.68M hexane solution, 7.1 ml) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Next, N-fluorodibenzenesulfonimide (3.15 g) was added and the mixture was stirred at the same temperature for 15 minutes, then, the cooling bath was removed, and the temperature was raised to room temperature.
The reaction mixture was added to ice water (200 ml), extracted with ether (200 ml × 2), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (1.78 g, 8
0%) was obtained as a colorless oil. IR spectrum (KBr) ν _max cm ⁻¹ : 167
2,1545; NMR spectrum (CDCl ₃ ) δppm: 3.6
2 (3H, s), 5.45 (2H, s), 7.43-
7.52 (3H, m), 7.70-7.80 (2H,
m).

(C) 4-fluoro-3-hydroxy-
5-Phenylisoxazole 4-Fluoro-3-methoxymethoxy-5-phenylisoxazole (0.44 g) was dissolved in 4N hydrochloric acid / dioxane solution (5.0 ml), and the mixture was stirred at room temperature for 1 hr. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with dichloromethane (10 ml) to obtain the target compound (0.30 g, 83%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 305
9,3014,2995,2919,2851,282
2,2747, 2645, 2565, 1674, 158
2,1527; NMR spectrum (DMSO-d ₆ ) δppm:
7.51-7.61 (3H, m), 7.73-7.74
(2H, m), 12.6 (1H, brs).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-
5-Phenylisoxazole 4-Fluoro-3-hydroxy-5-phenylisoxazole (100 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (108 mg) were reacted in the same manner as in Example 1 (a). And by post-processing,
The target compound (132 mg, 73%) was obtained as colorless crystals. Melting point: 103-104 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 332
5, 1718, 1667, 1549, 1532; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.60 (2H, q, J = 5.1H
z), 4.41 (2H, t, J = 5.1Hz), 4.9.
7 (1H, brs), 7.41-7.52 (3H,
m), 7.76-7.79 (2H, m).

(E) 3- (2-aminoethoxy) -4
-Fluoro-5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-5-phenylisoxazole (110 mg) was used as in Example 1 (b). The target compound (82 mg, 9 mg
3%) as colorless crystals. Melting point: 207-211 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 299
9,2965,2909,2845,1665,160
2, 1581, 1555, 1532; NMR spectrum (DMSO-d ₆ ) δppm:
3.32 (2H, t, J = 5.1Hz), 4.55 (2
H, t, J = 5.1 Hz), 7.55-7.64 (3
H, m), 7.75-7.78 (2H, m), 8.17.
(3H, brs).

Example 69 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 27) (a) 3- (2-bromoethoxy) -5-phenylisoxazole tri Phenylphosphine (15.7 g) was dissolved in toluene (200 ml), cooled to 5 ° C., diethyl azodicarboxylate (10.4 g) was added, and the mixture was stirred at the same temperature for 10 minutes. Then, 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) were sequentially added, and then at the same temperature for 10 minutes.
The mixture was further stirred at room temperature for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4
The target compound (12.1
g, 90%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 314
8, 1623, 1597, 1576, 1510; NMR spectrum (CDCl ₃ ) δ ppm: 3.7
1 (2H, t, J = 5.9Hz), 4.62 (2H,
t, J = 5.9 Hz), 6.19 (1H, s), 7.4
2-7.49 (3H, m), 7.70-7.77 (2
H, m).

(B) 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole Dimethylamine hydrochloride (815 mg) was added to methanol (5
0 ml) and then 3- (2-bromoethoxy)
-5-Phenylisoxazole (268 mg) and triethylamine (2.8 ml) were added, and the mixture was heated under reflux for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in ether (20 ml), and diluted with saline (20 m).
After washing with l), the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to obtain the target compound (146 mg, 63%) as colorless crystals. It was Melting point: 28-29 ° C; IR spectrum (KBr) ν _max cm ^-1 : 298
0,2951, 1625,1597,1577,151
4; NMR spectrum (CDCl ₃ ) δppm: 2.3
4 (6H, s), 2.75 (2H, t, J = 5.4H
z), 4.40 (2H, t, J = 5.4Hz), 6.1
8 (1H, s), 7.40-7.48 (3H, m),
7.69-7.73 (2H, m).

(C) 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole hydrochloride 3- (2-Dimethylaminoethoxy) -5-phenylisoxazole (130 mg) was added to dioxane (1.0 m).
l) and 4N hydrochloric acid / dioxane solution (0.2
(ml) was added, and the mixture was allowed to stand at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate (5 ml) to give the desired compound (148 mg, 98%).
Was obtained as colorless crystals. Melting point: 163-164 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 313
3, 1624, 1597, 1577, 1513; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.84 (6H, s), 3.55 (2H, t, J = 5.
0Hz), 4.61 (2H, t, J = 5.0Hz),
7.50-7.58 (3H, m), 7.81-7.87
(2H, m), 10.31 (1H, brs).

Example 70 5-Phenyl-3- (2- (1-piperidyl) ethoxy) isoxazole hydrochloride (Exemplary Compound No. 28) (a) 5-phenyl-3- (2- (1-piperidyl))
Ethoxy) isoxazole 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 ml), piperidine (426 mg) was added, and the mixture was heated under reflux for 3 hr. After adding the reaction solution to ice water (20 ml),
Ether extraction (20 ml x 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to obtain the target compound (251 mg, 92%) as colorless crystals. It was Melting point: 75-76 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 314
9, 1625, 1598, 1577, 1513; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
2-1.48 (2H, m), 1.54-1.67 (4
H, m), 2.50 (4H, brs), 2.79 (2
H, t, J = 5.8 Hz), 4.42 (2H, t, J =
5.8 Hz), 6.16 (1H, s), 7.41-7.
48 (3H, m), 7.69-7.75 (2H, m).

(B) 5-phenyl-3- (2- (1-
Piperidyl) ethoxy) isoxazole hydrochloride 5-phenyl-3- (2-piperidylethoxy) isoxazole (200 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (181m).
g, 80%) as colorless crystals. Melting point: 190-192 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 295
0,2938,1620,1595,1576,151
1; NMR spectrum (DMSO-d ₆ ) δppm:
1.32-1.44 (2H, m), 1.68-1.86
(4H, m), 2.95-3.04 (2H, m), 3.
45-3.58 (4H, m), 4.64 (2H, t, J
= 4.7 Hz), 6.87 (1 H, s), 7.50-
7.58 (3H, m), 7.81-7.85 (2H,
m), 9.94-10.05 (1H, brs).

Example 71 5-Phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole hydrochloride (Exemplary compound number: 135)
0) (a) 5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole Piperidine (710 mg) was added to 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg), and the mixture was heated to 100 ° C. It was stirred for 1 hour. Ice water (20 m
l) was added, ether extraction (20 ml × 2) was performed, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give the target compound (2
11 mg, 82%) was obtained as colorless crystals. Melting point: 61-62 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 162
3, 1596, 1575, 1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.7
7-1.87 (4H, m), 2.57-2.65 (4
H, m), 2.92 (2H, t, J = 5.5Hz),
4.43 (2H, t, J = 5.5Hz), 6.18 (1
H, s), 7.40-7.48 (3H, m), 7.69.
-7.75 (2H, m).

(B) 5-phenyl-3- (2- (1-
Pyrrolidinyl) ethoxy) isoxazole hydrochloride 5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole (200 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (211 mg). , 93%) as colorless crystals. Melting point: 182-184 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 298
2,2950,2884,2848,2671,265
3,2607,2560,2480,1619,159
5,1576,1511; NMR spectrum (DMSO-d ₆ ) δppm:
1.83-2.08 (4H, m), 3.01-3.21
(2H, m), 3.50-3.68 (4H, m), 4.
60 (2H, t, J = 5.1Hz), 6.87 (1H,
s), 7.50-7.58 (3H, m), 7.81-
7.87 (2H, m), 10.63 (1H, brs).

Example 72 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 29) (a) 3- (2- (4-morpholinyl) ethoxy)-
5-Phenylisoxazole 3- (2-Bromoethoxy) -5-phenylisoxazole (268 mg) was added with morpholine (871 mg), and the mixture was stirred at 100 ° C for 1 hr. Ice water (20 m
l) was added, ether extraction (20 ml × 2) was performed, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give the target compound (2
50 mg, 91%) was obtained as colorless crystals. Melting point: 66-67 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 315
2, 1623, 1596, 1575, 1512; NMR spectrum (CDCl ₃ ) δ ppm: 2.5
7 (2H, t, J = 5.4Hz), 2.82 (2H,
t, J = 5.4 Hz), 3.75 (2H, t, J = 5.
5Hz), 4.44 (2H, t, J = 5.5Hz),
6.17 (1H, s), 7.41-7.50 (3H,
m), 7.69-7.76 (2H, m).

(B) 3- (2- (4-morpholinyl))
Ethoxy) -5-phenylisoxazole hydrochloride 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole (200 mg) is reacted in the same manner as in Example 1 (b) and post-treated. Thus, the target compound (202 mg, 89%) was obtained as colorless crystals. Melting point: 180-182 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 298
1,925,2897,2878,2683,264
6,2584, 2512, 2469, 2429, 162
0,1595,1576,1512; NMR Spectrum (DMSO-d ₆₎ δppm:
3.10-3.25 (2H, m), 3.40-3.55
(2H, m), 3.55-3.65 (2H, m), 3.
70-3.85 (2H, m), 3.90-4.05 (2
H, m), 4.67 (2H, brs), 6.86 (1
H, s), 7.50-7.58 (3H, m), 7.81
-7.87 (2H, m), 10.96 (1H, br
s).

Example 73 5-Phenyl-3- (2- (1-piperazinyl) ethoxy) isoxazole dihydrochloride (Exemplified compound No. 13)
51) (a) 3- (2- (4-N-tert-butoxycarbonyl-1-piperazinyl) ethoxy) -5-phenylisoxazole 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) Was dissolved in methanol (1.0 ml), piperazine (861 mg) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was added to dilute saline solution (40 ml),
After performing dichloromethane extraction (40 ml × 2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, the obtained residue was dissolved in dichloromethane (5 ml), ditert-butyl dicarbonate (1.09 g) was added, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give the desired compound (310 mg, 83%). Was obtained as colorless crystals. Melting point: 110-111 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 314
6,1696,1626,1598,1577,151
4; NMR spectrum (CDCl ₃ ) δppm: 1.4
6 (9H, s), 2.51 (2H, t, J = 5.0H
z), 2.83 (2H, t, J = 5.5Hz), 3.4.
7 (2H, t, J = 5.0Hz), 4.43 (2H,
t, J = 5.5 Hz), 6.16 (1H, s), 7.4
1-7.49 (3H, m), 7.69-7.75 (2
H, m).

(B) 5-phenyl-3- (2- (1-
Piperazinyl) ethoxy) isoxazole dihydrochloride 3- (2- (4-tert-butoxycarbonyl-1
-Piperazinyl) ethoxy) -5-phenylisoxazole (250 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (222 mg,
95%) as colorless crystals. Melting point: 216-222 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 344
3,3189,3123,3001,2972,295
0,2915,2771,715,2623,252
7,2422,1704,1648,1621,159
6,1578,1565,1514; NMR spectrum (DMSO-d ₆ ) δppm:
3.00-3.85 (10H, brs), 4.64 (2
H, brs), 6.86 (1H, s), 7.50-7.
57 (3H, m), 7.82-7.85 (2H, m),
9.10-9.80 (1H, brs).

Example 74 3- (2-N-methylaminoethoxy) -5-phenylisoxazole hydrochloride (Exemplified compound No. 25) (a) 3- (2- (N-tert-butoxycarbonyl-N) -Methylamino) ethoxy) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (304
mg) in dimethylformamide (3 ml),
Sodium hydride [> 55% (oil-based), 52 mg] was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was cooled to 5 ° C., methyl iodide (220 mg) was added, and the mixture was stirred at the same temperature for 15 minutes and further at room temperature for 1 hour. After the reaction was completed, the reaction solution was added to ice water (20 ml) and extracted with ether (20 ml x
After performing 2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (296 mg, 93%) as colorless Was obtained as a crystal. Melting point: 72-73 ° C; IR spectrum (KBr) ν _max cm ^-1 : 312
5,1680, 1626, 1596, 1578, 151
4; NMR spectrum (CDCl ₃ ) δppm: 1.4
9 (9H, s), 2.97 (3H, s), 3.64 (2
H, brs), 4.41 (2H, brs), 6.14
(1H, s), 7.41-7.52 (3H, m), 7.
69-7.75 (2H, m).

(B) 3- (2-Methylaminoethoxy) -5-phenylisoxazole hydrochloride 3- (2- (N-tertiarybutoxycarbonyl-N)
-Methylamino) ethoxy) -5-phenylisoxazole (250 mg) was reacted in the same manner as in Example 1 (b) and post-treated to give the target compound (197 mg,
99%) as colorless crystals. Melting point: 219-221 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 313
4,3022,2981,2954,2883,286
9,2843,2803,2785,2734,162
1,1597,1578,1516; NMR spectrum (DMSO-d ₆ ) δppm:
2.62 (3H, s), 3.37 (2H, t, J = 5.
1Hz), 4.50 (1H, t, J = 5.1Hz),
6.85 (1H, s), 7.50-7.58 (3H,
m), 7.82-7.88 (2H, m), 8.79 (2
H, brs).

Example 75 3- (2-Acetylaminoethoxy) -5-phenylisoxazole (Exemplary Compound No. 1347) 3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) After suspending in anhydrous tetrahydrofuran (5 ml) and cooling to 5 ° C., acetyl chloride (94 mg) and triethylamine (243 mg) were added, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was added to ice water (40 ml) and extracted with ethyl acetate (40 m
After performing lx2), the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The obtained crystals were recrystallized from ethyl acetate to give the object compound (225 mg, 91%) as colorless crystals. Melting point: 144-145 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 331
6,1641, 1624, 1597, 1578, 154
7,1509; NMR spectrum (CDCl ₃ ) δ ppm: 2.0
3 (3H, s), 3.70 (2H, q, J = 5.1H
z), 4.39 (2H, q, J = 5.1Hz), 6.1
6 (1H, brs), 6.26 (1H, s), 7.41
-7.49 (3H, m), 7.70-7.75 (2H,
m).

Example 76 3- (2-Benzoylaminoethoxy) -5-phenylisoxazole (Exemplified compound number: 1349) 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) After suspending in anhydrous tetrahydrofuran (5 ml) and cooling to 5 ° C., benzoyl chloride (168 mg) and triethylamine (243 m)
g) was added, and the mixture was stirred at the same temperature for 30 minutes. After the reaction,
The reaction mixture was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized with ethyl acetate to give the object compound (276 mg, 90%) as colorless crystals. Melting point: 129-130 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
9,1641, 1626, 1597, 1578, 153
4,1518; NMR spectrum (CDCl ₃ ) δppm: 3.9
2 (2H, q, J = 5.1Hz), 4.52 (2H,
q, J = 5.1 Hz), 6.17 (1H, s), 6.7
4 (1H, brs), 7.42-7.53 (6H,
m), 7.71-7.74 (2H, m), 7.79-
7.88 (2H, m).

Example 77 3- (2-Methoxycarbonylaminoethoxy) -5-
Phenylisoxazole (Exemplified compound number: 134
8) 3- (2-Aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), cooled to 5 ° C, and then methyl chloroformate (113 mg) and triethylamine (243 m).
g) was added, and the mixture was stirred at the same temperature for 30 minutes. After the reaction,
The reaction mixture was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized using a mixed solvent of ethyl acetate and ether to give the object compound (233 mg, 89%) as colorless crystals. Melting point: 95-96 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 329
3,1729, 1624, 1596, 1577, 155
2,1516; NMR spectrum (CDCl ₃ ) δppm: 3.6
3 (2H, q, J = 5.1Hz), 3.70 (3H,
s), 4.37 (2H, q, J = 5.1Hz), 5.1
1 (1H, brs), 6.14 (1H, s), 7.40
-7.49 (3H, m), 7.69-7.75 (2H,
m).

Example 78 3- (2-Aminoethylthio) -5-phenylisoxazole hydrochloride (Exemplary Compound No. 15) (a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-Phenylisoxazole 2- (N-tert-butoxycarbonylamino) ethanethiol (300 mg) was dissolved in dimethylformamide (3.0 ml) and cooled to 5 ° C, and then sodium under hydrogen [> 55% ( (Oiliness), 73 mg] was added, and the mixture was stirred and stirred at the same temperature for 30 minutes. Then 3-chloro-5-
Phenylisoxazole (300 mg) was added, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 3 days. After the reaction,
The reaction mixture was added to ice water (40 ml), extracted with ethyl acetate (40 ml × 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give the target compound (130 mg,
24%) as colorless crystals.

Melting point: 87-88 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 337
6,1682, 1613, 1572, 1521, 149
4; NMR spectrum (CDCl ₃ ) δppm: 1.4
4 (9H, s), 3.27 (2H, t, J = 6.3H
z), 3.53 (2H, q, J = 6.3Hz), 5.0
1 (1H, brs), 6.44 (1H, s), 7.42
-7.50 (3H, m), 7.71-7.76 (2H,
m).

(B) 3- (2-aminoethylthio)-
5-Phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-phenylisoxazole (64
mg) was reacted in the same manner as in Example 1 (b) and post-treated to obtain the target compound (40 mg, 78%) as colorless crystals. Melting point: 196-198 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 314
1,988,2951,923,1609,159
0,1569,1492; NMR Spectrum (DMSO-d ₆₎ δppm:
3.18 (2H, t, J = 7.2Hz), 3.36 (2
H, t, J = 7.2 Hz), 7.23 (1H, s),
7.53-7.59 (3H, m), 7.83-7.97
(2H, m), 7.97 (3H, brs).

Example 79 3- (2-aminoethoxy) -4-isopropyl-5-
(3-Pyridyl) isoxazole dihydrochloride (Exemplified compound number: 1065) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3
-Pyridyl) isoxazole 3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole (0.12 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.0
9 g) was reacted in the same manner as in Example 9 (a) and post-treated to obtain the target compound (0.14 g, 74%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 332
3,3247,2979,1753,1690; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
1 (6H, d, J = 6.8Hz), 1.46 (9H,
s), 3.06 (1H, qq, J = 6.8Hz, J =
6.8 Hz), 3.60 (2H, q, J = 5.2H
z), 4.39 (2H, t, J = 5.2Hz), 4.8.
4 (1H, brs), 7.43 (1H, dd, J = 8.
0 Hz, J = 4.7 Hz), 7.90 (1H, ddd,
J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz),
8.69 (1H, dd, J = 4.7Hz, J = 1.4H
z), 8.83 (1H, d, J = 2.0 Hz).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5- (3-pyridyl) isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole (0.13 g) was carried out. The target compound (0.07 g, 64%) was obtained as colorless crystals by performing a reaction and a post-treatment in the same manner as in Example 9 (b). Melting point: 193-197 ° C. (decomposition); IR spectrum (KBr) ν _max cm ⁻¹ : 304
9,2963,2874,1549; NMR Spectrum (DMSO-d ₆₎ δppm:
1.27 (6H, d, J = 7.0Hz), 3.03 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.2
9 (2H, t, J = 5.4Hz), 4.48 (2H,
t, J = 5.4 Hz), 7.68 (1H, dd, J =
8.0 Hz, J = 5.0 Hz), 8.12 (1H, dd
d, J = 8.0 Hz, J = 2.0 Hz, J = 1.4H
z), 8.28 (3H, brs), 8.78 (1H, d
d, J = 5.0 Hz, J = 1.4 Hz), 8.85 (1
H, d, J = 2.0 Hz).

Example 80 3- (2-Aminoethoxy) -4- (1-chloropropyl) -5-phenylisoxazole hydrochloride (Exemplified Compound No. 1802) (a) 3- (2- (N- Tertiary butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0. Two
g), butyllithium (1.6M hexane solution, 0.9
ml) and propionaldehyde (0.06 ml) were reacted in the same manner as in Example 44 (a) and post-treated to obtain the target compound (0.14 g, 58%) as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 36
02,3459,2980,2937,1712; NMR spectrum (CDCl ₃ ) δppm: 0.9
5 (3H, t, J = 7.4Hz), 1.45 (9H,
s), 1.83-2.08 (2H, m), 2.51 (1
H, brs), 3.57 (2H, q, J = 5.2H
z), 4.39 (2H, t, J = 5.2Hz), 4.6
8 (1H, t, J = 7.2 Hz), 4.94 (1H, b
rs), 7.43-7.52 (3H, m), 7.64-
7.75 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-Chloropropyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5
-Phenylisoxazole (0.13g) in Example 1
The target compound (0.10 g, 91%) was obtained as colorless crystals by reacting in the same manner as in (b) and post-treating. Melting point: 122-124 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
4,2936,2878,1631,1600,157
7; NMR spectrum (DMSO-d ₆ ) δppm:
0.94 (3H, t, J = 7.3Hz), 2.11-
2.28 (2H, m), 3.31 (2H, t, J = 5.
1Hz), 4.50 (2H, t, J = 5.1Hz),
5.14 (1H, t, J = 6.5Hz), 7.61-
7.65 (3H, m), 7.72-7.75 (2H,
m).

Example 81 3- (2-Aminoethoxy) -4- (1-chloroisobutyl) -5-phenylisoxazole hydrochloride (Exemplified compound number: 1804) (a) 3- (2- (N- Tertiary butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0. Two
g), butyllithium (1.6M hexane solution, 0.9
ml) and isobutyraldehyde (0.07 ml) were reacted in the same manner as in Example 44 (a) and post-treated to obtain the target compound (0.21 g, 84%) as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 36
06,3459,2981,2937,1712,16
37; NMR spectrum (CDCl ₃ ) δppm: 0.7
9 (3H, d, J = 6.6Hz), 1.11 (3H,
d, J = 6.6 Hz), 1.45 (9H, s), 2.1
6-2.29 (1H, m), 2.56 (1H, br
s), 3.58 (2H, q, J = 5.1Hz), 4.3
0-4.48 (3H, m), 4.94 (1H, br
s), 7.46-7.51 (3H, m), 7.70-
7.74 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-Chloroisobutyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl)-
5-Phenylisoxazole (0.20 g) in Example 1
The target compound (0.11 g, 65%) was obtained as colorless crystals by reacting in the same manner as in (b) and post-treating. Melting point: 165-167 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 296
7, 2902, 2870, 1636, 1600; NMR spectrum (DMSO-d ₆ ) δ ppm:
0.78 (3H, d, J = 6.6Hz), 1.15 (3
H, d, J = 6.6 Hz), 2.53-2.63 (1
H, m), 3.30 (2H, t, J = 5.2Hz),
4.50 (2H, t, J = 5.2Hz), 4.85 (1
H, d, J = 10.7 Hz), 7.60-7.65 (3
H, m), 7.71-7.75 (2H, m), 8.25.
(3H, brs).

Example 82 3- (2-Aminoethoxy) -4- (1-chloroisopentyl) -5-phenylisoxazole hydrochloride (Exemplified compound number: 1806) (a) 3- (2- (N -Tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl) -5-phenylisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole ( 0.2
g), butyllithium (1.6M hexane solution, 0.9
ml) and isovaleraldehyde (0.09 ml) were reacted in the same manner as in Example 44 (a) and post-treated to obtain the target compound (0.2 g, 77%) as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 36
01,3459,2981,2961,2936,17
12, 1639; NMR spectrum (CDCl ₃ ) δppm: 0.8
7 (3H, d, J = 6.3Hz), 0.92 (3H,
d, J = 6.3 Hz), 1.45 (9H, s), 1.6
3-1.78 (2H, m), 1.83-1.98 (1
H, m), 3.58 (2H, q, J = 5.2Hz),
4.40 (2H, t, J = 5.2Hz), 4.75-
5.00 (2H, m), 7.44-7.50 (3H,
m), 7.66-7.71 (2H, m).

(B) 3- (2-aminoethoxy) -4
-(1-Chloroisopentyl) -5-phenylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl)
-5-Phenylisoxazole (0.19 g) was reacted in the same manner as in Example 1 (b) and post-treated to obtain the target compound (0.11 g, 69%) as colorless crystals. Melting point: 134-136 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 296
1,2905,2873,1630; NMR Spectrum (DMSO-d ₆₎ δppm:
0.79 (3H, d, J = 6.6Hz), 0.82 (3
H, d, J = 6.6 Hz), 1.57 (1H, qq, J
= 6.6 Hz, J = 6.6 Hz), 2.00-2.12
(2H, m), 3.31 (2H, t, J = 5.4H
z), 4.51 (2H, t, J = 5.4Hz), 5.2
1 (1H, t, J = 8.0 Hz), 7.62-7.65
(3H, m), 7.69-7.72 (2H, m), 8.
22 (3H, brs).

Example 83 3- (2-aminoethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole hydrochloride (Exemplified compound number: 99) (a) 3- (2- ( N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole ( 0.2 g) and 2-
By reacting (N-tert-butoxycarbonylamino) ethanol (0.16 g) in the same manner as in Example 1 (a) and post-treating, the target compound (0.25 g,
78%) as a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 340
0.2980, 2936, 1683; NMR spectrum (CDCl ₃ ) δ ppm: 1.2
2 (6H, d, J = 6.9Hz), 1.46 (9H,
s), 2.78 (1H, qq, J = 6.9 Hz, J =
6.9 Hz), 3.59 (2H, q, J = 5.2H
z), 4.38 (2H, t, J = 5.2Hz), 4.8.
6 (1H, brs), 6.90-7.03 (2H,
m), 7.42-7.50 (1H, m).

(B) 3- (2-aminoethoxy) -5
-(2,4-Difluorophenyl) -4-isopropylisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl)
-4-Isopropylisoxazole (0.24 g) was reacted in the same manner as in Example 1 (b) and post-treated to obtain the target compound (0.17 g, 85%) as colorless crystals. Melting point: 177-179 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
3,2936,1642,1614,1590; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.18 (6H, d, J = 6.9Hz), 2.76 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.2
9 (2H, t, J = 5.3Hz), 4.46 (2H,
t, J = 5.3 Hz), 7.28-7.33 (1H,
m), 7.50-7.56 (1H, m), 7.60-
7.66 (1H, m), 8.12 (3H, brs).

Example 84 3- (2-Aminoethoxy) -4-isopropyl-5-
(4-Methylphenyl) isoxazole hydrochloride (Exemplified compound number: 266) (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4
-Methylphenyl) isoxazole 3-hydroxy-4-isopropyl-5- (4-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.16 g) were used in Example 1 ( By reacting in the same manner as in a) and post-treating, the target compound (0.27 g, 82
%) As a colorless powder. IR spectrum (KBr) ν _max cm ⁻¹ : 338
3,2965,1686; NMR spectrum (CDCl ₃ ) δppm: 1.2
8 (6H, d, J = 7.0Hz), 1.46 (9H,
s), 2.41 (3H, s), 3.06 (1H, qq,
J = 7.0 Hz, J = 7.0 Hz), 3.59 (2H,
q, J = 5.2 Hz), 4.37 (2H, t, J = 5.
2Hz), 4.84 (1H, brs), 7.27 (2
H, d, J = 8.1 Hz), 7.46 (2H, d, J =
8.1 Hz).

(B) 3- (2-aminoethoxy) -4
-Isopropyl-5- (4-methylphenyl) isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole (0.25 g) Example 1
The target compound (0.13 g, 65%) was obtained as colorless crystals by performing a reaction and a post-treatment in the same manner as in (b). Melting point: 208-210 ° C .; IR spectrum (KBr) ν _max cm ⁻¹ : 297
1,2877,1641,1522; NMR Spectrum (DMSO-d ₆₎ δppm:
1.25 (6H, d, J = 7.0Hz), 2.38 (3
H, s), 3.02 (1H, qq, J = 7.0 Hz, J
= 7.0 Hz), 3.28 (2H, t, J = 5.2H)
z), 4.44 (2H, t, J = 5.2 Hz), 7.3
7 (2H, d, J = 8.1Hz), 7.47 (2H,
d, J = 8.1 Hz), 8.20 (3H, brs).

Reference Example 1 4-chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole (a) 4-chlorocinnamic acid ethyl ester 4-chlorocinnamic acid (300 g) was added to benzene (1200 m).
It was suspended in 1), ethanol (340 g) and concentrated sulfuric acid (14 ml) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was washed successively with diluted saline (500 ml), saturated aqueous sodium hydrogen carbonate solution (500 ml) and diluted saline (500 ml), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was distilled under reduced pressure to give the target compound (3
34 g, 97%) was obtained as a colorless liquid. Boiling point: 147-148 ℃ (4mmHg); NMR Spectrum (CDCl ₃₎ δppm: 1.3
3 (3H, t, J = 7.0Hz), 4.30 (2H,
q, J = 7.0 Hz), 6.47 (1H, d, J = 1)
6.0 Hz), 7.63 (1H, d, J = 16.0H)
z), 7.63 (4H, ca.s).

(B) α, β-Dibromo-4-chlorocinnamic acid ethyl ester 4-chlorocinnamic acid ethyl ester (330 g) was dissolved in carbon tetrachloride (1200 ml), and bromine (251 g) was added dropwise under stirring at room temperature. did. After stirring at room temperature for 4 hours, it was left overnight. The solvent was distilled off under reduced pressure to obtain the target compound (572 g, 99%) as colorless crystals. Melting point: 67-68 ° C .; NMR spectrum (CDCl ₃ ) δppm: 1.3
4 (3H, t, J = 7.0Hz), 4.37 (2H,
q, J = 7.0 Hz), 4.80 (1H, d, J = 1)
2.0Hz), 5.32 (1H, d, J = 12.0H
z), 7.37 (4H, ca.s).

(C) 5- (4-chlorophenyl) -3
-Hydroxyisoxazole Sodium hydroxide (151 g) was added to methanol (600 m
1), and under stirring at 0 ° C., a hydroxylamine hydrochloride (45 g) aqueous solution (50 ml) was added dropwise, and then α, β-dibromo-4-chlorocinnamic acid ethyl ester (200 g) in dioxane (200 ml) was added. Was dripped. The mixture was stirred at room temperature for 4 hours, heated under reflux for 5 hours, cooled to 5 ° C., adjusted to pH 2 with concentrated hydrochloric acid and then added to water (5 L). The precipitated crystals were filtered, washed with water (2 L), and then washed with ethanol (1
L) to give 90 g (85%) of the target compound as a pale yellow powder. Melting point: 215 to 220 ° C. (decomposition); NMR spectrum (DMF-d ₇ ) δppm: 6.
66 (1H, s), 7.52-8.20 (4H, m),
11.5-12.0 (1H, brs).

(D) 4-Chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole 5- (4-chlorophenyl) -3-hydroxyisoxazole (50.0 g) was added to dry tetrahydrofuran (30
A solution of sulfuryl chloride (34.5 g) in dry benzene (50 ml) was added dropwise under stirring at 5 ° C. After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature for 1 hour, heated under reflux for 3 hours, the solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethanol to give the target compound ( 44.2 g, 76.8
%) As colorless needles. Mp: 235-238 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 7.
60-8.20 (4H, m), 12.6-13.6 (1
H, brs).

Reference Example 2 3-hydroxy-5- (2-thienyl) isoxazole 2-thiophene acrylic acid was used as Reference Example 1 (a) and Reference Example 1.
(B) Then, the reaction was carried out in the same manner as in Reference Example 1 (c) and post-treatment was carried out to obtain the target compound. Melting point: 163-165 ° C .; NMR spectrum (DMSO-d ₆ ) δppm:
6.38 (1H, s), 7.20-7.25 (1H,
m), 7.60-7.80 (2H, m), 11.2-1
1.6 (1H, brs).

Reference Example 3 4-Chloro-3-hydroxy-5- (2-thienyl) isoxazole 3-Hydroxy-5- (2-thienyl) isoxazole was reacted in the same manner as in Reference Example 1 (d) and post-treated. By doing so, the target compound was obtained. Mp: 191-194 ° C.; NMR Spectrum _{(DMF-d 7) δppm:} 7.
21-7.45 (1H, m), 7.70-8.20 (2
H, m), 10.0-13.0 (1H, brs).

Reference Example 4 3-hydroxy-5- (3-pyridyl) isoxazole 3-pyridineacrylic acid was used as Reference Example 1 (a) and Reference Example 1.
(B) Then, the reaction was carried out in the same manner as in Reference Example 1 (c) and post-treatment was carried out to obtain the target compound. Mp: 212-214 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 6.
76 (1H, s), 7.40-7.80 (1H, m),
8.10-8.50 (1H, m), 8.66-9.00
(1H, m), 9.05-9.33 (1H, m).

Reference Example 5 4-Chloro-3-hydroxy-5- (2-pyridyl) isoxazole 3-hydroxy-5- (2-pyridyl) isoxazole is reacted in the same manner as in Reference Example 1 (d) and post-treated. Thus, the target compound is obtained. Reference Example 6 3-Hydroxy-4-isopropyl-5-phenylisoxazole Ethyl benzoylacetate was added to Agricultural and Biological Chemistry, vol. 50, p. 1831 (1986) [ Agric. Biol. Chem. EN , 50 , 1831 (198
6).] And the reaction was carried out in the same manner as described in [1] to give the desired compound. Mp: 203-205 ° C.; NMR Spectrum (DMSO-d ₆₎ δppm:
1.24 (6H, d, J = 7.1Hz), 3.01 (1
H, q, J = 7.1 Hz), 7.47-7.61 (5
H, m), 11.2-11.6 (1H, brs).

Reference Example 7 2- (N-tertiary butoxycarbonylamino) ethanol 2-Aminoethanol (6.1 g) was dissolved in a mixed solution of tetrahydrofuran and water (1: 1,100 ml), and stirred under ice-cooling. Shary butyl dicarbonate (2
1.8 g) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 5 hours. Ethyl acetate (200 ml) was added to the reaction solution, washed with water, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the target compound (15.3 g, 95%). %) As a colorless oil. Rf value: 0.35 (developing solvent: cyclohexane / ethyl acetate = 1/1); NMR spectrum (CDCl ₃ ) δppm: 1.4
5 (9H, s), 2.35-2.50 (1H, br
s), 3.29 (2H, q, J = 5.3Hz), 3.7.
1 (2H, q, J = 5.3Hz), 4.85-5.05
(1H, brs). Reference Example 8 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole (a) 2-benzoyl-3,3-dimethylbutyric acid ethyl ester Diisopropylamine (5.6 ml) was dissolved in tetrahydrofuran (56 ml). And butyllithium (1.6M hexane solution, 25m under stirring at 5 ° C under nitrogen atmosphere)
1) was added dropwise and stirred for 15 minutes. The reaction solution was cooled to -70 ° C, 3,3-dimethylbutyric acid ethyl ester (6.7 ml) was added dropwise, and the mixture was stirred for 10 minutes, benzoyl chloride (2.3 ml) was added dropwise, and the mixture was kept at the same temperature for 10 minutes. It was stirred. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 20/1) to give the target compound (4.5 g, 91 %) As a colorless oil. (B) 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole 2-benzoyl-3,3-dimethylbutyric acid ethyl ester (2.0 g) was dissolved in methanol (20 ml),
Under a nitrogen atmosphere, at 5 ° C., sodium methoxide (28
% Methanol solution, 1.6 ml) was added dropwise, and the mixture was stirred for 10 minutes. After cooling the reaction solution to -30 ° C, a methanol suspension (10 ml) of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 6.2 ml) was added dropwise, and the mixture was kept at the same temperature for 30 minutes. After stirring, 6N hydrochloric acid (14 ml) was added, and the mixture was stirred at 80 ° C for 1 hr. After completion of the reaction, the solvent was distilled off under reduced pressure, the resulting residue was poured into ice water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. . After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was crystallized with isopropyl ether to give the object compound (0.35 g, 20%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 302
7,2993,2960,2936,2869,279
0,2697,2623,2574,1644,160
0; NMR spectrum (CDCl ₃ ) δppm: 1.2
2 (9H, s), 7.39-7.50 (5H, m).

Reference Example 9 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (a) 2- (4-chlorobenzoyl) isovaleric acid ethyl ester 4-chlorobenzoyl chloride (2.5 ml) And isovaleric acid ethyl ester (1.5 ml) were reacted in the same manner as in Reference Example 8 (a) and post-treated to obtain the target compound (2.2 g, 82%) as a colorless oily substance. (B) 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole 2- (4-chlorobenzoyl) isovaleric acid ethyl ester (2.1 g), hydroxylamine hydrochloride (1.1
g) and sodium methoxide (28% methanol solution, 7.5 ml) were reacted in the same manner as in Reference Example 8 (b),
By post-treatment, the target compound (1.3 g, 71
%) As colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 306
5,3018,2970,2935,2875,282
0,2768,2695,2609,1646; NMR spectrum (CDCl ₃ ) δppm: 1.3
5 (6H, d, J = 7.0Hz), 3.06 (1H, q
q, J = 7.0 Hz, J = 7.0 Hz), 7.46 (2
H, d, J = 8.6 Hz), 7.54 (2H, d, J =
8.6 Hz). Reference Example 10 5- (2,4-difluorophenyl) -3-hydroxyisoxazole (a) 2,4-difluorocinnamic acid ethyl ester 2,4-difluorocinnamic acid (10.1 g) in ethanol (100 ml). Dissolve, add concentrated sulfuric acid (1 ml),
The mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, the resulting residue was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was anhydrous sulfuric acid. Dried with magnesium. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (11.2 g, 97%) as a colorless oily substance. (B) α, β-Dibromo-2,4-difluorocinnamic acid ethyl ester 2,4-difluorocinnamic acid ethyl ester (11.2
g) was dissolved in carbon tetrachloride (110 ml), bromine (2.7 ml) was added dropwise with stirring at room temperature, and then the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain the target compound (19.6 g, quantitative) as a colorless powder. (C) 5- (2,4-Difluorophenyl) -3-hydroxyisoxazole Sodium hydroxide (10.9 g) was added to methanol (110).
ml), and a solution of hydroxylamine hydrochloride (4.2 g) in water (10 ml) was added dropwise with stirring at 5 ° C.
α, β-Dibromo-2,4-difluorocinnamic acid ethyl ester (19.6 g) in tetrahydrofuran (20 m
l) The solution was added dropwise, the mixture was stirred at room temperature for 2 hours, and then heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the obtained residue was poured into ice water, the pH of the solution was adjusted to 2 with concentrated hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated saline, The organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: cyclohexane / ethyl acetate = 1/1) to give the target compound (8.2 g, 79 %) As colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 317
0,3090,3028,2848,2806,268
9, 2655, 2603, 1630; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.38 (1H, s), 7.25-7.32 (1H,
m), 7.47-7.56 (1H, m), 7.89-
7.99 (1H, m), 11.62 (1H, brs).

Reference Example 11 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole (a) 2-trifluoromethylcinnamic acid ethyl ester 2-trifluoromethylcinnamic acid (10.1 g), concentrated sulfuric acid (1 ml) ) And ethanol (100 ml) in Reference Example 10
The target compound (10.8 g, 95%) was obtained as a colorless oily substance by reacting in the same manner as in (a) and post-treating. (B) α, β-Dibromo-2-trifluoromethylcinnamic acid ethyl ester 2-trifluoromethylcinnamic acid ethyl ester (1
0.8 g) and bromine (2.3 ml) were reacted in the same manner as in Reference Example 10 (b) and post-treated to obtain the target compound (17.9 g, quantitative) as a colorless powder. (C) 3-Hydroxy-5- (2-trifluoromethylphenyl) isoxazole α, β-dibromo-2-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and hydroxylation. The target compound (7.6 g, 76%) was obtained as colorless crystals by reacting sodium (9.1 g) in the same manner as in Reference Example 10 (c) and performing post-treatment. IR spectrum (KBr) ν _max cm ⁻¹ : 317
6,3096,3022,2950,2836,279
6,2669,1620,1600; NMR spectrum (DMSO-d ₆ ) δppm:
6.34 (1H, s), 7.73-7.87 (3H,
m), 7.92-7.95 (1H, m), 11.58
(1H, brs).

Reference Example 12 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole (a) 4-trifluoromethylcinnamic acid ethyl ester 4-trifluoromethylcinnamic acid (10.2 g), concentrated sulfuric acid (1 ml) ) And ethanol (100 ml) in Reference Example 10
The target compound (10.9 g, 95%) was obtained as a colorless oily substance by performing a reaction and a post-treatment in the same manner as in (a). (B) α, β-Dibromo-4-trifluoromethylcinnamic acid ethyl ester 4-trifluoromethylcinnamic acid
The target compound (17.9 g, quantitative) was obtained as a colorless powder by reacting ethyl ester (10.8 g) and bromine (2.4 ml) in the same manner as in Reference Example 10 (b) and post-treating. . (C) 3-Hydroxy-5- (4-trifluoromethylphenyl) isoxazole α, β-dibromo-4-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and hydroxylation. The target compound (8.3 g, 83%) was obtained as colorless crystals by reacting sodium (9.1 g) in the same manner as in Reference Example 10 (c) and performing post-treatment. IR spectrum (KBr) ν _max cm ⁻¹ : 315
4,3018,2987,2838,2788,267
3,2637,2607,2547,1631,161
4; NMR spectrum (DMSO-d ₆ ) δppm:
6.77 (1H, s), 7.88 (2H, d, J = 8.
4 Hz), 8.03 (2H, d, J = 8.4 Hz), 1
1.60 (1H, brs).

Reference Example 13 3-Hydroxy-5- (4-isopropylphenyl) isoxazole (a) 4-isopropylcinnamic acid ethyl ester 4-isopropylcinnamic acid (5.0 g), concentrated sulfuric acid (0.5 g)
ml) and ethanol (50 ml) in Reference Example 10 (a)
The target compound (5.5 g, 97%) was obtained as a colorless oily substance by reacting in the same manner as above and post-treating. (B) α, β-dibromo-4-isopropylcinnamic acid
Ethyl ester 4-isopropyl cinnamic acid ethyl ester (5.5 g)
And bromine (1.3 ml) were reacted in the same manner as in Reference Example 10 (b) and post-treated to give the target compound (9.5 g,
Quantitative) was obtained as a colorless powder. (C) 3-Hydroxy-5- (4-isopropylphenyl) isoxazole α, β-dibromo-4-isopropylcinnamic acid ethyl ester (9.5 g), hydroxylamine hydrochloride (2.2)
g) and sodium hydroxide (5.2 g) in Reference Example 10
The target compound (3.6 g, 71%) was obtained as colorless crystals by reacting in the same manner as in (c) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 301
3,2964, 2934, 2893, 2872, 279
3,2665,2631,2542,1624; NMR Spectrum (DMSO-d ₆₎ δppm:
1.22 (6H, d, J = 6.9Hz), 2.94 (1
H, qq, J = 6.9 Hz, J = 6.9 Hz), 6.4
8 (1H, s), 7.39 (2H, d, J = 8.3H
z), 7.72 (2H, d, J = 8.3Hz).

Reference Example 14 3-Hydroxy-5- (4-phenoxyphenyl) isoxazole (a) 4-phenoxycinnamic acid 4-phenoxybenzaldehyde (10.0 g) and potassium acetate (9.8 g) were mixed with acetic anhydride (9. 5 ml) and the mixture was heated to reflux at 180 ° C. for 5 hours. After completion of the reaction, the pH of the solution was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried with anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the target compound (6.5 g, 54 %) As colorless crystals. (B) 4-phenoxycinnamic acid ethyl ester 4-phenoxycinnamic acid (4.0 g), concentrated sulfuric acid (0.4 m
l) and ethanol (40 ml) were reacted in the same manner as in Reference Example 10 (a) and post-treated to obtain the target compound (4.4 g, 98%) as a colorless oily substance. (C) α, β-Dibromo-4-phenoxycinnamic acid ethyl ester 4-phenoxycinnamic acid ethyl ester (4.4 g) and bromine (0.84 ml) were reacted in the same manner as in Reference Example 10 (b), and post-treatment. The target compound (7.0 g,
Quantitative) was obtained as a colorless powder. (D) 3-Hydroxy-5- (4-phenoxyphenyl) isoxazole α, β-dibromo-4-phenoxycinnamic acid ethyl ester (7.0 g), hydroxylamine hydrochloride (1.4
g) and sodium hydroxide (3.3 g) in Reference Example 10
The target compound (3.4 g, 83%) was obtained as colorless crystals by reacting in the same manner as in (c) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 314
7,3013,2951,2852,2785,261
4,2557,1627; NMR Spectrum (DMSO-d ₆₎ δppm:
6.47 (1H, s), 7.07-7.25 (5H,
m), 7.42-7.48 (2H, m), 7.79-
7.83 (2H, m), 11.36 (1H, brs).

Reference Example 15 3-hydroxy-5- (1-naphthyl) isoxazole (a) 1-naphthylacrylic acid 1-naphthaldehyde (30.5 g), potassium acetate (38.3 g) and acetic anhydride (36.9 ml). ) Is reacted in the same manner as in Reference Example 14 (a) and post-treated,
The target compound (22.4 g, 58%) was obtained as a colorless powder. (B) 1-naphthyl acrylic acid ethyl ester 1-naphthyl acrylic acid (9.5 g), concentrated sulfuric acid (1 m
l) and ethanol (100 ml) in Reference Example 10 (a)
The target compound (10.2 g, 94%) was obtained as a colorless oily substance by reacting in the same manner as above and post-treating. (C) α, β-dibromo-1-naphthylacrylic acid
Ethyl ester 1-naphthyl acrylic acid ethyl ester (10.1
g) and bromine (2.5 ml) were reacted in the same manner as in Reference Example 10 (b) and post-treated to give the desired compound (17.
2 g, quantitative) was obtained as a colorless powder. (D) 3-hydroxy-5- (1-naphthyl) isoxazole α, β-dibromo-1-naphthylacrylic acid ethyl ester (6.0 g), hydroxylamine hydrochloride (1.3
g) and sodium hydroxide (7.2 g) in Reference Example 10
The target compound (2.6 g, 78%) was obtained as colorless crystals by reacting in the same manner as in (c) and post-treating. IR spectrum (KBr) ν _max cm ⁻¹ : 313
6,3045, 3017, 2790, 2710, 264
0, 2569, 1628; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.53 (1H, s), 7.61-7.70 (3H,
m), 7.84-7.87 (1H, m), 8.03-
8.13 (2H, m), 8.22-8.28 (1H,
m).

Reference Example 16 3-Hydroxy-5- (4-hydroxyphenyl) isoxazole 3-Hydroxy-5- (4-methoxyphenyl) isoxazole (5.0 g) was suspended in dichloromethane (50 ml), and aluminum chloride ( 7.0 g) was added and the mixture was heated to reflux for 66 hours. After completion of the reaction, the reaction solution was poured into ice water,
After adding normal hydrochloric acid, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: cyclohexane / ethyl acetate = 2/1).
The target compound (3.8 g,
83%) was obtained as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 314
0,3074,1624,1588; NMR Spectrum (DMSO-d ₆₎ δppm:
6.24 (1H, s), 6.86 (2H, d, J = 8.
2Hz), 7.62 (2H, d, J = 8.2Hz), 1
0.03 (1H, s), 11.24 (1H, brs).

Reference Example 17 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole (a) 2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester 2,4-difluoro Benzoyl chloride (4.9 ml) and isovaleric acid ethyl ester (3.0 ml) were used in Reference Example 8.
The target compound (3.65 g, 68%) was obtained as a colorless liquid by performing a reaction and a post-treatment in the same manner as in (a). (B) 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole 2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester (1.7 g), hydroxylamine hydrochloride (0 2.9 g) and sodium methoxide (28% methanol solution, 7.5 ml) were reacted in the same manner as in Reference Example 8 (b) and post-treated to give the target compound (0.59).
g, 39%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 308
2,3033,2980,2968,2935,291
3,2877,2836,2795,2699,263
6, 2604, 1660, 1610; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.28 (6H, d, J = 7.0Hz), 2.81 (1
H, qq, J = 7.0 Hz, J = 7.0 Hz), 6.9
1-7.05 (2H, m), 7.43-7.52 (1
H, m).

Reference Example 18 4-Cyclopropyl-3-hydroxy-5-phenylisoxazole (a) 2-Benzoyl-2-cyclopropylacetic acid methyl ester Benzoyl chloride (1.0 ml) and 2-cyclopropylacetic acid methyl ester (2.0 g) was reacted in the same manner as in Reference Example 8 (a) and post-treated to obtain the target compound (1.05 g, 28%) as a colorless liquid. (B) 4-Cyclopropyl-3-hydroxy-5-phenylisoxazole 2-benzoyl-2-cyclopropylacetic acid methyl ester (0.9 g), hydroxylamine hydrochloride (0.6 g) and sodium methoxide (2).
An 8% methanol solution (4.0 ml) was reacted in the same manner as in Reference Example 8 (b) and post-treated to obtain the target compound (0.32 g, 39%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 308
5,3066,3012,2972,2909,285
1,2778, 2716, 2652, 2601, 164
6; NMR spectrum (CDCl ₃ ) δppm: 0.7
9-0.85 (2H, m), 0.91-0.98 (2
H, m), 1.67-1.77 (1H, m), 7.43
-7.53 (3H, m), 7.86-7.90 (2H,
m).

Reference Example 19 3-Hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole (a) 2-Nicotinoylisovaleric acid ethyl ester Nicotinic acid chloride hydrochloride (0.9 g) and isovaleric acid ethyl ester (2) .3 ml), diisopropylamine (2.1 ml) and butyllithium (1.6 M hexane solution, 9.4 ml) were reacted in the same manner as in Reference Example 8 (a) and post-treated to give the target compound (0.78 g). ，
44%) was obtained as a colorless liquid. (B) 3-hydroxy-4-isopropyl-5- (3
-Pyridyl) isoxazole 2-nicotinoyl isovaleric acid ethyl ester (0.7
6 g), hydroxylamine hydrochloride (0.46 g) and sodium methoxide (28% methanol solution, 3.1 m)
l) was reacted in the same manner as in Reference Example 8 (b) and post-treated to obtain the target compound (0.15 g, 23%) as colorless crystals. IR spectrum (KBr) ν _max cm ⁻¹ : 306
9,3035,2970,2934,2876,280
9, 2770, 2709, 2665, 2605, 257
6,2519,1511; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
8 (6H, d, J = 7.0Hz), 3.10 (1H, q
q, J = 7.0 Hz, J = 7.0 Hz), 7.45 (1
H, dd, J = 7.9 Hz, J = 4.4 Hz), 7.9
4 (1H, d, J = 7.9 Hz), 8.72 (1H,
d, J = 4.4 Hz), 8.88 (1H, s).

Reference Example 20 4-Chloro-3-hydroxy-5- (3-pyridyl) isoxazole 3-Hydroxy-5- (3-pyridyl) isoxazole is reacted in the same manner as in Reference Example 1 (d) and post-treated. Thus, the target compound was obtained. Mp: 220-224 ° C. (decomposition); NMR Spectrum _{(DMF-d 7) δppm:} 7.
60-8.20 (4H, m), 12.6-13.6 (1
H, brs).

Test Example 1 Type A Monoamine Oxidase Inhibitory Activity Biochemical Pharmacology, Volume 12, 143
Page 9 (1963) [ Biochem, Pharmacol. , 12 , 1439 (196
3).] And the Journal of Neurochemistry,
Volume 35, p. 109 (1980) [ J. Neurochem. , 35 ,
109 (1980).]. To 30 μl of mouse brain crude mitochondrial preparation (30 μg protein), 210 μl of phosphate buffer (pH 7.4) and 30 μl of test compound (dissolved in 10% DMSO-water) were added and preincubated at 38 ° C. for 20 minutes. . Then, ¹⁴ C-5-hydroxytryptamine (5-HT,
(Final concentration: 100 μM) was added and reacted at 38 ° C. for 20 minutes. After stopping the reaction by adding 2N hydrochloric acid (200 μl), the metabolites from the enzymatic reaction labeled with ¹⁴ C were extracted with a solvent (ethyl acetate: toluene = 1: 1) and their ¹⁴ C radioactivity was determined. The concentration of the compound that reduces the control ¹⁴ C radioactivity by 50% (IC ₅₀ ) was determined by measurement with a liquid scintillation counter. As a result of using this test, for example, Examples 1, 2, 3, 4, 5, 6, 7, 8,
The compounds of 54, 57, 58, 59, ₆₀ , 62 and 67 showed particularly excellent action with an IC ₅₀ of 28 nM or less.

Formulation Example 1 Hard Capsule 50 mg of the compound of Example 4 in powder form, 128.7 mg lactose, 70 mg cellulose and 1.3 mg magnesium stearate are mixed and passed through a 60 mesh sieve before The powder is placed in a 250 mg No. 3 gelatin capsule to form a capsule. Formulation Example 2 Tablets 50 mg of the compound of Example 4 in powder form, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed and tableted by a tableting machine to give 1 tablet 200.
mg tablets. This tablet can be sugar-coated if necessary.

[0363]

The isoxazole derivative (I) of the present invention
Has excellent A-type monoamine oxidase inhibitory action and weak toxicity, so depression, Parkinson's disease,
As a therapeutic or preventive drug (especially therapeutic drug) for neurological diseases (particularly depression) such as Alzheimer's dementia (cognitive impairment based on Alzheimer's disease) or cerebrovascular dementia (cognitive impairment based on cerebrovascular dementia) It is useful.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/50 ABR A61K 31/50 ABR 31/505 ABS 31/505 ABS 31/535 31/535 C07D 261/12 C07D 261/12 261/14 261/14 261/18 261/18 413/04 207 413/04 207 213 213 231 231 233 233 233 237 237 239 239 241 241 261 261 263 263 263 307 307 333 333 433 417/04 261 417/04 261 C12N 9/99 C12N 9/99 (72) Inventor Masao Kitsuka 1-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kenji Yoshimi Hiroshi, Shinagawa-ku, Tokyo 1-58, Machi Sankyo Co., Ltd. (72) Inventor Second son Kaneko 1-2-5, Hiromachi, Shinagawa-ku, Tokyo No. 8 Sankyo Stock Company

Claims (21)

[Claims] 1. A compound of the general formula {In the formula, R ¹ may be the same or different and may have 1 to 3 substituents selected from the following substituent group: C ₆ -C ₁₄
It may have an aryl group or 1 to 3 said substituents,
A 5-membered to 6-membered aromatic heterocyclic group having 1 to 2 heteroatoms selected from the same or different from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom is shown. ; C ₁ -C ₆ alkyl; halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl substituted by; C ₁ -C ₆ alkoxy; same or different 1 to 3 of which are selected from the following group May have a substituent,
C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ aralkyl, C ₆ -C
₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C
It is ₁ -C ₆ alkoxy. ); Cyano; nitro; hydroxyl group; C ₁ -C ₇ alkanoyl; C ₁ -C ₇ alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl and mono-C ₇ -C ₁₅ arylcarbonylamino which may have 1 to 3 substituents which are the same or different and are selected from the following groups (the group of the substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy). ], R ² is a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl group substituted by halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl group; C
₂ -C ₆ alkynyl group; C ₃ -C ₁₀ cycloalkyl group;
C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; a cyano group; a carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; a carbamoyl group; a mono (C ₁ -C ₆ An alkyl) carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group, wherein R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group,
A di (C ₁ -C ₆ alkyl) amino group, a mono C ₁ -C ₇ alkanoylamino group, a mono C ₂ -C ₇ alkoxycarbonylamino group, the same or different, and 1 to 3 substituents selected from the following groups Mono C ₇ -C _{15 which} may have a group
An arylcarbonylamino group (the group of substituents is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) or one nitrogen atom, and further one nitrogen atom or oxygen atom A 5-membered to 6-membered saturated heterocyclic group (provided that the group is bonded on a nitrogen atom), X is an oxygen atom or a sulfur atom, and n is an integer of 2 to 6. Indicates. } Isoxazole derivative or a pharmaceutically acceptable salt thereof. 2. The C ₆ -C ₁₄ aryl group according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups, or 5-membered to 6-membered fragrance having 1 to 2 heteroatoms which may be substituted with 1 to 3 substituents and are the same or different from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Isoxazole derivative which is a group heterocyclic group or a pharmacologically acceptable salt thereof [the group of the substituent is halogen; C ₁ -C ₆ alkyl;
C substituted with halogen or C ₁ -C ₆ alkoxy
C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may be the same or different and may have 1 to 3 substituents selected from the following groups. , Halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy); benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; phenoxy, 4-fluorophenoxy. , 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-
Dimethylbenzyloxy, 4-methoxybenzyloxy; cyano; nitro; hydroxyl; acetoxy; C ₂ -C ₇
Alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆
Alkyl) carbamoyl; benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino,
2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino. ]. 3. The C ₆ -C ₁₄ aryl group as defined in claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups, or 5-membered to 6-membered fragrance having 1 to 2 heteroatoms which may be substituted with 1 to 3 substituents and are the same or different from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Isoxazole derivative which is a group heterocyclic group or a pharmaceutically acceptable salt thereof [the group of the substituent is halogen; C ₁ -C ₆ alkyl;
C substituted with halogen or C ₁ -C ₆ alkoxy
₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; same or different groups of 1 to 3 of which may have a substituent C ₆ -C ₁₄ aryl (the substituent is selected from the following group , Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); cyano; C ₂ -C ₇ alkoxycarbonyl; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; and di (C _1- ). a C ₆ alkyl) carbamoyl. ]. 4. The C ₆ -C ₁₄ aryl group or R 1 according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent groups. 5- or 6-membered fragrance having 1 or 2 heteroatoms, which may be substituted by 1 or 2 substituents, and which are the same or different and are selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Isoxazole derivative which is a group heterocyclic group or a pharmacologically acceptable salt thereof [the group of the substituent is halogen, C ₁ -C ₄ alkyl,
Fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2 , 4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl. ]. 5. The phenyl group according to claim 1, wherein R ¹ is the same or different and may have 1 to 3 substituents selected from the following substituent group, or 1 or 2 An isoxazole derivative which is a furyl group, a thienyl group or a pyridyl group which may have the substituent, or a pharmacologically acceptable salt thereof.
[This group of substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl. ]. 6. The phenyl group according to claim 1, wherein R ¹ may be the same or different, and may have 1 or 2 substituents selected from the following substituent groups, or 1 substituent. May have,
A isoxazole derivative which is a furyl group, a thienyl group or a pyridyl group or a pharmaceutically acceptable salt thereof [the group of the substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy. ]. 7. The R 1 according to claim 1, wherein R ¹ is a phenyl group, a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group, a methylphenyl group or 2-
An isoxazole derivative having a furyl group, a 3-furyl group, a 2-thienyl group or a 3-thienyl group, or a pharmacologically acceptable salt thereof. 8. The method according to claim 1, wherein R ¹ is a phenyl group or 2
-Chlorophenyl group, 4-chlorophenyl group, 2,4-
Difluorophenyl group, 2,4-dichlorophenyl group,
An isoxazole derivative having a 2-furyl group or a 2-thienyl group or a pharmacologically acceptable salt thereof. 9. A method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom or C ₁ -C ₆
Alkyl group, fluoromethyl group, difluoromethyl group,
Trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, a methoxy group, an ethoxy group, a cyano group, a carboxy Group, formyl group, acetyl group, methoxycarbonyl group,
An isoxazole derivative which is an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group or an N, N-dimethylcarbamoyl group, or a pharmacologically acceptable salt thereof. 10. A method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom or C ₁ -C.
₆ alkyl group, C ₂ -C ₆ alkenyl or C ₂ -C ₆
An isoxazole derivative which is an alkynyl group or a pharmacologically acceptable salt thereof. 11. The method according to claim 1, wherein R ² is a hydrogen atom, a halogen atom or C ₁ -C.
_{4. An} isoxazole derivative which is an alkyl group, an allyl group, an isopropenyl group, a 2-butenyl group or a propargyl group, or a pharmacologically acceptable salt thereof. 12. The method according to claim 1, wherein R ² is hydrogen atom, chlorine atom, ethyl group, propyl group, isopropyl group, isobutyl group or t-butyl group. An isoxazole derivative or a pharmacologically acceptable salt thereof. 13. An isoxazole derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R ² is a hydrogen atom or an isopropyl group. 14. The method according to claim 1, wherein R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group or a di (C ₁ -C ₆ alkyl) amino group. Or 1
Isoxazole derivative or a 5-membered to 6-membered saturated heterocyclic group containing one nitrogen atom and optionally one nitrogen atom or an oxygen atom (provided that the group is bonded on the nitrogen atom). A pharmacologically acceptable salt. 15. The method according to claim 1, wherein R ³ is an amino group, a methylamino group, an ethylamino group, an N, N-dimethylamino group, a piperidyl group or a morpholinyl group. Isoxazole derivative or a pharmaceutically acceptable salt thereof. 16. An isoxazole derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R ³ is an amino group. 17. An isoxazole derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein X is an oxygen atom. 18. The isoxazole derivative according to claim 1, wherein n is 2, or a pharmaceutically acceptable salt thereof, in one of the claims 1 to 17. 19. 3- (2-Aminoethoxy) -5-phenylisoxazole, 3- (2-aminoethoxy) -4-chloro-5-phenylisoxazole, 3- (2-aminoethoxy)- 4-Ethyl-5-phenylisoxazole, 3- (2-aminoethoxy) -5-phenyl-4-propylisoxazole, 3- (2-aminoethoxy) -4-isopropyl-5
Phenylisoxazole, 3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole, 3- (2-aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole, 3 -(2-aminoethoxy) -5- (4-chlorophenyl) isoxazole, 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole, 3- (2-aminoethoxy)- 5- (2,4-dichlorophenyl) -4-isopropylisoxazole, 3- (2-aminoethoxy) -5- (2-furyl) -4
-Isopropylisoxazole, 3- (2-aminoethoxy) -5- (2-thienyl) isoxazole, 3- (2-aminoethoxy) -4-chloro-5- (2-
Thienyl) isoxazole, 3- (2-aminoethoxy) -4-isopropyl-5-
(2-thienyl) isoxazole, or 4-allyl-3
-(2-Aminoethoxy) -5-phenylisoxazole or a pharmacologically acceptable salt thereof. 20. An A-type monoamine oxidase inhibitor comprising the isoxazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 as an active ingredient. 21. A therapeutic or prophylactic agent for depression, which comprises the isoxazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 as an active ingredient.