JP3228663B2 - Isoxazoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has excellent B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity (especially B-type monoamine oxidase inhibitory activity), and is useful for Parkinson's disease, depression, Alzheimer's disease. The present invention relates to an isoxazole derivative having a therapeutic or preventive action for a neurological disease such as a disease (particularly Parkinson's disease) and a monoamine oxidase inhibitor containing the isoxazole derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Parkinson's disease is a chronic progressive disease that results in immobility, muscle stiffness and tremor as a result of degeneration of dopaminergic nerves in the nigrostriatal tract. The causes of Parkinson's disease
It is known that degenerative, vascular and inflammatory changes in the basal ganglia result from a decrease in the content of the neurotransmitter dopamine in the brain, particularly in the caudate nucleus and putamen. As a therapeutic agent, levodopa administration is the most effective and widely applied for the purpose of supplementing reduced dopamine in the brain, especially in the striatum. However, levodopa monotherapy has a problem with large side effects. In recent years, attempts have been made actively to treat Parkinson's disease by inhibiting B-type monoamine oxidase, which is a protease for decomposing dopamine, and suppressing degradation of dopamine. It is supposed to be. By the way, Japanese Patent Publication No. 47-6302 discloses that benzoisoxazole derivatives, for example, compounds A and B are locally anesthetized,
It is described that it can be used as an antihistamine, an anti-inflammatory, a tonic and in general as an antispasmodic having cardiovascular effects as well as effects on the nervous system.

[0003]

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Further, Pharmaco Eddy Scientifica, Vol. 23, p. 1081 (1968) and Vol. 24, p. 440 (1969) [Farmaco, Ed. S.
ci., 23 , 1081 (1968)., ibid., 24 , 440 (1969).] describes that Compound B has an anti-inflammatory effect and a local (invasive) anesthetic effect. However, it is not known at all that compounds A and B have a monoamine oxidase inhibitory action.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies over many years on the synthesis of isoxazole derivatives and their pharmacological actions with the aim of developing an excellent therapeutic agent for Parkinson's disease and the like. The derivative has strong B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity (particularly strong B-type monoamine oxidase inhibitory activity), and is effective against neurological diseases such as Parkinson's disease, depression and Alzheimer's disease (especially Parkinson's disease). The present invention has been found to have a therapeutic or preventive action, and the present invention has been completed. The present invention provides an isoxazole derivative having excellent B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity, a process for producing the same, and a monoamine oxidase inhibitor containing the isoxazole derivative as an active ingredient.

[0006]

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

[0007]

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[0008] In the above formula, R ¹ represents a hydrogen atom; a halogen atom; C ₁ -C ₆ alkyl group; a halogen or a C ₁ -C
C ₁ -C ₄ alkyl group substituted with ₄ alkoxy; C ₁
-C ₆ alkoxy group; a halogeno C ₁ -C ₆ alkoxy group; a hydroxyl group; C ₁ -C ₆ alkylthio group; an amino group; a mono C ₁ -C ₆ alkylamino group; di-C ₁ -C ₆ alkylamino group; C ₁ A C ₁ -C ₆ alkanoylamino group; a C ₁ -C ₆ alkanoylamino group; a C ₁ -C ₆ alkanoyloxy group;
A C ₁ -C ₆ alkoxycarbonyl group; a carboxy group;
A (C ₁ -C ₆ alkylthio) thiocarbonyl group; a carbamoyl group; a mono C ₁ -C ₆ alkylcarbamoyl group; a di-C ₁ -C ₆ alkylcarbamoyl group; a nitro group; or a cyano group, and R ² represents an amino group. And m represents an integer of 1 to 3, n represents an integer of 1 to 6, and ring A represents a phenyl ring fused with isoxazole or a naphthyl ring fused with isoxazole, or an oxygen fused with isoxazole. , A 5- or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from a heteroatom group consisting of nitrogen and sulfur atoms, and X represents an oxygen atom or a sulfur atom.
However, when m represents an integer of 2 or 3, R ¹ represents the same or different groups.

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

[0010]

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[0011] In the above formulas, R ^1, m, n, ring A and X are the same meanings as described above, R ² a is an amino group; a mono C ₁
-C ₄ alkylamino group; di-C ₁ -C ₄ alkylamino group; wherein or one nitrogen atom, further one may also 5- to contain nitrogen or oxygen atom in 6-membered Hajime Tamaki (provided that
The group is attached on the nitrogen atom. ).

The "halogen atom" in the definition of R ^{1 in} the above general formulas (I) and (II) includes, for example, a fluorine atom,
It can be a chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, more preferably
It is a fluorine atom or a chlorine atom.

[0013] "C ₁ in the definition of R ¹ in the above -
"C ₆ alkyl group" includes, 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, 1,3-dimethylbutyl group, 2,3
A straight-chain or branched alkyl group having 1 to 6 carbon atoms such as -dimethylbutyl group or 2-ethylbutyl group;
Preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, particularly preferably methyl group.

[0014] C ₁ -C substituted with "halogen or C ₁ -C ₄ alkoxy in the definition of R ¹ in the above
_The " ₄ alkyl group" is the above-mentioned halogen or C ₁ -C
₄ alkoxy represents a group bonded to the C ₁ -C ₄ alkyl group, and examples of a group in which halogen is bonded to an alkyl group include, for example, a fluoromethyl group, a difluoromethyl group,
Trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 3
-Fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 4-fluorobutyl group or 4-chlorobutyl group. Examples of the group in which alkoxy is bonded to an alkyl group include methoxymethyl group and ethoxymethyl Group, propoxymethyl group, butoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group,
It may be a butoxyethyl group, a propoxypropyl group or a butoxybutyl group, and is preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2,2-triethyl group. A fluoroethyl group, a methoxymethyl group or a methoxyethyl group, more preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, It is a methyl group or a methoxyethyl group, more preferably a trifluoromethyl group, a 2,2,2-trifluoroethyl group or a methoxymethyl group, and particularly preferably a trifluoromethyl group.

In the above, "C _1- " in the definition of R ¹
The “C ₆ alkoxy group” is the “C ₁ -C ₆ alkyl group”
Represents a group bonded to an oxygen atom, for example, a methoxy group,
Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,
Pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpent Toxyl group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2
-Dimethylbutoxy group, 1,3-dimethylbutoxy group,
It can be a 2,3-dimethylbutoxy group or a 2-ethylbutoxy group, preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group or an ethoxy group, particularly preferably a methoxy group. .

The "halogeno C ₁ -C ₆ alkoxy group" in the above definition of R ¹ represents a group in which the halogen atom is bonded to the C ₁ -C ₆ alkoxy group, and is, for example, a fluoromethoxy group, a chloromethoxy group. , Bromomethoxy group, iodomethoxy group, difluoromethoxy group,
Dichloromethoxy group, dibromomethoxy group, trifluoromethoxy group, trichloromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2
It may be a 2-trichloroethoxy group, a 3-fluoropropoxy group, a 3-bromopropoxy group, a 4-fluorobutoxy group, a 5-fluoropentoxy group or a 6-iodohexyloxy group, preferably a fluoromethoxy group, a chloromethoxy group. Group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group or 2,2,2-trifluoroethoxy group, More preferably, they are a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group or a 2,2,2-trifluoromethoxy group, and particularly preferably a difluoromethoxy group.

In the above, "C _1- " in the definition of R ¹
“C ₆ alkylthio group” refers to a group in which the above “C ₁ -C ₆ alkyl group” is bonded to a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s- Butylthio, t-butylthio _, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-
Methylpentylthio group, 3-methylpentylthio group, 2
-Methylpentylthio group, 1-methylpentylthio group,
3,3-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 1,3-dimethylbutylthio group,
It can be a 2,3-dimethylbutylthio group or a 2-ethylbutylthio group, preferably a C ₁ -C ₄ alkylthio group, more preferably a methylthio group or an ethylthio group, particularly preferably a methylthio group. It is.

In the above, “mono C” in the definition of R ¹
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- butyl amino group, t- butyl amino group which may be pentylamino group or hexylamino group, preferably a mono-C ₁ -C ₄ alkylamino group, more preferably methylamino Or an ethylamino group, particularly preferably a methylamino group.

The "di C ₁ in the definition of R ¹ in the above
-C ₆ alkylamino group ", for example, dimethylamino group, ethylmethylamino group, methylpropylamino group,
Isopropylmethylamino group, butylmethylamino group,
Isobutylmethylamino group, s-butylmethylamino group, t-butylmethylamino group, diethylamino group, ethylpropylamino group, ethylisobutylamino group, dipropylamino group, dibutylamino group, dipentylamino group or dihexylamino group Obtained, preferably di C ₁
—C ₄ alkylamino, more preferably dimethylamino or diethylamino, particularly preferably dimethylamino.

In the above, "C _1- " in the definition of R ¹
"C ₆ alkanoyl group" includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group,
It may be a linear or branched alkanoyl group having 1 to 6 carbon atoms such as a pentanoyl group, a pivaloyl group, a valeryl group or an isovaleryl group, preferably a C ₁ -C ₄ alkanoyl group, more preferably Is a formyl group or an acetyl group.

The "C ₁ in the definition of R ¹ in the above -
"C ₆ alkanoylamino group" includes, for example, carbon atoms such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, pivaloylamino, valerylamino or isovalerylamino. It may be a linear or branched alkanoylamino group having 1 to 6 carbon atoms, preferably C ₁
—C ₄ alkanoylamino group, more preferably formylamino group or acetylamino group.

In the above, "C _1- " in the definition of R ¹
"C ₆ alkanoyloxy group" includes, for example, carbon atoms such as formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, pentanoyloxy group, pivaloyloxy group, valeryloxy group and isovaleryloxy group. It may be a straight-chain or branched-chain alkanoyloxy group having 1 to 6 carbon atoms, preferably C ₁
—C ₄ alkanoyloxy group, more preferably formyloxy group or acetyloxy group.

The "C ₁ in the definition of R ¹ in the above -
"C ₆ alkoxycarbonyl group" includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentoxycarbonyl group it is a group or hexyloxy group, preferably a C ₁ -C ₄ alkoxycarbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, particularly preferably a methoxycarbonyl group.

[0024] "in the definition of R ¹ in the above (C ₁
—C ₆ alkylthio) thiocarbonyl group ”includes, for example, (methylthio) thiocarbonyl group, (ethylthio) thiocarbonyl group, (propylthio) thiocarbonyl group,
(Isopropylthio) thiocarbonyl group, (butylthio) thiocarbonyl group, (isobutylthio) thiocarbonyl group, (s-butylthio) thiocarbonyl group, (t-
It may be a thiocarbonyl group to which a linear or branched alkylthio group having 1 to 6 carbon atoms such as a butylthio) thiocarbonyl group, a (pentylthio) thiocarbonyl group or a (hexylthio) thiocarbonyl group is bonded. (C
An ₁ -C ₄ alkylthio) thiocarbonyl group, an even more preferably (methylthio) thiocarbonyl group, or (ethylthio) thiocarbonyl group, particularly preferably a (methylthio) thiocarbonyl group.

In the above, “mono C” in the definition of R ¹
₁ -C ₆ alkylcarbamoyl group ", for example, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, iso-butylcarbamoyl group, s- butylcarbamoyl group, t-butylcarbamoyl group, pentylcarbamoyl group Alternatively, it may be a hexylcarbamoyl group, preferably a mono-C ₁ -C ₄ alkylcarbamoyl group, more preferably a methylcarbamoyl group or an ethylcarbamoyl group.

The "di C ₁ in the definition of R ¹ in the above
-C ₆ alkylcarbamoyl group ", for example, dimethylcarbamoyl group, ethylmethylcarbamoyl group, a diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoyl group, diisobutylcarbamoylphosphine group, di -s- butylcarbamoyl group, di - t- butylcarbamoyl group which may be di-pentylcarbamoyl group or Hye alkoxy carbamoyl group, preferably a di-C ₁ -C ₄ alkylcarbamoyl group, further preferably a dimethylcarbamoyl group or a diethylcarbamoyl group, a particularly preferred It is a dimethylcarbamoyl group.

In the above definition, in the definition of ring A, “5- to 6-membered aromatic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms fused to isoxazole The `` heterocycle '' can be, for example, a furyl ring, a thienyl ring, a pyrrolyl ring, an imidazolyl ring, a pyrazolyl ring, a thiazolyl ring, an isothiazolyl ring, an oxazolyl ring, an isoxazolyl ring, a pyridyl ring, a pyrazinyl ring, a pyrimidinyl ring or a pyridazinyl ring, and is preferable. Is a furyl ring, a thienyl ring or a pyridyl ring, and more preferably a pyridyl ring.

The isoxazole compound condensed with a furyl ring, thienyl ring or pyridyl ring is, for example, a compound having the following structural formulas (III) to (XII):
Preferably, structural formulas (III), (IV), (IX),
A compound having the formula (X), (XI) or (XII), more preferably a compound having the structural formula (IX), (X), (XI) or (XII); A compound having the formula (IX) or (XII),
Particularly preferred are compounds having structural formula (XII).

[0029]

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The "mono-C in the definition of R ² a in the above
₁ -C ₄ alkylamino group "are as defined in R ¹ described above, preferably a methylamino group.

In the above definition, “di C ₁ ” in the definition of R ² a
The “—C ₄ alkylamino group” has the same meaning as the definition of R ¹ described above, and is preferably a dimethylamino group.

[0032] includes a "one nitrogen atom in the definition of R ² a in the above, further one nitrogen or contain an oxygen atom or 5-membered or six-membered Hajime Tamaki (provided that said group on the nitrogen atom ") Is, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperidinyl group, a piperazinyl group, or a morpholinyl group. Represents a piperidinyl group or a morpholinyl group.

When R ¹ in the compounds (I) and (II) of the present invention is a basic group such as an amino group or an alkylamino group, the compound is treated with an acid according to a conventional method to obtain the corresponding pharmacologically active substance. It can be a salt acceptable above. For example, compound (I) or (II) is treated with a corresponding acid in a solvent (for example, ethers, especially dioxane) for 5 to 30 minutes at room temperature, and the precipitated crystals are collected by filtration or the solvent is removed under reduced pressure. It can be obtained by distillation. Such salts include hydrochlorides, hydrobromides,
Minerates such as hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate Sulfonates such as salts; carboxylates such as fumarate, succinate, citrate, tartrate, oxalate or maleate; or amino acid salts such as glutamate or aspartate. Can be. Further, the compound (I) of the present invention
In the case of (II) and (II), when R ¹ is an acidic group such as a hydroxyl group or a carboxy group, the corresponding pharmacologically acceptable salt can be obtained by treating with a base according to a conventional method. For example, compound (I) or (II)
In a solvent (for example, ethers, especially ether or tetrahydrofuran) at room temperature for 5 to 30 minutes with a corresponding base, and the precipitated crystals are collected by filtration or the solvent is distilled off under reduced pressure. it can. Examples of such salts include alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as calcium salt or magnesium salt, and organic base salts such as guanidine, triethylamine or dicyclohexylamine.

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

The compound (I) or (II) of the present invention or a salt thereof may have an asymmetric carbon in the molecule, and there are stereoisomers each having R-coordination and S-coordination. However, each of them, or a mixture thereof in any proportion thereof, is included in the present invention.

In the compound (I) of the present invention, preferred examples of the compound include: (1) R ¹ is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl Group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C
₁ -C ₄ alkoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group,
1-fluoroethoxy group, 2-fluoroethoxy group, 2
- chloroethoxy group, 2,2,2-trifluoroethoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, an amino group,
Mono C ₁ -C ₄ alkylamino group, di-C ₁ -C ₄ alkylamino group, formyl group, acetyl group, formylamino group, acetylamino group, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkoxycarbonyl Group, carboxy group, (methylthio) thiocarbonyl group, (ethylthio)
Thiocarbonyl group, a carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, compound a nitro group or a cyano group, (2) R ¹ is a hydrogen atom, a halogen atom, C ₁ -C ₄ Alkyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₁ -C ₄ alkoxy group, difluoro Methoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, formyl group, acetyl group, formylamino group, acetylamino group, C ₁ -C ₄ Alkoxycarbonyl group, carboxy group, carbamoyl group, methylcarbamo Group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, compound a nitro group or a cyano group,
(3) R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a hydroxyl group, a methylthio group, an ethylthio group, an amino group , Methylamino group, ethylamino group, dimethylamino group, formyloxy group, acetyloxy group, methoxycarbonyl group,
A compound which is an ethoxycarbonyl group, a carboxy group, a carbamoyl group, a nitro group or a cyano group, (4) R ¹
Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a methylthio group, a difluoromethoxy group, a methoxycarbonyl group, a nitro group or a cyano group; (5) a compound wherein m is 2; (6) a compound wherein m is 1; (7) a compound wherein n is 2 to 4;
(8) a compound wherein n is 2; (9) ring A is a phenyl ring, naphthyl ring, furyl ring, thienyl ring, pyrrolyl ring,
A compound in which an imidazolyl ring, a pyrazolyl ring, a thiazolyl ring, an isothiazolyl ring, an oxazolyl ring, an isoxazolyl ring, a pyridyl ring, a pyrazinyl ring, a pyrimidinyl ring, or a pyridazinyl ring; (11) a compound wherein Ring A is a phenyl ring or a pyridyl ring, (12) a compound wherein Ring A is a phenyl ring, (13) a compound wherein X is an oxygen atom, (14) 3- (2-aminoethoxy)
Benzoisoxazole, 3- (2-aminoethylthio)
Benzoisoxazole, 3- (2-aminoethoxy)-
Fluorobenzoisoxazole, 3- (2-aminoethylthio) -fluorobenzoisoxazole, 3- (2-
Aminoethoxy) -fluoro-methylbenzisoxazole, 3- (2-aminoethylthio) -fluoro-methylbenzisoxazole, 3- (2-aminoethoxy)
-Fluoro-methylthiobenzisoxazole, 3-
(2-aminoethoxy) -fluoro-methoxycarbonylbenzisoxazole, 3- (2-aminoethoxy)
-Fluoro-carbamoylbenzisoxazole, 3-
(2-aminoethoxy) -fluoro-cyanobenzisoxazole, 3- (2-aminoethylthio) -fluoro-cyanobenzisoxazole, 3- (2-aminoethoxy) -chlorobenzisoxazole, 3- (2-aminoethylthio) -chlorobenzisoxazole, 3-
(2-aminoethoxy) -dichlorobenzisoxazole, 3- (2-aminoethylthio) -dichlorobenzisoxazole, 3- (2-aminoethoxy) -chloro-
Methylbenzisoxazole, 3- (2-aminoethylthio) -chloro-methylbenzisoxazole, 3-
(2-aminoethoxy) -chloro-carbamoylbenzisoxazole, 3- (2-aminoethoxy) -chloro-cyanobenzisoxazole, 3- (2-aminoethylthio) -chloro-cyanobenzisoxazole, 3-
(2-aminoethoxy) -dichloro-methylbenzisoxazole, 3- (2-aminoethoxy) -bromobenzisoxazole, 3- (2-aminoethoxy) -bromo-methylbenzisoxazole, 3- ( 2-aminoethoxy) -methylbenzisoxazole, 3- (2-aminoethylthio) -methylbenzisoxazole, 3-
(2-aminoethoxy) -dimethylbenzisoxazole, 3- (2-aminoethoxy) -methyl-methoxybenzisoxazole, 3- (2-aminoethoxy) -methyl-methylthiobenzisoxazole, 3- ( 2-aminoethoxy) -methyl-methoxycarbonylbenzisoxazole, 3- (2-aminoethoxy) -methyl-
Carbamoylbenzoisoxazole, 3- (2-aminoethoxy) -methyl-cyanobenzisoxazole, 3
-(2-aminoethoxy) -trifluoromethylbenzisoxazole, 3- (2-aminoethoxy) -methoxybenzisoxazole, 3- (2-aminoethylthio) -methoxybenzisoxazole, 3- ( 2- (aminoethoxy) -difluoromethoxybenzisoxazole, 3- (2-aminoethoxy) -hydroxybenzisoxazole, 3- (2-aminoethoxy) -aminobenzisoxazole, 3- (2-aminoethyl Thio)-
Aminobenzoisoxazole, 3- (2-aminoethoxy) -methylaminobenzoisoxazole, 3- (2-
Aminoethoxy) -dimethylaminobenzisoxazole, 3- (2-aminoethoxy) -acetyloxybenzisoxazole, 3- (2-aminoethoxy) -carboxybenzisoxazole, 3- (2-aminoethoxy) -Methoxycarbonylbenzisoxazole, 3-
(2-aminoethoxy) -carbamoylbenzisoxazole, 3- (2-aminoethoxy) -nitrobenzisoxazole, 3- (2-aminoethylthio) -nitrobenzisoxazole, 3- (2-amino Ethoxy)-
Cyanobenzoisoxazole, 3- (2-aminoethoxy) naphthoisoxazole, 3- (2-aminoethoxy) pyridisoxazole, 3- (2-aminoethoxy) -chloropyridisoxazole, 3 -(2-aminoethylthio) -chloropyridisoxazole, 3- (2
-Aminoethoxy) -methylpyridisoxazole and 3- (2-aminoethoxy) -trifluoromethylpyridisoxazole, and (1)-
(4), (5)-(6), (7)-(8), (9)-
It is also preferable to select 1 to 5 from the groups (12) and (13) and arbitrarily combine them. For example, the following combinations can be mentioned. (15)
(1) and (7), (16) (2), (7) and (9), (17) (2), (8) and (10), (1)
8) (3), (8) and (10), (19)
(3), (5), (8) and (11), (20)
(4), (8) and (10), (21) (4),
(5), (8) and (11), (22) (4),
(5), (8) and (12).

In the compound (II) which is an active ingredient of the monoamine oxidase inhibitor of the present invention, preferable compounds include (1) R ¹ is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, Methyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C
₁ -C ₄ alkoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group,
1-fluoroethoxy group, 2-fluoroethoxy group, 2
- chloroethoxy group, 2,2,2-trifluoroethoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, an amino group,
Mono C ₁ -C ₄ alkylamino group, di-C ₁ -C ₄ alkylamino group, formyl group, acetyl group, formylamino group, acetylamino group, C ₁ -C ₄ alkanoyloxy group, C ₁ -C ₄ alkoxycarbonyl Group, carboxy group, (methylthio) thiocarbonyl group, (ethylthio)
Thiocarbonyl group, a carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, compound a nitro group or a cyano group, (2) R ¹ is a hydrogen atom, a halogen atom, C ₁ -C ₄ Alkyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₁ -C ₄ alkoxy group, difluoro Methoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, formyl group, acetyl group, formylamino group, acetylamino group, C ₁ -C ₄ Alkoxycarbonyl group, carboxy group, carbamoyl group, methylcarbamo Group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, compound a nitro group or a cyano group,
(3) R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a hydroxyl group, a methylthio group, an ethylthio group, an amino group , Methylamino group, ethylamino group, dimethylamino group, formyloxy group, acetyloxy group, methoxycarbonyl group,
A compound which is an ethoxycarbonyl group, a carboxy group, a carbamoyl group, a nitro group or a cyano group, (4) R ¹
But a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a methylthio group, a difluoromethoxy group, a methoxycarbonyl group, compound a nitro group or a cyano group, (5) R ² a is amino group, Methylamino group,
Dimethylamino group, piperidinyl group or compound morpholinyl group, (6) R ² a is amino group, a piperidinyl group or a compound which is a morpholinyl group, (7) Compound R ² a is an amino group, (8) m A compound that is 2,
(9) a compound wherein m is 1; (10) n is 2 to 4
(11) a compound wherein n is 2, (1)
2) ring A is a phenyl ring, naphthyl ring, furyl ring, thienyl ring, pyrrolyl ring, imidazolyl ring, pyrazolyl ring,
A compound having a thiazolyl ring, an isothiazolyl ring, an oxazolyl ring, an isoxazolyl ring, a pyridyl ring, a pyrazinyl ring, a pyrimidinyl ring or a pyridazinyl ring; (13) a compound wherein Ring A is a phenyl ring, a naphthyl ring or a pyridyl ring; Is a phenyl ring or a pyridyl ring; (15) a compound wherein Ring A is a phenyl ring;
(16) a compound wherein X is an oxygen atom, (17) 3-
(2-aminoethoxy) benzisoxazole, 3-
(2-aminoethylthio) benzisoxazole, 3-
(2-aminoethoxy) -fluorobenzisoxazole, 3- (2-aminoethylthio) -fluorobenzisoxazole, 3- (2-aminoethoxy) -fluoro-methylbenzisoxazole, 3- (2 -Aminoethylthio) -fluoro-methylbenzisoxazole, 3
-(2-aminoethoxy) -fluoro-methylthiobenzisoxazole, 3- (2-aminoethoxy) -fluoro-methoxycarbonylbenzisoxazole, 3-
(2-aminoethoxy) -fluoro-carbamoylbenzisoxazole, 3- (2-aminoethoxy) -fluoro-cyanobenzisoxazole, 3- (2-aminoethylthio) -fluoro-cyanobenzisoxazole, 3- (2-aminoethoxy) -chlorobenzisoxazole, 3- (2-aminoethylthio) -chlorobenzisoxazole, 3- (2-aminoethoxy) -dichlorobenzisoxazole, 3- (2 -Aminoethylthio) -dichlorobenzisoxazole, 3- (2-aminoethoxy) -chloro-methylbenzisoxazole,
3- (2-aminoethylthio) -chloro-methylbenzisoxazole, 3- (2-aminoethoxy) -chloro-carbamoylbenzoisoxazole, 3- (2-aminoethoxy) -chloro-cyanobenzoisoxazole Zol,
3- (2-aminoethylthio) -chloro-cyanobenzisoxazole, 3- (2-aminoethoxy) -dichloro-methylbenzisoxazole, 3- (2-aminoethoxy) -bromobenzisoxazole, 3- (2-aminoethoxy) -bromo-methylbenzisoxazole, 3- (2-aminoethoxy) -methylbenzisoxazole, 3- (2-aminoethylthio) -methylbenzisoxazole, 3- (2-aminoethoxy) -dimethylbenzisoxazole, 3- (2-aminoethoxy) -methyl-methoxybenzisoxazole, 3-
(2-aminoethoxy) -methyl-methylthiobenzisoxazole, 3- (2-aminoethoxy) -methyl-
Methoxycarbonylbenzisoxazole, 3- (2-
Aminoethoxy) -methyl-carbamoylbenzisoxazole, 3- (2-aminoethoxy) -methyl-cyanobenzisoxazole, 3- (2-aminoethoxy)
-Trifluoromethylbenzisoxazole, 3- (2
-Aminoethoxy) -methoxybenzisoxazole,
3- (2-aminoethylthio) -methoxybenzisoxazole, 3- (2-aminoethoxy) -difluoromethoxybenzisoxazole, 3- (2-aminoethoxy) -hydroxybenzisoxazole, 3- ( 2-aminoethoxy) -aminobenzoisoxazole, 3-
(2-aminoethylthio) -aminobenzoisoxazole, 3- (2-aminoethoxy) -methylaminobenzoisoxazole, 3- (2-aminoethoxy) -dimethylaminobenzoisoxazole, 3- (2 -Aminoethoxy) -acetyloxybenzisoxazole, 3-
(2-aminoethoxy) -carboxybenzoisoxazole, 3- (2-aminoethoxy) -methoxycarbonylbenzisoxazole, 3- (2-aminoethoxy)
-Carbamoylbenzisoxazole, 3- (2-aminoethoxy) -nitrobenzisoxazole, 3- (2
-Aminoethylthio) -nitrobenzisoxazole,
3- (2-aminoethoxy) -cyanobenzisoxazole, 3- (2-aminoethoxy) naphthoisoxazole, 3- (2-aminoethoxy) pyridisoxazole, 3- (2-aminoethoxy) -Chloropyridisoxazole, 3- (2-aminoethylthio) -chloropyridisoxazole, 3- (2-aminoethoxy) -methylpyridisoxazole, or 3- (2-aminoethoxy) -Trifluoromethylpyridisoxazole, and (1)-(4), (5)-(7),
(8)-(9), (10)-(11), (12)-(1
It is also preferable to select 1 to 6 from the groups 5) and (16) and arbitrarily combine them. For example, the following combinations can be mentioned. (17) (1),
(5) and (10), (18) (2), (7), (1)
0) and (12), (19) (2), (7), (1)
1) and (13), (20) (3), (7), (1)
1) and (13), (21) (3), (7),
(8), (11) and (14), (22) (4),
(7), (11) and (13), (23) (4),
(7), (8), (11) and (14), (24)
(4), (7), (8), (11) and (15).

The representative compounds of the present invention include, for example, the compounds described in the following table, but the present invention is not limited to these compounds.

The abbreviations in the table are as follows. Ac: acetyl Et: ethyl Me: methyl Ph: phenyl Pip: piperidino Pr ^i: isopropyl Mor: morpholino provided that, (R ¹⁾ _m is one of the substituents on the total ring A, two substituents or three substituents Represents a group.

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[Table 1] Compound No. _{^{(R 1) m n X 1-1}} H 1 O 1-2 H 1 S 1-3 H 2 O 1-4 H 2 S 1-5 H 3 O 1-6 H 3 S 1-7 H 4 O 1-8 H 4 S 1-9 H 5 O 1-10 H 5 S 1-11 H 6 O 1-12 H 6 S 1-13 4-F 2 O 1-14 4-F 2 S 1-15 5-F 2 O 1-16 5-F 4-F 2 O 1-17 5-F 6-F 2 O 1-18 5-F 7-F 2 O 1-19 5-F 4-Cl 2 O 1 -20 5-F 6-Cl 2 O 1-21 5-F 7-Cl 2 O 1-22 5-F 4-Me 2 O 1-23 5-F 6-Me 2 O 1-24 5-F 7 -Me 2 O 1-25 5-F 4-OMe 2 O 1-26 5-F 6-OMe 2 O 1-27 5-F 7-OMe 2 O 1-28 5-F 4-CN 2 O 1- 29 5-F 6-CN 2 O 1-30 5-F 7-CN 2 O 1-31 5-F 2 S 1-32 5-F 4-F 2 S 1-33 5-F 6-F 2 S 1-34 5-F 7-F 2 S 1-35 5-F 4-Cl 2 S 1-36 5-F 6-Cl 2 S 1-37 5-F 7-Cl 2 S 1-38 5-F 4-Me 2 S 1-39 5-F 6-Me 2 S 1-40 5-F 7-Me 2 S 1-41 5-F 4-OMe 2 S 1-42 5-F 6-OMe 2 S 1 -43 5-F 7-OMe 2 S 1-44 5-F 4-CN 2 S 1-45 5-F 6-CN 2 S 1-46 5-F 7-CN 2 S 1-47 6-F 2 O 1-48 6-F 2 S 1-49 7-F 2 O 1-50 7-F 2 S 1-51 4-Cl 2 O 1-52 4-Cl 2 S 1-53 5-Cl 2 O 1 -54 5-Cl 4-F 2 O 1-55 5-Cl 6-F 2 O 1-56 5-Cl 7-F 2 O 1-57 5-Cl 4-Cl 2 O 1-58 5-Cl 6 -Cl 2 O 1-59 5-Cl 7-Cl 2 O 1-60 5-Cl 4-Me 2 O 1-61 5-Cl 6-Me 2 O 1-6 2 5-Cl 7-Me 2 O 1-63 5-Cl 4-OMe 2 O 1-64 5-Cl 6-OMe 2 O 1-65 5-Cl 7-OMe 2 O 1-66 5-Cl 4- CN 2 O 1-67 5-Cl 6-CN 2 O 1-68 5-Cl 7-CN 2 O 1-69 5-Cl 2 S 1-70 5-Cl 4-F 2 S 1-71 5-Cl 6-F 2 S 1-72 5-Cl 7-F 2 S 1-73 5-Cl 4-Cl 2 S 1-74 5-Cl 6-Cl 2 S 1-75 5-Cl 7-Cl 2 S 1 -76 5-Cl 4-Me 2 S 1-77 5-Cl 6-Me 2 S 1-78 5-Cl 7-Me 2 S 1-79 5-Cl 4-OMe 2 S 1-80 5-Cl 6 -OMe 2 S 1-81 5-Cl 7-OMe 2 S 1-82 5-Cl 4-CN 2 S 1-83 5-Cl 6-CN 2 S 1-84 5-Cl 7-CN 2 S 1- 85 6-Cl 2 O 1-86 6-Cl 7-Cl 2 O 1-87 6-Cl 4-Me 2 O 1-88 6-Cl 5-Me 2 O 1-89 6-Cl 7-Me 2 O 1-90 6-Cl 4-OMe 2 O 1-91 6-Cl 5-OMe 2 O 1-92 6-Cl 7-OMe 2 O 1-93 6-Cl 4-CN 2 O 1-94 6-Cl 5-CN 2 O 1-95 6-Cl 7-CN 2 O 1-96 6-Cl 2 S 1-97 7-Cl 2 O 1-98 7-Cl 4-Me 2 O 1-99 7-Cl 5 -Me 2 O 1-100 7-Cl 6-Me 2 O 1-101 7-Cl 4-OMe 2 O 1-102 7-Cl 5-OMe 2 O 1-103 7-Cl 6-OMe 2 O 1- 104 7-Cl 4-CN 2 O 1-105 7-Cl 5-CN 2 O 1-106 7-Cl 6-CN 2 O 1-107 7-Cl 2 S 1-108 7-Cl 4-Me 2 S 1-109 7-Cl 5-Me 2 S 1-110 7-Cl 6-Me 2 S 1-111 7-Cl 4-OMe 2 S 1-112 7-Cl 5-OMe 2 S 1-113 7-Cl 6-OMe 2 S 1-114 7-Cl 4-C N 2 S 1-115 7-Cl 5-CN 2 S 1-116 7-Cl 6-CN 2 S 1-117 4-Br 2 O 1-118 4-Br 2 S 1-119 5-Br 2 O 1 -120 5-Br 4-F 2 O 1-121 5-Br 6-F 2 O 1-122 5-Br 7-F 2 O 1-123 5-Br 4-Cl 2 O 1-124 5-Br 6 -Cl 2 O 1-125 5-Br 7-Cl 2 O 1-126 5-Br 4-Me 2 O 1-127 5-Br 6-Me 2 O 1-128 5-Br 7-Me 2 O 1- 129 5-Br 4-OMe 2 O 1-130 5-Br 6-OMe 2 O 1-131 5-Br 7-OMe 2 O 1-132 5-Br 4-CN 2 O 1-133 5-Br 6- CN 2 O 1-134 5-Br 7-CN 2 O 1-135 5-Br 2 S 1-136 6-Br 2 O 1-137 6-Br 2 S 1-138 7-Br 2 O 1-139 7 -Br 2 S 1-140 4-Me 2 O 1-141 4-Me 2 S 1-142 5-Me 2 O 1-143 5-Me 6-Me 2 O 1-144 5-Me 7-Me 2 O 1-145 5-Me 4-OMe 2 O 1-146 5-Me 6-OMe 2 O 1-147 5-Me 7-OMe 2 O 1-148 5-Me 4-CN 2 O 1-149 5-Me 6-CN 2 O 1-150 5-Me 7-CN 2 O 1-151 5-Me 2 S 1-152 5-Me 6-Me 2 S 1-153 5-Me 7-Me 2 S 1-154 5 -Me 4-OMe 2 S 1-155 5-Me 6-OMe 2 S 1-156 5-Me 7-OMe 2 S 1-157 5-Me 4-CN 2 S 1-158 5-Me 6-CN 2 S 1-159 5-Me 7-CN 2 S 1-160 6-Me 2 O 1-161 6-Me 7-Me 2 O 1-162 6-Me 4-OMe 2 O 1-163 6-Me 5- OMe 2 O 1-164 6-Me 7-OMe 2 O 1-165 6-Me 4-CN 2 O 1-166 6-Me 5-CN 2 O 1-167 6-Me 7-CN 2 O 1-168 6-Me 2 S 1-169 7-Me 2 O 1-170 7-Me 4-OMe 2 O 1-171 7-Me 5-OMe 2 O 1 -172 7-Me 6-OMe 2 O 1-173 7-Me 4-CN 2 O 1-174 7-Me 5-CN 2 O 1-175 7-Me 6-CN 2 O 1-176 7-Me 2 S 1-177 7-Me 4-OMe 2 S 1-178 7-Me 5-OMe 2 S 1-179 7-Me 6-OMe 2 S 1-180 7-Me 4-CN 2 S 1-181 7- Me 5-CN 2 S 1-182 7-Me 6-CN 2 S 1-183 4-Et 2 O 1-184 4-Et 2 S 1-185 5-Et 2 O 1-186 5-Et 2 S 1 -187 6-Et 2 O 1-188 6-Et 2 S 1-189 7-Et 2 O 1-190 7-Et 2 S 1-191 4-OMe 2 O 1-192 4-OMe 2 S 1-193 5-OMe 2 O 1-194 5-OMe 4-CN 2 O 1-195 5-OMe 6-CN 2 O 1-196 5-OMe 7-CN 2 O 1-197 5-OMe 2 S 1-198 6 -OMe 2 O 1-199 6-OMe 2 S 1-200 7-OMe 2 O 1-201 7-OMe 4-Me 2 O 1-202 7-OMe 5-OMe 2 O 1-203 7-OMe 6- OMe 2 O 1-204 7-OMe 4-CN 2 O 1-205 7-OMe 5-CN 2 O 1-206 7-OMe 6-CN 2 O 1-207 7-OMe 2 S 1-208 7-OMe 4-Me 2 S 1-209 7-OMe 5-OMe 2 S 1-210 7-OMe 6-Me 2 S 1-211 7-OMe 4-CN 2 S 1-212 7-OMe 5-CN 2 S 1 -213 7-OMe 6-CN 2 S 1-214 4-OEt 2 O 1-215 4-OEt 2 S 1-216 5-OEt 2 O 1-217 5-OEt 2 S 1-218 6-OEt 2 O 1-219 6-OEt 2 S 1-220 7-OEt 2 O 1 -221 7-OEt 2 S 1-222 4-OCHF ₂ 2 O 1-223 4-OCHF ₂ 2 S 1-224 5-OCHF ₂ 2 O 1-225 5-OCHF ₂ 4-F 2 O 1-226 5 _{-OCHF 2 6-F 2 O 1-227} 5-OCHF 2 7-F 2 O 1-228 5-OCHF 2 4-Cl 2 O 1-229 5-OCHF 2 6-Cl 2 O 1-230 5-OCHF _{2 7-Cl 2 O 1-231 5} -OCHF 2 4-Me 2 O 1-232 5-OCHF 2 6-Me 2 O 1-233 5-OCHF 2 7-Me 2 O 1-234 5-OCHF 2 4 _{-OMe 2 O 1-235 5-OCHF 2} 6-OMe 2 O 1-236 5-OCHF 2 7-OMe 2 O 1-237 5-OCHF 2 4-CN 2 O 1-238 5-OCHF 2 6-CN 2 O 1-239 5-OCHF ₂ 7-CN 2 O 1-240 5-OCHF ₂ 2 S 1-241 6-OCHF ₂ 2 O 1-242 6-OCHF ₂ 2 S 1-243 7-OCHF ₂ 2 O 1-244 7-OCHF ₂ 2 S 1-245 4-OH 2 O 1-246 4-OH 2 S 1-247 5-OH 2 O 1-248 5-OH 4-F 2 O 1-249 5-OH 6-F 2 O 1-250 5-OH 7-F 2 O 1-251 5-OH 4-Cl 2 O 1-252 5-OH 6-Cl 2 O 1-253 5-OH 7-Cl 2 O 1 -254 5-OH 4-Me 2 O 1-255 5-OH 6-Me 2 O 1-256 5-OH 7-Me 2 O 1-257 5-OH 4-OMe 2 O 1-258 5-OH 6 -OMe 2 O 1-259 5-OH 7-OMe 2 O 1-260 5-OH 4-CN 2 O 1-261 5-OH 6-CN 2 O 1-262 5-OH 7-CN 2 O 1- 263 5-OH 2 S 1-264 6-OH 2 O 1-265 6-OH 2 S 1-266 7-OH 2 O 1-267 7-OH 2 S 1-268 4-SMe 2 O 1-269 4 -SMe 5-F 2 O 1-270 4-SMe 6-F 2 O 1-271 4-SMe 7-F 2 O 1-272 4-SMe 5-Cl 2 O 1-273 4-SMe 6-Cl 2 O 1-274 4-SMe 7-Cl 2 O 1-275 4- SMe 5-Me 2 O 1-276 4-SMe 6-Me 2 O 1-277 4-SMe 7-Me 2 O 1-278 4-SMe 5-OMe 2 O 1-280 4-SMe 7-OMe 2 O 1-281 4-SMe 5-CN 2 O 1-282 4-SMe 6-CN 2 O 1-283 4-SMe 7-CN 2 O 1-284 4-SMe 2 S 1-285 5-SMe 2 O 1 -286 5-SMe 2 S 1-287 6-SMe 2 O 1-288 6-SMe 2 S 1-289 7-SMe 2 O 1-290 7-SMe 2 S 1-291 4-NH ₂ 2 O 1- _{292 4-NH 2 2 S 1-293} 5-NH 2 2 O 1-294 5-NH 2 2 S 1-295 5-NH 2 4-F 2 S 1-296 5-NH 2 6-F 2 S 1 _{-297 5-NH 2 7-F} 2 S 1-298 5-NH 2 4-Cl 2 S 1-299 5-NH 2 6-Cl 2 S 1-300 5-NH 2 7-Cl 2 S 1-301 _{5-NH 2 4-Me 2} S 1-302 5-NH 2 6-Me 2 S 1-303 5-NH 2 7-Me 2 S 1-304 5-NH 2 4-OMe 2 S 1-305 5- _{NH 2 6-OMe 2 S 1-306} 5-NH 2 7-OMe 2 S 1-307 5-NH 2 4-CN 2 S 1-308 5-NH 2 6-CN 2 S 1-309 5-NH 2 7-CN 2 S 1-310 6-NH ₂ 2 O 1-311 6-NH ₂ 2 S 1-312 7-NH ₂ 2 O 1-313 7-NH ₂ 4-F 2 O 1-314 7-NH ₂ 5-F 2 O 1-315 7-NH ₂ 6-F 2 O 1-316 7-NH ₂ 4-Cl 2 O 1-317 7-NH ₂ 5-Cl 2 O 1-318 7-NH ₂ 6 -Cl 2 O 1-319 7-NH ₂ 4-Me 2 O 1-320 7-NH ₂ 5-Me 2 O _{1-321 7-NH 2 6-Me} 2 O 1-322 7-NH 2 4-OMe 2 O 1-323 7-NH 2 5-OMe 2 O 1-324 7-NH 2 6-OMe 2 O 1- 325 7-NH ₂ 4-CN 2 O 1-326 7-NH ₂ 5-CN 2 O 1-327 7-NH ₂ 6-CN 2 O 1-328 7-NH ₂ 2 S 1-329 7-NH ₂ 4-F 2 S 1-330 7-NH ₂ 5-F 2 S 1-331 7-NH ₂ 6-F 2 S 1-332 7-NH ₂ 4-Cl 2 S 1-333 7-NH ₂ 5- _{Cl 2 S 1-334 7-NH 2} 6-Cl 2 S 1-335 7-NH 2 4-Me 2 S 1-336 7-NH 2 5-Me 2 S 1-337 7-NH 2 6-Me 2 S 1-338 7-NH ₂ 4-OMe 2 S 1-339 7-NH ₂ 5-OMe 2 S 1-340 7-NH ₂ 6-OMe 2 S 1-341 7-NH ₂ 4-CN 2 S 1 _{-342 7-NH 2 5-CN} 2 S 1-343 7-NH 2 6-CN 2 S 1-344 4-NHMe 2 O 1-345 4-NHMe 2 S 1-346 5-NHMe 2 O 1-347 5-NHMe 4-F 2 O 1-348 5-NHMe 6-F 2 O 1-349 5-NHMe 7-F 2 O 1-350 5-NHMe 4-Cl 2 O 1-351 5-NHMe 6-Cl 2 O 1-352 5-NHMe 7-Cl 2 O 1-353 5-NHMe 4-Me 2 O 1-354 5-NHMe 6-Me 2 O 1-355 5-NHMe 7-Me 2 O 1-356 5 -NHMe 4-OMe 2 O 1-357 5-NHMe 6-OMe 2 O 1-358 5-NHMe 7-OMe 2 O 1-359 5-NHMe 4-CN 2 O 1-360 5-NHMe 6-CN 2 O 1-361 5-NHMe 7-CN 2 O 1-362 5-NHMe 2 S 1-363 6-NHMe 2 O 1-364 6-NHMe 2 S 1-365 7-NHMe 2 O 1-366 7-NHMe 4-F 2 O 1-367 7-NHMe 5-F 2 O 1-368 7-NHMe 6-F 2 O 1-369 7-NHMe 4-Cl 2 O 1-370 7-NHMe 5-Cl 2 O 1-371 7-NHMe 6-Cl 2 O 1-372 7-NHMe 4-Me 2 O 1-373 7-NHMe 5-Me 2 O 1-374 7-NHMe 6-Me 2 O 1-375 7-NHMe 4-OMe 2 O 1-376 7-NHMe 5-OMe 2 O 1-377 7 -NHMe 6-OMe 2 O 1-378 7-NHMe 4-CN 2 O 1-379 7-NHMe 5-CN 2 O 1-380 7-NHMe 6-CN 2 O 1-381 7-NHMe 2 S 1- 382 4-OAc 2 O 1-383 4-OAc 2 S 1-384 5-OAc 2 O 1-385 5-OAc 4-F 2 O 1-386 5-OAc 6-F 2 O 1-387 5-OAc 7-F 2 O 1-388 5-OAc 4-Cl 2 O 1-389 5-OAc 6-Cl 2 O 1-390 5-OAc 7-Cl 2 O 1-391 5-OAc 4-Me 2 O 1 -392 5-OAc 6-Me 2 O 1-393 5-OAc 7-Me 2 O 1-394 5-OAc 4-OMe 2 O 1-395 5-OAc 6-OMe 2 O 1-396 5-OAc 7 -OMe 2 O 1-397 5-OAc 4-CN 2 O 1-398 5-OAc 6-CN 2 O 1-399 5-OAc 7-CN 2 O 1-400 5-OAc 2 S 1-401 6- OAc 2 O 1-402 6-OAc 2 S 1-403 7-OAc 2 O 1-404 7-OAc 2 S

[0042]

[Table 1] continued Compound No. _{^{(R 1) m n X 1-405}} 4-COOMe 2 O 1-406 4-COOMe 5-F 2 O 1-407 4-COOMe 6-F 2 O 1-408 4-COOMe 7-F 2 O 1-409 4-COOMe 5-Cl 2 O 1-410 4-COOMe 6-Cl 2 O 1-411 4-COOMe 7-Cl 2 O 1-412 4-COOMe 5-Me 2 O 1-413 4-COOMe 6-Me 2 O 1-414 4-COOMe 7-Me 2 O 1-415 4-COOMe 5-OMe 2 O 1-416 4-COOMe 6-OMe 2 O 1-417 4-COOMe 7-OMe 2 O 1 -418 4-COOMe 5-CN 2 O 1-419 4-COOMe 6-CN 2 O 1-420 4-COOMe 7-CN 2 O 1-421 4-COOMe 2 S 1-422 5-COOMe 2 O 1- 423 5-COOMe 4-F 2 O 1-424 5-COOMe 6-F 2 O 1-425 5-COOMe 7-F 2 O 1-426 5-COOMe 4-Cl 2 O 1-427 5-COOMe 6- Cl 2 O 1-428 5-COOMe 7-Cl 2 O 1-429 5-COOMe 4-Me 2 O 1-430 5-COOMe 6-Me 2 O 1-431 5-COOMe 7-Me 2 O 1-432 5-COOMe 4-OMe 2 O 1-433 5-COOMe 6-OMe 2 O 1-434 5-COOMe 7-OMe 2 O 1-435 5-COOMe 4-CN 2 O 1-436 5-COOMe 6-CN 2 O 1-437 5-COOMe 7-CN 2 O 1-438 5-COOMe 2 S 1-439 6-COOMe 2 O 1-440 6-COOMe 2 S 1-441 7-COOMe 2 O 1-442 7- COOMe 4-F 2 O 1-443 7-COOMe 5-F 2 O 1-444 7-COOMe 6-F 2 O 1-445 7-COOMe 4-Cl 2 O 1-446 7-COOMe 5-Cl 2 O 1-447 7-COOMe 5-Br 2 O 1-448 7-CO OMe 4-Me 2 O 1-449 7-COOMe 5-Me 2 O 1-450 7-COOMe 6-Me 2 O 1-451 7-COOMe 4-OMe 2 O 1-452 7-COOMe 5-OMe 2 O 1-453 7-COOMe 6-OMe 2 O 1-454 7-COOMe 4-CN 2 O 1-455 7-COOMe 5-CN 2 O 1-456 7-COOMe 6-CN 2 O 1-457 7-COOMe 2 S 1-458 4-COOH 2 O 1-459 4-COOH 2 S 1-460 5-COOH 2 O 1-461 5-COOH 2 S 1-462 6-COOH 2 O 1-463 6-COOH 2 S 1-464 7-COOH 2 O 1-465 5-CF ₃ 4-Me 2 O 1-466 5-CF ₃ 7-Me 2 O 1-467 5-CF ₃ 4-CN 2 O 1-468 5-CF ₃ 7-CN 2 O 1-469 5-CF ₃ 4-CF ₃ 2 O 1-470 5-CF ₃ 7-CF ₃ 2 O 1-471 4-CF ₃ 2 O 1-472 4-CF ₃ 5- Me 2 O 1-473 4-CF ₃ 5-F 2 O 1-474 4-CF ₃ 5-OMe 2 O 1-475 4-CF ₃ 5-SMe 2 O 1-476 4-CF ₃ 5-CN 2 O 1-477 4-CF ₃ 5-N (Me) ₂ 2 O 1-478 4-CF ₃ 5-NO ₂ 2 O 1-479 4-CF ₃ 5-Cl 2 O 1-480 7-CF ₃ 2 _{O 1-481 4-CONH 2 2 O} 1-482 4-CONH 2 5-F 2 O 1-483 4-CONH 2 6-F 2 O 1-484 4-CONH 2 7-F 2 O 1-485 4 _{-CONH 2 5-Cl 2 O 1-486} 4-CONH 2 6-Cl 2 O 1-487 4-CONH 2 7-Cl 2 O 1-488 4-CONH 2 5-Me 2 O 1-489 4-CONH _{2 6-Me 2 O 1-490 4} -CONH 2 7-Me 2 O 1-491 4-CONH 2 5-OMe 2 O 1-492 4-CONH 2 6-OMe 2 O 1-493 4-CONH 2 7 -OMe 2 O 1- _{494 4-CONH 2 5-CN} 2 O 1-495 4-CONH 2 6-CN 2 O 1-496 4-CONH 2 7-CN 2 O 1-497 4-CONH 2 2 S 1-498 5-CONH 2 2 O 1-499 5-CONH ₂ 2 S 1-500 6-CONH ₂ 2 O 1-501 6-CONH ₂ 2 S 1-502 7-CONH ₂ 2 O 1-503 5-SMe 4-Me 2 O 1 -504 5-SMe 5-CN 2 O 1 -505 5-SMe 7-Me 2 O 1 -506 5-SMe 7-CN 2 O 1-507 5-CN 4-Me 2 O 1-508 5-CN 4 _{-CN 2 O 1-509 7-CONH 2} 4-Me 2 O 1-510 5-CN 7-CN 2 O 1-511 7-CONH 2 6-Me 2 O 1-512 7-SMe 5-Cl 2 O 1-513 7-SMe 5-Br 2 O 1-514 7-SMe 5-NO ₂ 2 O 1-515 7-SMe 5-OMe 2 O 1-516 7-SMe 5-CN 2 O 1-517 7- SMe 4-CN 2 O 1-518 7-CONH ₂ 2 S 1-519 4-NO ₂ 2 O 1-520 4-NO ₂ 2 S 1-521 5-NO ₂ 2 O 1-522 5-NO ₂ 4 _{-F 2 O 1-523 5-NO 2} 6-F 2 O 1-524 5-NO 2 7-F 2 O 1-525 5-NO 2 4-Cl 2 O 1-526 5-NO 2 6-Cl _{2 O 1-527 5-NO 2 7} -Cl 2 O 1-528 5-NO 2 4-Me 2 O 1-529 5-NO 2 6-Me 2 O 1-530 5-NO 2 7-Me 2 O _{1-531 5-NO 2 4-OMe} 2 O 1-532 5-NO 2 6-OMe 2 O 1-533 5-NO 2 7-OMe 2 O 1-534 5-NO 2 4-CN 2 O 1- _{535 5-NO 2 6-CN} 2 O 1-536 5-NO 2 7-CN 2 O 1-537 5-NO 2 2 S 1-538 5-NO 2 4-F 2 S 1-539 5-NO 2 6-F 2 S 1-540 5-NO ₂ 7-F 2 S 1-541 5-NO ₂ 4- _{Cl 2 S 1-542 5-NO 2} 6-Cl 2 S 1-543 5-NO 2 7-Cl 2 S 1-544 5-NO 2 4-Me 2 S 1-545 5-NO 2 6-Me 2 _{S 1-546 5-NO 2 7-} Me 2 S 1-547 5-NO 2 4-OMe 2 S 1-548 5-NO 2 6-OMe 2 S 1-549 5-NO 2 7-OMe 2 S 1 _{-550 5-NO 2 4-CN} 2 S 1-551 5-NO 2 6-CN 2 S 1-552 5-NO 2 7-CN 2 S 1-553 6-NO 2 2 O 1-554 6-NO _{2 2 S 1-555 7-NO 2} 2 O 1-556 7-NO 2 2 S 1-557 7-NO 2 4-F 2 S 1-558 7-NO 2 5-F 2 S 1-559 7- _{NO 2 6-F 2 S 1-560} 7-NO 2 4-Cl 2 S 1-561 7-NO 2 5-Cl 2 S 1-562 7-NO 2 6-Cl 2 S 1-563 7-NO 2 4-Me 2 S 1-564 7- NO 2 5-Me 2 S 1-565 7-NO 2 6-Me 2 S 1-566 7-NO 2 4-OMe 2 S 1-567 7-NO 2 5- _{OMe 2 S 1-568 7-NO 2} 6-OMe 2 S 1-569 7-NO 2 4-CN 2 S 1-570 7-NO 2 5-CN 2 S 1-571 7-NO 2 6-CN 2 S 1-572 4-CN 2 O 1-573 4-CN 2 S 1-574 5-CN 2 O 1-575 5-CN 2 S 1-576 6-CN 2 O 1-577 6-CN 2 S 1 -578 7-CN 2 O 1 -579 7-CN 2 S 1 -580 5-OMe 4-Me 2 O 1 -581 7-Me 4-Me 2 O 1-582 6-Me 4-Me 2 O 1- 583 5-Me 4-Me 2 O 1-584 4-N (Me) ₂ 2 O 1-585 4-N (Me) ₂ 2 S 1-586 5-N (Me) ₂ 2 O 1-587 5- N (Me) ₂ 2 S 1-588 6-N (Me) ₂ 2 O 1-589 6-N (Me) ₂ 2 S 1-590 7-N (Me) ₂ 2 O 1-591 7-N (Me) ₂ 2 S 1-592 4-Cl 6-Me 2 O 1-593 4-Cl 6-Me 2 S 1-594 4-F 5-Me 2 O 1-595 4-F 5-Me 2 S 1-596 4-F 7-Me 2 O 1-597 4-F 7-Me 2 S 1-598 5-Cl 7-CONH ₂ 2 O 1-599 5-Cl 7-CONH ₂ 2 S 1-600 5 -F 4-CS ₂ Me 2 O 1-601 5-F 4-CS ₂ Me 2 S 1-602 5-F 4-CF ₃ 2 S 1-603 7-CF ₃ 2 S 1-604 4-F 7 -Cl 2 O 1-605 4-F 7-Cl 2 S 1-606 4-F 7-CN 2 O 1-607 4-F 7-CN 2 S 1-608 7-F 4-Cl 2 O 1- 609 7-F 4-Cl 2 S 1-610 7-F 4-Me 2 O 1-611 7-F 4-Me 2 S 1-612 7-F 4-CN 2 O 1-613 7-F 4- CN 2 S 1-614 4-Me 7-CN 2 O 1-615 4-Me 7-CN 2 S 1-616 5-F 7-F 4-Me 2 O 1-617 5-F 7-F 4- Me 2 S 1-618 5-Cl 7-Cl 4-Me 2 O 1-619 5-Cl 7-Cl 4-Me 2 S 1-620 5-Cl 7-Cl 4-COOH 2 O 1-621 5- Cl 7-Cl 4-COOH 2 S 1-623 5-Cl 7-Cl 4-COOMe 2 S 1-624 5-Cl 7-Cl 4-CONH ₂ 2 O 1-625 5-Cl 7-Cl 4-CONH ₂ 2 S 1-626 5-Cl 7-Cl 4-CN 2 O 1-627 5-Cl 7-Cl 4-CN 2 S

[0043]

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[0044]

[Table 2] Compound No. _{^{(R 1) m n X 2-1}} H 1 O 2-2 H 1 S 2-3 H 2 O 2-4 4-F 2 O 2-5 5-F 2 O 2-6 6-F 2 O 2-7 7-F 2 O 2-8 8-F 2 O 2-9 9-F 2 O 2-10 4-Cl 2 O 2-11 5-Cl 2 O 2-12 6-Cl 2 O 2 -13 7-Cl 2 O 2-14 8-Cl 2 O 2-15 9-Cl 2 O 2-16 5-NHMe 2 O 2-17 6-NHMe 2 O 2-18 7-NHMe 2 O 2-19 4-Me 2 O 2-20 5-Me 2 O 2-21 6-Me 2 O 2-22 7-Me 2 O 2-23 8-Me 2 O 2-24 9-Me 2 O 2-25 5- N (Me) ₂ 2 O 2-26 6-N (Me) ₂ 2 O 2-27 7-N (Me) ₂ 2 O 2-28 8-N (Me) ₂ 2 O 2-29 4-OMe 2 O 2-30 5-OMe 2 O 2-31 6-OMe 2 O 2-32 7-OMe 2 O 2-33 8-OMe 2 O 2-34 9-OMe 2 O 2-35 5-OEt 2 O 2 -36 6-OEt 2 O 2-37 7-OEt 2 O 2-38 8-OEt 2 O 2-39 5-OCHF ₂ 2 O 2-40 6-OCHF ₂ 2 O 2-41 7-OCHF ₂ 2 O 2-42 8-OCHF ₂ 2 O 2-43 5-NO ₂ 2 O 2-44 6-NO ₂ 2 O 2-45 7-NO ₂ 2 O 2-46 8-NO ₂ 2 O 2-47 4- CN 2 O 2-48 5-CN 2 O 2-49 6-CN 2 O 2-50 7-CN 2 O 2-51 8-CN 2 O 2-52 9-CN 2 O 2-53 H 2 S 2 -54 4-F 2 S 2-55 5-F 2 S 2-56 6-F 2 S 2-57 7-F 2 S 2-58 8-F 2 S 2-59 9-F 2 S 2-60 4-Cl 2 S 2-61 5-Cl 2 S 2-62 6-Cl 2 S 2-63 7-Cl 2 S 2-64 8-Cl 2 S 2-65 9-Cl 2 S 2-66 5- NHMe 2 S 2-67 6-N HMe 2 S 2-68 7-NHMe 2 S 2-69 4-Me 2 S 2-70 5-Me 2 S 2-71 6-Me 2 S 2-72 7-Me 2 S 2-73 8-Me 2 S 2-74 9-Me 2 S 2-75 5-N (Me) 2 2 S 2-76 6-N (Me) 2 2 S 2-77 7-N (Me) 2 2 S 2-78 8- N (Me) ₂ 2 S 2-79 4-OMe 2 S 2-80 5-OMe 2 S 2-81 6-OMe 2 S 2-82 7-OMe 2 S 2-83 8-OMe 2 S 2-84 9-OMe 2 S 2-85 5-OEt 2 S 2-86 6-OEt 2 S 2-87 7-OEt 2 S 2-88 8-OEt 2 S 2-89 5-OCHF ₂ 2 S 2-90 6 _{-OCHF 2 2 S 2-91 7-OCHF} 2 2 S 2-92 8-OCHF 2 2 S 2-93 5-NO 2 2 S 2-94 6-NO 2 2 S 2-95 7-NO 2 2 S 2-96 8-NO ₂ 2 S 2-97 4-CN 2 S 2-98 5-CN 2 S 2-99 6-CN 2 S 2-100 7-CN 2 S 2-101 8-CN 2 S 2 -102 9-CN 2 S 2-103 H 3 O 2-104 H 3 S 2-105 H 4 O 2-106 H 4 S 2-107 H5 O 2-108 H5 S 2-109 H 6 O 2 -110 H 6 S

[0045]

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[0046]

[Table 3] Compound No. _{^{(R 1) m n X 3-1}} H 1 O 3-2 H 2 O 3-3 H 2 S 3-4 H 3 O 3-5 4-F 2 O 3-6 4-F 2 S 3 -7 4-F 3 O 3-8 4-F 4 O 3-9 5-F 2 O 3-10 5-F 2 S 3-11 5-F 3 O 3-12 6-F 2 O 3-13 6-F 2 S 3-14 6-F 3 O 3-15 4-Cl 2 O 3-16 4-Cl 2 S 3-17 4-Cl 3 O 3-18 5-Cl 2 O 3-19 5- Cl 2 S 3-20 5-Cl 3 O 3-21 6-Cl 2 O 3-22 6-Cl 2 S 3-23 6-Cl 3 O 3-24 4-Cl 6-Cl 2 O 3-25 4 -Cl 6-Cl 2 S 3-26 4-Br 2 O 3-27 4-Br 2 S 3-28 5-Br 2 O 3-29 5-Br 2 S 3-30 5-Br 3 O 3-31 6-Br 2 O 3-32 6-Br 2 S 3-33 6-Br 3 O 3-34 4-Br 6-Cl 2 O 3-35 4-Br 6-Cl 2 S 3-36 4-Me 2 O 3-37 4-Me 2 S 3-38 5-Me 2 O 3-39 5-Me 2 S 3-40 5-Me 3 O 3-41 6-Me 2 O 3-42 6-Me 2 S 3 -43 6-Me 3 O 3-44 6-Me 4-Cl 2 O 3-45 6-Me 4-Cl 2 S 3-46 4-CN 2 O 3-47 4-CN 2 S 3-48 5- CN 2 O 3-49 5-CN 2 S 3-50 5-CN 3 O 3-51 6-CN 2 O 3-52 6-CN 2 S 3-53 6-CN 3 O 3-54 6-CN 4 -Cl 2 O 3-55 6-Et 4-Cl 2 S 3-56 4-OMe 2 O 3-57 4-OMe 2 S 3-58 5-OMe 2 O 3-59 5-OMe 2 S 3-60 5-OMe 3 O 3-61 6-OMe 2 O 3-62 6-OMe 2 S 3-63 6-OMe 3 O 3-64 4-OEt 2 O 3-65 4-OEt 2 S 3-66 5- OEt 2 O 3-67 5-OEt 2 S 3- 68 5-OEt 3 O 3-69 6 -OEt 2 O 3-70 6-OEt 2 S 3-71 6-OEt 3 O 3-72 4-NO 2 2 O 3-73 4-NO 2 2 S 3- 74 4-NO ₂ 3 O 3-75 5-NO ₂ 2 O 3-76 5-NO ₂ 2 S 3-77 5-NO ₂ 3 O 3-78 6-NO ₂ 2 O 3-79 6-NO _{2 2 S 3-80 6-NO 2 3} O 3-81 4-NO 2 6-Cl 2 O 3-82 4-NO 2 6-Cl 2 S 3-83 4-CF 3 2 O 3-84 4-CF _{3 2 S 3-85 5-CF 3} 2 O 3-86 5-CF 3 2 S 3-87 5-CF 3 3 O 3-88 6-CF 3 2 O 3-89 6-CF 3 2 S 3- 90 6-CF ₃ 3 O

[0047]

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[0048]

[Table 4] Compound No. _{^{(R 1) m n X 4-1}} H 1 O 4-2 H 2 O 4-3 H 2 S 4-4 H 3 O 4-5 5-F 2 O 4-6 5-F 2 S 4 -7 5-F 3 O 4-8 6-F 2 O 4-9 6-F 2 S 4-10 6-F 3 O 4-11 7-Cl 2 O 4-12 7-Cl 2 S 4-13 7-Cl 3 O 4-14 5-Cl 2 O 4-15 5-Cl 2 S 4-16 5-Cl 3 O 4-17 6-Cl 2 O 4-18 6-Cl 2 S 4-19 6- Cl 3 O 4-20 7-Br 2 O 4-21 7-Br 2 S 4-22 5-Br 2 O 4-23 5-Br 2 S 4-24 5-Br 3 O 4-25 6-Br 2 O 4-26 6-Br 2 S 4-27 6-Br 3 O 4-28 7-Br 6-Cl 2 O 4-29 7-Br 6-Cl 2 S 4-30 7-Me 2 O 4-31 7-Me 2 S 4-32 5-Me 2 O 4-33 5-Me 2 S 4-34 5-Me 3 O 4-35 6-Me 2 O 4-36 6-Me 2 S 4-37 6- Me 3 O 4-38 6-Me 7-Cl 2 O 4-39 6-Me 7-Cl 2 S 4-40 7-CN 2 O 4-41 7-CN 2 S 4-42 5-CN 2 O 4 -43 5-CN 2 S 4-44 5-CN 3 O 4-45 6-CN 2 O 4-46 6-CN 2 S 4-47 6-CN 3 O 4-48 6-CN 7-Cl 2 O 4-49 6-Et 7-Cl 2 S 4-50 7-OMe 2 O 4-51 7-OMe 2 S 4-52 5-OMe 2 O 4-53 5-OMe 2 S 4-54 5-OMe 3 O 4-55 6-OMe 2 O 4-56 6-OMe 2 S 4-57 6-OMe 3 O 4-58 7-OEt 2 O 4-59 7-OEt 2 S 4-60 5-OEt 2 O 4 -61 5-OEt 2 S 4-62 5-OEt 3 O 4-63 6-OEt 2 O 4-64 6-OEt 2 S 4-65 6-OEt 3 O 4-66 7-NO ₂ 2 O 4- 67 7-NO _{2 2} S 4-68 7-NO ₂ 3 O 4-69 5-NO ₂ 2 O 4-70 5-NO ₂ 2 S 4-71 5-NO ₂ 3 O 4-72 6-NO ₂ 2 O 4-73 6- _{NO 2 2 S 4-74 6-NO} 2 3 O 4-75 7-NO 2 6-Cl 2 O 4-76 7-NO 2 6-Cl 2 S

[0049]

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[0050]

[Table 5] Compound No. _{^{(R 1) m n X 5-1}} H 1 O 5-2 H 2 O 5-3 H 2 S 5-4 H 3 O 5-5 4-F 2 O 5-6 4-F 2 S 5 -7 4-F 3 O 5-8 6-F 2 O 5-9 6-F 2 S 5-10 6-F 3 O 5-11 7-Cl 2 O 5-12 7-Cl 2 S 5-13 7-Cl 3 O 5-14 4-Cl 2 O 5-15 4-Cl 2 S 5-16 4-Cl 3 O 5-17 6-Cl 2 O 5-18 6-Cl 2 S 5-19 6- Cl 3 O 5-20 7-Br 2 O 5-21 7-Br 2 S 5-22 4-Br 2 O 5-23 4-Br 2 S 5-24 4-Br 3 O 5-25 6-Br 2 O 5-26 6-Br 2 S 5-27 6-Br 3 O 5-28 7-Br 6-Cl 2 O 5-29 7-Br 6-Cl 2 S 5-30 7-Me 2 O 5-31 7-Me 2 S 5-32 4-Me 2 O 5-33 4-Me 2 S 5-34 4-Me 3 O 5-35 6-Me 2 O 5-36 6-Me 2 S 5-37 6- Me 3 O 5-38 6-Me 7-Cl 2 O 5-39 6-Me 7-Cl 2 S 5-40 7-CN 2 O 5-41 7-CN 2 S 5-42 4-CN 2 O 5 -43 4-CN 2 S 5-44 4-CN 3 O 5-45 6-CN 2 O 5-46 6-CN 2 S 5-47 6-CN 3 O 5-48 6-CN 7-Cl 2 O 5-49 6-Et 7-Cl 2 S 5-50 7-OMe 2 O 5-51 7-OMe 2 S 5-52 4-OMe 2 O 5-53 4-OMe 2 S 5-54 4-OMe 3 O 5-55 6-OMe 2 O 5-56 6-OMe 2 S 5-57 6-OMe 3 O 5-58 7-OEt 2 O 5-59 7-OEt 2 S 5-60 4-OEt 2 O 5 -61 4-OEt 2 S 5-62 4-OEt 3 O 5-63 6-OEt 2 O 5-64 6-OEt 2 S 5-65 6-OEt 3 O 5-66 7-NO ₂ 2 O 5- 67 7-NO _{2 2} S 5-68 7-NO ₂ 3 O 5-69 4-NO ₂ 2 O 5-70 4-NO ₂ 2 S 5-71 4-NO ₂ 3 O 5-72 6-NO ₂ 2 O 5-73 6- _{NO 2 2 S 5-74 6-NO} 2 3 O 5-75 7-NO 2 6-Cl 2 O 5-76 7-NO 2 6-Cl 2 S

[0051]

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[0052]

[Table 6] Compound No. _{^{(R 1) m n X 6-1}} H 1 O 6-2 H 2 O 6-3 H 2 S 6-4 H 3 O 6-5 4-F 2 O 6-6 4-F 2 S 6 -7 4-F 3 O 6-8 5-F 2 O 6-9 5-F 2 S 6-10 5-F 3 O 6-11 7-Cl 2 O 6-12 7-Cl 2 S 6-13 7-Cl 3 O 6-14 4-Cl 2 O 6-15 4-Cl 2 S 6-16 4-Cl 3 O 6-17 5-Cl 2 O 6-18 5-Cl 2 S 6-19 5- Cl 3 O 6-20 7-Br 2 O 6-21 7-Br 2 S 6-22 4-Br 2 O 6-23 4-Br 2 S 6-24 4-Br 3 O 6-25 5-Br 2 O 6-26 5-Br 2 S 6-27 5-Br 3 O 6-28 7-Br 5-Cl 2 O 6-29 7-Br 5-Cl 2 S 6-30 7-Me 2 O 6-31 7-Me 2 S 6-32 4-Me 2 O 6-33 4-Me 2 S 6-34 4-Me 3 O 6-35 5-Me 2 O 6-36 5-Me 2 S 6-37 5- Me 3 O 6-38 5-Me 7-Cl 2 O 6-39 5-Me 7-Cl 2 S 6-40 7-CN 2 O 6-41 7-CN 2 S 6-42 4-CN 2 O 6 -43 4-CN 2 S 6-44 4-CN 3 O 6-45 5-CN 2 O 6-46 5-CN 2 S 6-47 5-CN 3 O 6-48 5-CN 7-Cl 2 O 6-49 5-Et 7-Cl 2 S 6-50 7-OMe 2 O 6-51 7-OMe 2 S 6-52 4-OMe 2 O 6-53 4-OMe 2 S 6-54 4-OMe 3 O 6-55 5-OMe 2 O 6-56 5-OMe 2 S 6-57 5-OMe 3 O 6-58 7-OEt 2 O 6-59 7-OEt 2 S 6-60 4-OEt 2 O 6 -61 4-OEt 2 S 6-62 4-OEt 3 O 6-63 5-OEt 2 O 6-64 5-OEt 2 S 6-65 5-OEt 3 O 6-66 7-NO ₂ 2 O 6- 67 7-NO _{2 2} S _{6-68 7-NO 2 3 O 6-69} 4-NO 2 2 O 6-70 4-NO 2 2 S 6-71 4-NO 2 3 O 6-72 5-NO 2 2 O 6-73 5- _{NO 2 2 S 6-74 5-NO} 2 3 O 6-75 7-NO 2 5-Cl 2 O 6-76 7-NO 2 5-Cl 2 S

[0053]

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[0054]

[Table 7] Compound No. _{^{(R 1) m n X 7-1}} H 2 O 7-2 H 2 S 7-3 5-F 2 O 7-4 5-F 2 S 7-5 6-F 2 O 7-6 6- F 2 S 7-7 5-Cl 2 O 7-8 5-Cl 2 S 7-9 6-Cl 2 O 7-10 6-Cl 2 S 7-11 6-Cl 3 O 7-12 5-Br 2 O 7-13 5-Br 2 S 7-14 6-Br 2 O 7-15 6-Br 2 S 7-16 5-Me 2 O 7-17 5-Me 2 S 7-18 6-Me 2 O 7 -19 6-Me 2 S 7-20 5-Et 2 O 7-21 5-Et 2S 7-22 6-Et 2 O 7-23 6-Et 2S 7-24 5-OMe 2 O 7-25 5-OMe 2 S 7-26 6-OMe 2 O 7-27 6-OMe 2 S 7-28 5-OEt 2 O 7-29 5-OEt 2 S 7-30 6-OEt 2 O 7-31 6- _{OEt 2 S 7-32 5-NO 2} 2 O 7-33 5-NO 2 2 S 7-34 6-NO 2 2 O 7-35 6-NO 2 2 S

[0055]

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[0056]

[Table 8] Compound No. _{^{(R 1) m n X 8-1}} H 2 O 8-2 H 2 S 8-3 4-F 2 O 8-4 4-F 2 O 8-5 5-F 2 O 8-6 5- F 2 S 8-7 4-Cl 2 O 8-8 5-Cl 2 O 8-9 4-Br 2 O 8-10 4-Br 2 S 8-11 5-Br 2 O 8-12 5-Br 2 S 8-13 4-Me 2 O 8-14 4-Me 2 S 8-15 5-Me 2 O 8-16 5-Me 2 S 8-17 4-Et 2 O 8-18 4-Et 2 S 8 -19 5-Et 2 O 8-20 5-Et 2 S 8-21 4-OMe 2 O 8-22 4-OMe 2 S 8-23 5-OMe 2 O 8-24 5-OMe 2 S 8-25 4-OEt 2 O 8-26 4-OEt 2 S 8-27 5-OEt 2 O 8-28 5-OEt 2 S 8-29 4-NO ₂ 2 O 8-30 4-NO ₂ 2 S 8-31 5-NO ₂ 2 O 8-32 5-NO ₂ 2 S

[0057]

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[0058]

[Table 9] Compound No. _{^{(R 1) m n R 2}} b X 9-1 H 2 NHMe O 9-2 H 2 NMe 2 O 9-3 H 2 Pip O 9-4 H 2 Mor O 9-5 H 2 NHMe S 9- 6 H 2 NMe ₂ S 9-7 H 2 Pip S 9-8 H 2 Mor S 9-9 4-F 2 Pip O 9-10 4-F 2 Mor O 9-11 4-F 2 Pip S 9-12 4-F 2 Mor S 9-13 5-F 2 NHMe O 9-14 5-F 2 NMe ₂ O 9-15 5-F 2 Pip O 9-16 5-F 2 Mor O 9-17 5-F 2 NHMe S 9-18 5-F 2 NMe ₂ S 9-19 6-F 2 NHMe O 9-20 6-F 2 NMe ₂ O 9-21 6-F 2 Pip O 9-22 6-F 2 Mor O 9 -23 6-F 2 NHMe S 9-24 6-F 2 NMe ₂ S 9-25 7-F 2 NHMe O 9-26 7-F 2 NMe ₂ O 9-27 7-F 2 Pip O 9-28 7 -F 2 Mor O 9-29 5-F 7-Cl 2 NHMe O 9-30 5-F 7-Cl 2 NMe ₂ O 9-31 5-F 7-Cl 2 Pip O 9-32 5-F 7- Cl 2 Mor O 9-33 5-F 7-Cl 2 NHMe S 9-34 5-F 7-Cl 2 NMe ₂ S 9-35 7-F 5-Cl 2 Pip O 9-36 7-F 5-Cl 2 Mor O 9-37 4-Cl 2 NHMe O 9-38 4-Cl 2 NMe ₂ O 9-39 4-Cl 2 Pip O 9-40 4-Cl 2 Mor O 9-41 4-Cl 2 NHMe S 9 -42 4-Cl 2 NMe ₂ S 9-43 5-Cl 2 NHMe O 9-44 5-Cl 2 NMe ₂ O 9-45 5-Cl 2 Pip O 9-46 5-Cl 2 Mor O 9-47 5 -Cl 2 NHMe S 9-48 5-Cl 2 NMe ₂ S 9-49 6-Cl 2 NHMe O 9-50 6-Cl 2 NMe ₂ O 9-51 6-Cl 2 Pip O 9-52 6-Cl 2 Mo r O 9-53 7-Cl 2 NHMe O 9-54 7-Cl 2 NMe ₂ O 9-55 7-Cl 2 Pip O 9-56 7-Cl 2 Mor O 9-57 4-Cl 6-Cl 2 NHMe O 9-58 4-Cl 6-Cl 2 NMe ₂ O 9-59 4-Cl 6-Cl 2 Pip O 9-60 4-Cl 6-Cl 2 Mor O 9-61 5-Cl 7-Cl 2 NHMe O 9-62 5-Cl 7-Cl 2 NMe ₂ O 9-63 5-Cl 7-Cl 2 Pip O 9-64 5-Cl 7-Cl 2 Mor O 9-65 5-Cl 7-Cl 2 NHMe S 9 -66 5-Cl 7-Cl 2 NMe ₂ S 9-67 5-Cl 7-Cl 2 Pip S 9-68 5-Cl 7-Cl 2 Mor S 9-69 4-Br 2 Pip O 9-70 5- Br 2 NHMe O 9-71 5-Br 2 NMe ₂ O 9-72 5-Br 2 Pip O 9-73 5-Br 2 Mor O 9-74 6-Br 2 NHMe O 9-75 6-Br 2 NMe ₂ O 9-76 6-Br 2 Pip O 9-77 6-Br 2 Mor O 9-78 7-Br 2 NHMe O 9-79 7-Br 2 NMe ₂ O 9-80 7-Br 2 Pip O 9-81 7-Br 2 Mor O 9-82 4-Br 6-Cl 2 Pip O 9-83 5-Br 7-Cl 2 Pip O 9-84 4-Me 2 NHMe O 9-85 4-Me 2 NMe ₂ O 9 -86 4-Me 2 Pip O 9-87 4-Me 2 Mor O 9-88 5-Me 2 NHMe O 9-89 5-Me 2 NMe ₂ O 9-90 5-Me 2 Pip O 9-91 5- Me 2 Mor O 9-92 5-Me 2 NHMe S 9-93 5-Me 2 NMe ₂ S 9-94 5-Me 2 Pip S 9-95 5-Me 2 Mor S 9-96 6-Me 2 NHMe O 9-97 6-Me 2 NMe ₂ O 9-98 6-Me 2 Pip O 9-99 6-Me 2 Mor O 9-100 7-Me 2 NHMe O 9-101 7-Me 2 NMe ₂ O 9-102 7-Me 2 Pip O 9-103 7-Me 2 Mor O 9-104 5-Me 7-Cl 2 Pip O 9-105 5-Me 7-Cl 2 Pip S 9-106 6-Me 4-Cl 2 Pip O 9-107 7-Me 5-Cl 2 Pip O 9-108 7-Me 5-Cl 2 Pip S 9-109 4-Et 2 Pip O 9-110 4-Et 2 Mor O 9-111 5-Et 2 Pip O 9-112 5-Et 2 Mor O 9-113 6-Et 2 Pip O 9-114 6-Et 2 Mor O 9-115 7-Et 2 Pip O 9-116 7-Et 2 Mor O 9-117 5-Et 7-Cl 2 Mor O 9-118 6-Et 4-Cl 2 Mor O 9-119 7-Et 5-Cl 2 Mor O 9-120 4-OMe 2 NHMe O 9-121 4-OMe 2 NMe ₂ O 9-122 4-OMe 2 Pip O 9-123 4-OMe 2 Mor O 9-124 4-OMe 2 NHMe S 9-125 4-OMe 2 NMe ₂ S 9-126 4-OMe 2 Pip S 9- 127 4-OMe 2 Mor S 9-128 5-OMe 2 NHMe O 9-129 5-OMe 2 NMe ₂ O 9-130 5-OMe 2 Pip O 9-131 5-OMe 2 Mor O 9-132 5-OMe 2 NHMe S 9-133 5-OMe 2 NMe ₂ S 9-134 5-OMe 2 Pip S 9-135 5-OMe 2 Mor S 9-136 6-OMe 2 NHMe O 9-137 6-OMe 2 NMe ₂ O 9-138 6-OMe 2 Pip O 9-139 6-OMe 2 Mor O 9-140 7-OMe 2 NHMe O 9-141 7-OMe 2 NMe ₂ O 9-142 7-OMe 2 Pip O 9-143 7 -OMe 2 Mor O 9-144 5-OMe 7-Cl 2 Pip O 9-145 7-OMe 5-Cl 2 Pip O 9-146 4-OEt 2 Pip O 9-147 4-OEt 2 Mor O 9-148 5-OEt 2 Pip O 9-149 5-OEt 2 Mo r O 9-150 6-OEt 2 Pip O 9-151 6-OEt 2 Mor O 9-152 7-OEt 2 Pip O 9-153 7-OEt 2 Mor O 9-154 5-OEt 7-Cl 2 Mor O 9-155 7-OEt 5-Cl 2 Mor O 9-156 4-NO ₂ 2 NHMe O 9-157 4-NO ₂ 2 NMe ₂ O 9-158 4-NO ₂ 2 Pip O 9-159 4-NO _{2 2 Mor O 9-160 4-NO 2} 2 NHMe S 9-161 4-NO 2 2 NMe 2 S 9-162 4-NO 2 2 Pip S 9-163 4-NO 2 2 Mor S 9-164 5-NO _{2 2 NHMe O 9-165 5-NO} 2 2 NMe 2 O 9-166 5-NO 2 2 Pip O 9-167 5-NO 2 2 Mor O 9-168 5-NO 2 2 NHMe S 9-169 5- _{NO 2 2 NMe 2 S 9-170 5} -NO 2 2 Pip S 9-171 5-NO 2 2 Mor S 9-172 6-NO 2 2 NHMe O 9-173 6-NO 2 2 NMe 2 O 9-174 _{6-NO 2 2 Pip O 9-175} 6-NO 2 2 Mor O 9-176 7-NO 2 2 NHMe O 9-177 7-NO 2 2 NMe 2 O 9-178 7-NO 2 2 Pip O 9- 179 7-NO ₂ 2 Mor O 9-180 4-NO ₂ 6-Cl 2 Pip O 9-181 5-NO ₂ 7-Cl 2 Pip O 9-182 5-NO ₂ 7-Cl 2 Pip S

[0059]

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[0060]

[Table 10] Compound No. _{^{(R 1) m n R 2}} b X 10-1 H 2 NHMe O 10-2 H 2 NMe 2 O 10-3 H 2 Pip O 10-4 H 2 Mor O 10-5 H 2 NHMe S 10- 6 H 2 NMe ₂ S 10-7 H 2 Pip S 10-8 H 2 Mor S 10-9 4-F 2 NHMe O 10-10 5-F 2 NMe ₂ O 10-11 6-F 2 Pip O 10- 12 7-F 2 Mor O 10-13 8-F 2 Pip O 10-14 9-F 2 Mor O 10-15 5-F 2 NMe ₂ S 10-16 6-F 2 Pip S 10-17 7-F 2 Mor S 10-18 8-F 2 Pip S 10-19 5-Cl 2 NMe ₂ O 10-20 6-Cl 2 Pip O 10-21 7-Cl 2 Mor O 10-22 8-Cl 2 Pip O 10 -23 5-Cl 2 NMe ₂ S 10-24 6-Cl 2 Pip S 10-25 7-Cl 2 Mor S 10-26 8-Cl 2 Pip S 10-27 8-Br 2 Pip O 10-28 5- Br 2 NMe ₂ S 10-29 5-Me 2 NMe ₂ O 10-30 6-Me 2 Pip O 10-31 7-Me 2 Mor O 10-32 8-Me 2 Pip O 10-33 5-Me 2 NMe ₂ S 10-34 6-Me 2 Pip S 10-35 7-Me 2 Mor S 10-36 8-Me 2 Pip S 10-37 8-Et 2 Pip O 10-38 5-Et 2 NMe ₂ S 10- 39 5-OMe 2 NMe ₂ O 10-40 6-OMe 2 Pip O 10-41 7-OMe 2 Mor O 10-42 8-OMe 2 Pip O 10-43 5-OMe 2 NMe ₂ S 10-44 6- OMe 2 Pip S 10-45 7-OMe 2 Mor S 10-46 8-OMe 2 Pip S 10-47 8-OEt 2 Pip O 10-48 5-OEt 2 NMe 2 S 10-49 8-OCHF 2 2 Pip O 10-50 5-OCHF ₂ 2 NMe _{2 S 10-51 5-NO 2 2 NMe} 2 O 10-52 6-NO 2 2 Pip O 10-53 7-NO 2 2 Mor O 10-54 8-NO 2 2 Pip O 10-55 5-NO 2 2 _{NMe 2 S 10-56 6-NO 2} 2 Pip S 10-57 7-NO 2 2 Mor S 10-58 8-NO 2 2 Pip S 10-59 5-CN 2 NMe 2 O 10-60 6-CN 2 Pip O 10-61 7-CN 2 Mor O 10-62 8-CN 2 Pip O 10-63 5-CN 2 NMe ₂ S 10-64 6-CN 2 Pip S 10-65 7-CN 2 Mor S 10- 66 8-CN 2 Pip S

[0061]

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[0062]

[Table 11] Compound No. _{^{(R 1) m n R 2}} b X 11-1 H 2 NHMe O 11-2 H 2 NMe 2 O 11-3 H 2 Pip O 11-4 H 2 Mor O 11-5 H 2 NHMe S 11- 6 H 2 NMe ₂ S 11-7 H 2 Pip S 11-8 H 2 Mor S 11-9 4-F 2 Pip O 11-10 4-F 2 Mor O 11-11 4-F 2 Pip S 11-12 4-F 2 Mor S 11-13 5-F 2 NHMe O 11-14 5-F 2 NMe ₂ O 11-15 5-F 2 Pip O 11-16 5-F 2 Mor O 11-17 5-F 2 NHMe S 11-18 5-F 2 NMe ₂ S 11-19 6-F 2 NHMe O 11-20 6-F 2 NMe ₂ O 11-21 6-F 2 Pip O 11-22 6-F 2 Mor O 11 -23 4-Cl 2 NHMe O 11-24 4-Cl 2 NMe ₂ O 11-25 4-Cl 2 Pip O 11-26 4-Cl 2 Mor O 11-27 4-Cl 2 NHMe S 11-28 4- Cl 2 NMe ₂ S 11-29 5-Cl 2 NHMe O 11-30 5-Cl 2 NMe ₂ O 11-31 5-Cl 2 Pip O 11-32 5-Cl 2 Mor O 11-33 5-Cl 2 NHMe S 11-34 5-Cl 2 NMe ₂ S 11-35 5-Cl 2 Pip S 11-36 5-Cl 2 Mor S 11-37 6-Cl 2 NHMe O 11-38 6-Cl 2 NMe ₂ O 11- 39 6-Cl 2 Pip O 11-40 6-Cl 2 Mor O 11-41 4-Cl 6-Cl 2 NHMe O 11-42 4-Cl 6-Cl 2 NMe ₂ O 11-43 4-Cl 6-Cl 2 Pip O 11-44 4-Br 2 Mor O 11-45 5-Br 2 NHMe O 11-46 5-Br 2 NMe ₂ O 11-47 5-Br 2 Pip O 11-48 5-Br 2 Mor O 11 -49 5-Br 2 NHMe S 11-50 5-Br 2 NMe ₂ S 11-51 6-Br 2 NHMe O 11-52 6-Br 2 NMe ₂ O 11-53 6-Br 2 Pip O 11-54 6-Br 2 Mor O 11-55 4-Br 6-Cl 2 Pip O 11-56 4-Me 2 NHMe O 11-57 4-Me 2 NMe ₂ O 11-58 4-Me 2 Pip O 11-59 4-Me 2 Mor O 11-60 4-Me 2 NHMe S 11-61 4-Me 2 NMe ₂ S 11-62 4-Me 2 Pip S 11-63 4-Me 2 Mor S 11-64 5-Me 2 NHMe O 11-65 5-Me 2 NMe ₂ O 11-66 5-Me 2 Pip O 11-67 5-Me 2 Mor O 11-68 5-Me 2 NHMe S 11-69 5-Me 2 NMe ₂ S 11-70 6-Me 2 NHMe O 11-71 6-Me 2 NMe ₂ O 11-72 6-Me 2 Pip O 11-73 6-Me 2 Mor O 11-74 6-Me 4-Cl 2 Pip O 11-75 4-Et 2 Pip O 11-76 4-Et 2 Mor O 11- 77 5-Et 2 Pip O 11-78 5-Et 2 Mor O 11-79 5-Et 2 Pip S 11-80 5-Et 2 Mor S 11-81 6-Et 2 Pip O 11-82 6-Et 2 Mor O 11-83 6-Et 4-Cl 2 Mor O 11-84 4-OMe 2 NHMe O 11-85 4-OMe 2 NMe ₂ O 11-86 4-OMe 2 Pip O 11-87 4-OMe 2 Mor O 11-88 4-OMe 2 NHMe S 11-89 4-OMe 2 NMe ₂ S 11-90 4-OMe 2 Pip S 11-91 4-OMe 2 Mor S 11-92 5-OMe 2 NHMe O 11-93 5-OMe 2 NMe ₂ O 11-94 5-OMe 2 Pip O 11-95 5-OMe 2 Mor O 11-96 5-OMe 2 NHMe S 11-97 5-OMe 2 NMe ₂ S 11-98 5-OMe 2 Pip S 11-99 5-OMe 2 Mor S 11-1 00 6-OMe 2 NHMe O 11-101 6-OMe 2 NMe ₂ O 11-102 6-OMe 2 Pip O 11-103 6-OMe 2 Mor O 11-104 4-OEt 2 Pip O 11-105 4-OEt 2 Mor O 11-106 4-OEt 2 Pip S 11-107 4-OEt 2 Mor S 11-108 5-OEt 2 Pip O 11-109 5-OEt 2 Mor O 11-110 5-OEt 2 Pip S 11- 111 5-OEt 2 Mor S 11-112 6-OEt 2 Pip O 11-113 6-OEt 2 Mor O 11-114 4-NO 2 2 NHMe O 11-115 4-NO 2 2 NMe 2 O 11-116 4 _{-NO 2 2 Pip O 11-117 4-} NO 2 2 Mor O 11-118 4-NO 2 2 NHMe S 11-119 4-NO 2 2 NMe 2 S 11-120 4-NO 2 2 Pip S 11-121 _{4-NO 2 2 Mor S 11-122} 5-NO 2 2 NHMe O 11-123 5-NO 2 2 NMe 2 O 11-124 5-NO 2 2 Pip O 11-125 5-NO 2 2 Mor O 11- _{126 5-NO 2 2 NHMe S} 11-127 5-NO 2 2 NMe 2 S 11-128 5-NO 2 2 Pip S 11-129 5-NO 2 2 Mor S 11-130 6-NO 2 2 NHMe O 11 _{-131 6-NO 2 2 NMe 2} O 11-132 6-NO 2 2 Pip O 11-133 6-NO 2 2 Mor O 11-134 4-NO 2 6-Cl 2 Pip O

[0063]

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[0064]

[Table 12] Compound No. _{^{(R 1) m n R 2}} b X 12-1 H 2 NHMe O 12-2 H 2 NMe 2 O 12-3 H 2 Pip O 12-4 H 2 Mor O 12-5 H 2 NHMe S 12- 6 H 2 NMe ₂ S 12-7 H 2 Pip S 12-8 H 2 Mor S 12-9 7-F 2 Pip O 12-10 7-F 2 Mor O 12-11 7-F 2 Pip S 12-12 7-F 2 Mor S 12-13 5-F 2 NHMe O 12-14 5-F 2 NMe ₂ O 12-15 5-F 2 Pip O 12-16 5-F 2 Mor O 12-17 5-F 2 NHMe S 12-18 5-F 2 NMe ₂ S 12-19 6-F 2 NHMe O 12-20 6-F 2 NMe ₂ O 12-21 6-F 2 Pip O 12-22 6-F 2 Mor O 12 -23 7-Cl 2 NHMe O 12-24 7-Cl 2 NMe ₂ O 12-25 7-Cl 2 Pip O 12-26 7-Cl 2 Mor O 12-27 7-Cl 2 NHMe S 12-28 7- Cl 2 NMe ₂ S 12-29 5-Cl 2 NHMe O 12-30 5-Cl 2 NMe ₂ O 12-31 5-Cl 2 Pip O 12-32 5-Cl 2 Mor O 12-33 5-Cl 2 NHMe S 12-34 5-Cl 2 NMe ₂ S 12-35 5-Cl 2 Pip S 12-36 5-Cl 2 Mor S 12-37 6-Cl 2 NHMe O 12-38 6-Cl 2 NMe ₂ O 12- 39 6-Cl 2 Pip O 12-40 6-Cl 2 Mor O 12-41 7-Cl 6-Cl 2 NHMe O 12-42 7-Cl 6-Cl 2 NMe ₂ O 12-43 7-Cl 6-Cl 2 Pip O 12-44 7-Br 2 Mor O 12-45 5-Br 2 NHMe O 12-46 5-Br 2 NMe ₂ O 12-47 5-Br 2 Pip O 12-48 5-Br 2 Mor O 12 -49 5-Br 2 NHMe S 12-50 5-Br 2 NMe ₂ S 12-51 6-Br 2 NHMe O 12-52 6-Br 2 NMe ₂ O 12-53 6-Br 2 Pip O 12-54 6-Br 2 Mor O 12-55 7-Br 6-Cl 2 Pip O 12-56 7-Me 2 NHMe O 12-57 7-Me 2 NMe ₂ O 12-58 7-Me 2 Pip O 12-59 7-Me 2 Mor O 12-60 7-Me 2 NHMe S 12-61 7-Me 2 NMe ₂ S 12-62 7-Me 2 Pip S 12-63 7-Me 2 Mor S 12-64 5-Me 2 NHMe O 12-65 5-Me 2 NMe ₂ O 12-66 5-Me 2 Pip O 12-67 5-Me 2 Mor O 12-68 5-Me 2 NHMe S 12-69 5-Me 2 NMe ₂ S 12-70 6-Me 2 NHMe O 12-71 6-Me 2 NMe ₂ O 12-72 6-Me 2 Pip O 12-73 6-Me 2 Mor O 12-74 6-Me 7-Cl 2 Pip O 12-75 7-Et 2 Pip O 12-76 7-Et 2 Mor O 12- 77 5-Et 2 Pip O 12-78 5-Et 2 Mor O 12-79 5-Et 2 Pip S 12-80 5-Et 2 Mor S 12-81 6-Et 2 Pip O 12-82 6-Et 2 Mor O 12-83 6-Et 7-Cl 2 Mor O 12-84 7-OMe 2 NHMe O 12-85 7-OMe 2 NMe ₂ O 12-86 7-OMe 2 Pip O 12-87 7-OMe 2 Mor O 12-88 7-OMe 2 NHMe S 12-89 7-OMe 2 NMe ₂ S 12-90 7-OMe 2 Pip S 12-91 7-OMe 2 Mor S 12-92 5-OMe 2 NHMe O 12-93 5-OMe 2 NMe ₂ O 12-94 5-OMe 2 Pip O 12-95 5-OMe 2 Mor O 12-96 5-OMe 2 NHMe S 12-97 5-OMe 2 NMe ₂ S 12-98 5-OMe 2 Pip S 12-99 5-OMe 2 Mor S 12-1 00 6-OMe 2 NHMe O 12-101 6-OMe 2 NMe ₂ O 12-102 6-OMe 2 Pip O 12-103 6-OMe 2 Mor O 12-104 7-OEt 2 Pip O 12-105 7-OEt 2 Mor O 12-106 7-OEt 2 Pip S 12-107 7-OEt 2 Mor S 12-108 5-OEt 2 Pip O 12-109 5-OEt 2 Mor O 12-110 5-OEt 2 Pip S 12- 111 5-OEt 2 Mor S 12-112 6-OEt 2 Pip O 12-113 6-OEt 2 Mor O 12-114 7-NO 2 2 NHMe O 12-115 7-NO 2 2 NMe 2 O 12-116 7 _{-NO 2 2 Pip O 12-117 7-} NO 2 2 Mor O 12-118 7-NO 2 2 NHMe S 12-119 7-NO 2 2 NMe 2 S 12-120 7-NO 2 2 Pip S 12-121 _{7-NO 2 2 Mor S 12-122} 5-NO 2 2 NHMe O 12-123 5-NO 2 2 NMe 2 O 12-124 5-NO 2 2 Pip O 12-125 5-NO 2 2 Mor O 12- _{126 5-NO 2 2 NHMe S} 12-127 5-NO 2 2 NMe 2 S 12-128 5-NO 2 2 Pip S 12-129 5-NO 2 2 Mor S 12-130 6-NO 2 2 NHMe O 12 _{-131 6-NO 2 2 NMe 2} O 12-132 6-NO 2 2 Pip O 12-133 6-NO 2 2 Mor O 12-134 7-NO 2 6-Cl 2 Pip O

[0065]

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[0066]

[Table 13] Compound No. _{^{(R 1) m n R 2}} b X 13-1 H 2 NHMe O 13-2 H 2 NMe 2 O 13-3 H 2 Pip O 13-4 H 2 Mor O 13-5 H 2 NHMe S 13- 6 H 2 NMe ₂ S 13-7 H 2 Pip S 13-8 H 2 Mor S 13-9 7-F 2 Pip O 13-10 7-F 2 Mor O 13-11 7-F 2 Pip S 13-12 7-F 2 Mor S 13-13 4-F 2 NHMe O 13-14 4-F 2 NMe ₂ O 13-15 4-F 2 Pip O 13-16 4-F 2 Mor O 13-17 4-F 2 NHMe S 13-18 4-F 2 NMe ₂ S 13-19 6-F 2 NHMe O 13-20 6-F 2 NMe ₂ O 13-21 6-F 2 Pip O 13-22 6-F 2 Mor O 13 -23 7-Cl 2 NHMe O 13-24 7-Cl 2 NMe ₂ O 13-25 7-Cl 2 Pip O 13-26 7-Cl 2 Mor O 13-27 7-Cl 2 NHMe S 13-28 7- Cl 2 NMe ₂ S 13-29 4-Cl 2 NHMe O 13-30 4-Cl 2 NMe ₂ O 13-31 4-Cl 2 Pip O 13-32 4-Cl 2 Mor O 13-33 4-Cl 2 NHMe S 13-34 4-Cl 2 NMe ₂ S 13-35 4-Cl 2 Pip S 13-36 4-Cl 2 Mor S 13-37 6-Cl 2 NHMe O 13-38 6-Cl 2 NMe ₂ O 13- 39 6-Cl 2 Pip O 13-40 6-Cl 2 Mor O 13-41 7-Cl 6-Cl 2 NHMe O 13-42 7-Cl 6-Cl 2 NMe ₂ O 13-43 7-Cl 6-Cl 2 Pip O 13-44 7-Br 2 Mor O 13-45 4-Br 2 NHMe O 13-46 4-Br 2 NMe ₂ O 13-47 4-Br 2 Pip O 13-48 4-Br 2 Mor O 13 -49 4-Br 2 NHMe S 13-50 4-Br 2 NMe ₂ S 13-51 6-Br 2 NHMe O 13-52 6-Br 2 NMe ₂ O 13-53 6-Br 2 Pip O 13-54 6-Br 2 Mor O 13-55 7-Br 6-Cl 2 Pip O 13-56 7-Me 2 NHMe O 13-57 7-Me 2 NMe ₂ O 13-58 7-Me 2 Pip O 13-59 7-Me 2 Mor O 13-60 7-Me 2 NHMe S 13-61 7-Me 2 NMe ₂ S 13-62 7-Me 2 Pip S 13-63 7-Me 2 Mor S 13-64 4-Me 2 NHMe O 13-65 4-Me 2 NMe ₂ O 13-66 4-Me 2 Pip O 13-67 4-Me 2 Mor O 13-68 4-Me 2 NHMe S 13-69 4-Me 2 NMe ₂ S 13-70 6-Me 2 NHMe O 13-71 6-Me 2 NMe ₂ O 13-72 6-Me 2 Pip O 13-73 6-Me 2 Mor O 13-74 6-Me 7-Cl 2 Pip O 13-75 7-Et 2 Pip O 13-76 7-Et 2 Mor O 13- 77 4-Et 2 Pip O 13-78 4-Et 2 Mor O 13-79 4-Et 2 Pip S 13-80 4-Et 2 Mor S 13-81 6-Et 2 Pip O 13-82 6-Et 2 Mor O 13-83 6-Et 7-Cl 2 Mor O 13-84 7-OMe 2 NHMe O 13-85 7-OMe 2 NMe ₂ O 13-86 7-OMe 2 Pip O 13-87 7-OMe 2 Mor O 13-88 7-OMe 2 NHMe S 13-89 7-OMe 2 NMe ₂ S 13-90 7-OMe 2 Pip S 13-91 7-OMe 2 Mor S 13-92 4-OMe 2 NHMe O 13-93 4-OMe 2 NMe ₂ O 13-94 4-OMe 2 Pip O 13-95 4-OMe 2 Mor O 13-96 4-OMe 2 NHMe S 13-97 4-OMe 2 NMe ₂ S 13-98 4-OMe 2 Pip S 13-99 4-OMe 2 Mor S 13-1 00 6-OMe 2 NHMe O 13-101 6-OMe 2 NMe ₂ O 13-102 6-OMe 2 Pip O 13-103 6-OMe 2 Mor O 13-104 7-OEt 2 Pip O 13-105 7-OEt 2 Mor O 13-106 7-OEt 2 Pip S 13-107 7-OEt 2 Mor S 13-108 4-OEt 2 Pip O 13-109 4-OEt 2 Mor O 13-110 4-OEt 2 Pip S 13- 111 4-OEt 2 Mor S 13-112 6-OEt 2 Pip O 13-113 6-OEt 2 Mor O 13-114 7-NO 2 2 NHMe O 13-115 7-NO 2 2 NMe 2 O 13-116 7 _{-NO 2 2 Pip O 13-117 7-} NO 2 2 Mor O 13-118 7-NO 2 2 NHMe S 13-119 7-NO 2 2 NMe 2 S 13-120 7-NO 2 2 Pip S 13-121 _{7-NO 2 2 Mor S 13-122} 4-NO 2 2 NHMe O 13-123 4-NO 2 2 NMe 2 O 13-124 4-NO 2 2 Pip O 13-125 4-NO 2 2 Mor O 13- _{126 4-NO 2 2 NHMe S} 13-127 4-NO 2 2 NMe 2 S 13-128 4-NO 2 2 Pip S 13-129 4-NO 2 2 Mor S 13-130 6-NO 2 2 NHMe O 13 _{-131 6-NO 2 2 NMe 2} O 13-132 6-NO 2 2 Pip O 13-133 6-NO 2 2 Mor O 13-134 7-NO 2 6-Cl 2 Pip O

[0067]

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[0068]

[Table 14] Compound No. _{^{(R 1) m n R 2}} b X 14-1 H 2 NHMe O 14-2 H 2 NMe 2 O 14-3 H 2 Pip O 14-4 H 2 Mor O 14-5 H 2 NHMe S 14- 6 H 2 NMe ₂ S 14-7 H 2 Pip S 14-8 H 2 Mor S 14-9 7-F 2 Pip O 14-10 7-F 2 Mor O 14-11 7-F 2 Pip S 14-12 7-F 2 Mor S 14-13 4-F 2 NHMe O 14-14 4-F 2 NMe ₂ O 14-15 4-F 2 Pip O 14-16 4-F 2 Mor O 14-17 4-F 2 NHMe S 14-18 4-F 2 NMe ₂ S 14-19 5-F 2 NHMe O 14-20 5-F 2 NMe ₂ O 14-21 5-F 2 Pip O 14-22 5-F 2 Mor O 14 -23 7-Cl 2 NHMe O 14-24 7-Cl 2 NMe ₂ O 14-25 7-Cl 2 Pip O 14-26 7-Cl 2 Mor O 14-27 7-Cl 2 NHMe S 14-28 7- Cl 2 NMe ₂ S 14-29 4-Cl 2 NHMe O 14-30 4-Cl 2 NMe ₂ O 14-31 4-Cl 2 Pip O 14-32 4-Cl 2 Mor O 14-33 4-Cl 2 NHMe S 14-34 4-Cl 2 NMe ₂ S 14-35 4-Cl 2 Pip S 14-36 4-Cl 2 Mor S 14-37 5-Cl 2 NHMe O 14-38 5-Cl 2 NMe ₂ O 14- 39 5-Cl 2 Pip O 14-40 5-Cl 2 Mor O 14-41 7-Cl 5-Cl 2 NHMe O 14-42 7-Cl 5-Cl 2 NMe ₂ O 14-43 7-Cl 5-Cl 2 Pip O 14-44 7-Br 2 Mor O 14-45 4-Br 2 NHMe O 14-46 4-Br 2 NMe ₂ O 14-47 4-Br 2 Pip O 14-48 4-Br 2 Mor O 14 -49 4-Br 2 NHMe S 14-50 4-Br 2 NMe ₂ S 14-51 5-Br 2 NHMe O 14-52 5-Br 2 NMe ₂ O 14-53 5-Br 2 Pip O 14-54 5-Br 2 Mor O 14-55 7-Br 5-Cl 2 Pip O 14-56 7-Me 2 NHMe O 14-57 7-Me 2 NMe ₂ O 14-58 7-Me 2 Pip O 14-59 7-Me 2 Mor O 14-60 7-Me 2 NHMe S 14-61 7-Me 2 NMe ₂ S 14-62 7-Me 2 Pip S 14-63 7-Me 2 Mor S 14-64 4-Me 2 NHMe O 14-65 4-Me 2 NMe ₂ O 14-66 4-Me 2 Pip O 14-67 4-Me 2 Mor O 14-68 4-Me 2 NHMe S 14-69 4-Me 2 NMe ₂ S 14-70 5-Me 2 NHMe O 14-71 5-Me 2 NMe ₂ O 14-72 5-Me 2 Pip O 14-73 5-Me 2 Mor O 14-74 5-Me 7-Cl 2 Pip O 14-75 7-Et 2 Pip O 14-76 7-Et 2 Mor O 14- 77 4-Et 2 Pip O 14-78 4-Et 2 Mor O 14-79 4-Et 2 Pip S 14-80 4-Et 2 Mor S 14-81 5-Et 2 Pip O 14-82 5-Et 2 Mor O 14-83 5-Et 7-Cl 2 Mor O 14-84 7-OMe 2 NHMe O 14-85 7-OMe 2 NMe ₂ O 14-86 7-OMe 2 Pip O 14-87 7-OMe 2 Mor O 14-88 7-OMe 2 NHMe S 14-89 7-OMe 2 NMe ₂ S 14-90 7-OMe 2 Pip S 14-91 7-OMe 2 Mor S 14-92 4-OMe 2 NHMe O 14-93 4-OMe 2 NMe ₂ O 14-94 4-OMe 2 Pip O 14-95 4-OMe 2 Mor O 14-96 4-OMe 2 NHMe S 14-97 4-OMe 2 NMe ₂ S 14-98 4-OMe 2 Pip S 14-99 4-OMe 2 Mor S 14-1 00 5-OMe 2 NHMe O 14-101 5-OMe 2 NMe ₂ O 14-102 5-OMe 2 Pip O 14-103 5-OMe 2 Mor O 14-104 7-OEt 2 Pip O 14-105 7-OEt 2 Mor O 14-106 7-OEt 2 Pip S 14-107 7-OEt 2 Mor S 14-108 4-OEt 2 Pip O 14-109 4-OEt 2 Mor O 14-110 4-OEt 2 Pip S 14- 111 4-OEt 2 Mor S 14-112 5-OEt 2 Pip O 14-113 5-OEt 2 Mor O 14-114 7-NO ₂ 2 NHMe O 14-115 7-NO ₂ 2 NMe ₂ O 14-116 7 _{-NO 2 2 Pip O 14-117 7-} NO 2 2 Mor O 14-118 7-NO 2 2 NHMe S 14-119 7-NO 2 2 NMe 2 S 14-120 7-NO 2 2 Pip S 14-121 _{7-NO 2 2 Mor S 14-122} 4-NO 2 2 NHMe O 14-123 4-NO 2 2 NMe 2 O 14-124 4-NO 2 2 Pip O 14-125 4-NO 2 2 Mor O 14- _{126 4-NO 2 2 NHMe S} 14-127 4-NO 2 2 NMe 2 S 14-128 4-NO 2 2 Pip S 14-129 4-NO 2 2 Mor S 14-130 5-NO 2 2 NHMe O 14 -131 5-NO ₂ 2 NMe ₂ O 14-132 5-NO ₂ 2 Pip O 14-133 5-NO ₂ 2 Mor O 14-134 7-NO ₂ 5-Cl 2 Pip O

[0069]

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[0070]

[Table 15] Compound No. _{^{(R 1) m n R 2}} b X 15-1 H 2 NHMe O 15-2 H 2 NMe 2 O 15-3 H 2 Pip O 15-4 H 2 Mor O 15-5 H 2 NHMe S 15- 6 H 2 NMe ₂ S 15-7 H 2 Pip S 15-8 H 2 Mor S 15-9 5-F 2 NHMe O 15-10 5-F 2 NMe ₂ O 15-11 5-F 2 Pip O 15- 12 5-F 2 Mor O 15-13 6-F 2 NHMe O 15-14 6-F 2 NMe ₂ O 15-15 6-F 2 Pip O 15-16 6-F 2 Mor O 15-17 6-F 2 NHMe S 15-18 6-F 2 NMe ₂ S 15-19 6-F 2 Pip S 15-20 6-F 2 Mor S 15-21 5-Cl 2 NHMe O 15-22 5-Cl 2 NMe ₂ O 15-23 5-Cl 2 Pip O 15-24 5-Cl 2 Mor O 15-25 6-Cl 2 NHMe O 15-26 6-Cl 2 NMe ₂ O 15-27 6-Cl 2 Pip O 15-28 6 -Cl 2 Mor O 15-29 6-Cl 2 NHMe S 15-30 6-Cl 2 NMe ₂ S 15-31 6-Cl 2 Pip S 15-32 6-Cl 2 Mor S 15-33 5-Br 2 Mor O 15-34 6-Br 2 NHMe O 15-35 6-Br 2 NMe ₂ O 15-36 6-Br 2 Pip O 15-37 6-Br 2 Mor O 15-38 5-Me 2 NHMe O 15-39 5-Me 2 NMe ₂ O 15-40 5-Me 2 Pip O 15-41 5-Me 2 Mor O 15-42 6-Me 2 NHMe O 15-43 6-Me 2 NMe ₂ O 15-44 6-Me 2 Pip O 15-45 6-Me 2 Mor O 15-46 6-Me 2 NHMe S 15-47 6-Me 2 NMe ₂ S 15-48 6-Me 2 Pip S 15-49 6-Me 2 Mor S 15 -50 5-Et 2 Pip O 15-51 5-Et 2 Mor O 15-52 6-Et 2 Pip O 15-53 6-Et 2 Mor O 15-54 5-MeO 2 NHMe O 15-55 5-MeO 2 NMe ₂ O 15-56 5-MeO 2 Pip O 15- 57 5-MeO 2 Mor O 15-58 6-MeO 2 NHMe O 15-59 6-MeO 2 NMe ₂ O 15-60 6-MeO 2 Pip O 15-61 6-MeO 2 Mor O 15-62 6-MeO 2 NHMe S 15-63 6-MeO 2 NMe ₂ S 15-64 6-MeO 2 Pip S 15-65 6-MeO 2 Mor S 15-66 5-EtO 2 Pip O 15-67 5-EtO 2 Mor O 15 -68 6-EtO 2 Pip O 15-69 6-EtO 2 Mor O 15-70 5-NO 2 2 NHMe O 15-71 5-NO 2 2 NMe 2 O 15-72 5-NO 2 2 Pip O 15- _{73 5-NO 2 2 Mor O} 15-74 6-NO 2 2 NHMe O 15-75 6-NO 2 2 NMe 2 O 15-76 6-NO 2 2 Pip O 15-77 6-NO 2 2 Mor O 15 _{-78 6-NO 2 2 NHMe S} 15-79 6-NO 2 2 NMe 2 S 15-80 6-NO 2 2 Pip S 15-81 6-NO 2 2 Mor S

[0071]

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[0072]

[Table 16] Compound No. _{^{(R 1) m n R 2}} b X 16-1 H 2 NHMe O 16-2 H 2 NMe 2 O 16-3 H 2 Pip O 16-4 H 2 Mor O 16-5 H 2 NHMe S 16- 6 H 2 NMe ₂ S 16-7 H 2 Pip S 16-8 H 2 Mor S 16-9 4-F 2 Pip O 16-10 4-F 2 Mor O 16-11 4-F 2 Pip S 16-12 4-F 2 Mor S 16-13 5-F 2 NHMe O 16-14 5-F 2 NMe ₂ O 16-15 5-F 2 Pip O 16-16 5-F 2 Mor O 16-17 4-Cl 2 NHMe O 16-18 4-Cl 2 NMe ₂ O 16-19 4-Cl 2 Pip O 16-20 4-Cl 2 Mor O 16-21 4-Cl 2 NHMe S 16-22 4-Cl 2 NMe ₂ S 16 -23 4-Cl 2 Pip S 16-24 4-Cl 2 Mor S 16-25 5-Cl 2 NHMe O 16-26 5-Cl 2 NMe ₂ O 16-27 5-Cl 2 Pip O 16-28 5- Cl 2 Mor O 16-29 4-Br 2 NHMe O 16-30 4-Br 2 NMe ₂ O 16-31 4-Br 2 Pip O 16-32 5-Br 2 Mor O 16-33 4-Me 2 NHMe O 16-34 4-Me 2 NMe ₂ O 16-35 4-Me 2 Pip O 16-36 4-Me 2 Mor O 16-37 4-Me 2 NHMe S 16-38 4-Me 2 NMe ₂ S 16-39 4-Me 2 Pip S 16-40 4-Me 2 Mor S 16-41 5-Me 2 NHMe O 16-42 5-Me 2 NMe ₂ O 16-43 5-Me 2 Pip O 16-44 5-Me 2 Mor O 16-45 4-Et 2 Pip O 16-46 4-Et 2 Mor O 16-47 5-Et 2 Pip O 16-48 5-Et 2 Mor O 16-49 4-MeO 2 NHMe O 16-50 4-MeO 2 NMe ₂ O 16-51 4-M eO 2 Pip O 16-52 4-MeO 2 Mor O 16-53 4-MeO 2 NHMe S 16-54 4-MeO 2 NMe ₂ S 16-55 4-MeO 2 Pip S 16-56 4-MeO 2 Mor S 16-57 5-MeO 2 NHMe O 16-58 5-MeO 2 NMe ₂ O 16-59 5-MeO 2 Pip O 16-60 5-MeO 2 Mor O 16-61 4-EtO 2 Pip O 16-62 4 -EtO 2 Mor O 16-63 5-EtO 2 Pip O 16-64 5-EtO 2 Mor O 16-65 4-NO 2 2 NHMe O 16-66 4-NO 2 2 NMe 2 O 16-67 4-NO ₂ 2 Pip O 16-68 4-NO ₂ 2 Mor O 16-69 4-NO ₂ 2 NHMe S 16-70 4-NO ₂ 2 NMe ₂ S 16-71 4-NO ₂ 2 Pip S 16-72 4- _{NO 2 2 Mor S 16-73 5-} NO 2 2 NHMe O 16-74 5-NO 2 2 NMe 2 O 16-75 5-NO 2 2 Pip O 16-76 5-NO 2 2 Mor O Isoxazole derivatives having the general formula (I) of the present invention [formulas (Ia), (Ib), (Ic), (Id) and (I
e)], suitable compounds in 1-3, 1-1
3, 1-15, 1-19, 1-22, 1-25, 1-2
8, 1-31, 1-38, 1-41, 1-44, 1-4
7, 1-48, 1-49, 1-50, 1-51, 1-5
3, 1-56, 1-59, 1-60, 1-62, 1-6
6, 1-68, 1-69, 1-72, 1-75, 1-7
6, 1-85, 1-96, 1-97, 1-98, 1-1
07, 1-119, 1-122, 1-125, 1-12
6, 1-128, 1-135, 1-142, 1-14
8, 1-151, 1-160, 1-168, 1-16
9, 1-170, 1-173, 1-176, 1-18
5, 1-186, 1-191, 1-193, 1-19
7, 1-198, 1-199, 1-200, 1-20
4, 1-207, 1-216, 1-217, 1-21
8, 1-219, 1-220, 1-221, 1-22
4, 1-231, 1-240, 1-241, 1-24
2, 1-243, 1-244, 1-247, 1-26
3, 1-264, 1-265, 1-266, 1-26
7, 1-268, 1-269, 1-272, 1-27
5, 1-277, 1-278, 1-281, 1-28
3, 1-284, 1-285, 1-286, 1-28
7, 1-291, 1-292, 1-293, 1-29
4, 1-310, 1-311, 1-312, 1-32
8, 1-346, 1-362, 1-363, 1-36
4, 1-365, 1-381, 1-384, 1-40
0, 1-401, 1-402, 1-430, 1-40
4, 1-405, 1-406, 1-414, 1-42
1, 1-422, 1-423, 1-429, 1-43
5, 1-438, 1-439, 1-440, 1-44
1, 1-442, 1-448, 1-457, 1-46
0, 1-461, 1-462, 1-463, 1-46
4, 1-465, 1-471, 1-473, 1-47
4, 1-480, 1-481, 1-482, 1-49
0, 1-497, 1-498, 1-499, 1-50
0, 1-501, 1-502, 1-518, 1-51
9, 1-520, 1-521, 1-528, 1-53
4, 1-537, 1-550, 1-553, 1-55
4, 1-555, 1-556, 1-572, 1-57
3, 1-574, 1-575, 1-576, 1-57
7, 1-578, 1-579, 1-580, 1-58
1, 1-582, 1-583, 1-586, 1-59
4, 1-596, 1-598, 1-618, 2-3, 2,
-53, 3-2, 3-3, 3-18, 3-19, 3-4
1, 3-83, 4-2, 4-3, 5-2, 5-3, 6-
2 or 6-3.

Further preferred compounds are 1-3, 1-
13, 1-15, 1-22, 1-28, 1-31, 1-
38, 1-44, 1-51, 1-53, 1-59, 1-
60, 1-62, 1-68, 1-69, 1-75, 1-
76, 1-85, 1-97, 1-98, 1-107, 1
-119, 1-126, 1-128, 1-142, 1-
148, 1-151, 1-160, 1-169, 1-1
70, 1-173, 1-176, 1-191, 1-19
3, 1-197, 1-200, 1-207, 1-22
4, 1-247, 1-269, 1-275, 1-27
7, 1-293, 1-294, 1-312, 1-32
8, 1-346, 1-365, 1-384, 1-40
5, 1-406, 1-414, 1-422, 1-44
1, 1-464, 1-473, 1-480, 1-48
1, 1-482, 1-490, 1-498, 1-50
2, 1-521, 1-537, 1-556, 1-57
2, 1-574, 1-580, 1-581, 1-58
3, 1-586, 1-594, 1-596, 1-59
8, 1-618, 2-3, 3-2, 3-18, 3-1
9, 3-41, 3-83 or 4-2.

Particularly preferred compounds include: Compound No. 1-3: 3- (2-aminoethoxy) -1,
2-benzisoxazole, Compound No. 1-15: 3- (2-aminoethoxy) -5
-Fluoro-1,2-benzisoxazole, Compound No. 1-22: 3- (2-aminoethoxy) -5
-Fluoro-4-methyl-1,2-benzisoxazole, Compound No. 1-31: 3- (2-aminoethylthio)-
5-fluoro-1,2-benzisoxazole, Compound No. 1-53: 3- (2-aminoethoxy) -5
-Chloro-1,2-benzisoxazole, compound No. 1-59: 3- (2-aminoethoxy)-
5,7-dichloro-1,2-benzisoxazole, compound number 1-62: 3- (2-aminoethylthio)-
5-chloro-7-methyl-1,2-benzisoxazole, Compound No. 1-69: 3- (2-aminoethylthio)-
5-chloro-1,2-benzisoxazole, Compound No. 1-85: 3- (2-aminoethoxy) -6
-Chloro-1,2-benzisoxazole, compound number 1-97: 3- (2-aminoethoxy) -7
-Chloro-1,2-benzisoxazole, compound number 1-119: 3- (2-aminoethoxy)-
5-bromo-1,2-benzisoxazole, Compound No. 1-142: 3- (2-aminoethoxy)-
5-methyl-1,2-benzisoxazole, Compound No. 1-151: 3- (2-aminoethylthio)
-5-methyl-1,2-benzisoxazole, compound No. 1-160: 3- (2-aminoethoxy)-
6-methyl-1,2-benzisoxazole, compound number 1-169: 3- (2-aminoethoxy)-
7-methyl-1,2-benzisoxazole, compound number 1-193: 3- (2-aminoethoxy)-
5-methoxy-1,2-benzisoxazole, compound number 1-197: 3- (2-aminoethylthio)
-5-methoxy-1,2-benzisoxazole, compound number 1-224: 3- (2-aminoethoxy)-
5-difluoromethoxy-1,2-benzisoxazole, Compound No. 1-269: 3- (2-aminoethoxy)-
5-fluoro-4-methylthio-1,2-benzisoxazole, compound number 1-422: 3- (2-aminoethoxy)-
5-methoxycarbonyl-1,2-benzisoxazole, compound number 1-521: 3- (2-aminoethoxy)-
5-nitro-1,2-benzisoxazole, compound number 1-537: 3- (2-aminoethylthio)
-5-nitro-1,2-benzisoxazole, compound number 1-572: 3- (2-aminoethoxy)-
4-cyano-1,2-benzisoxazole; or compound number 3-2: 3- (2-aminoethoxy) pyrido [3,2-d] isoxazole.

The isoxazole derivatives having the general formula (II) [Formulas (Ia), (Ib), (Ic), (I)
d), (Ie), (IIa), (IIb), (II)
c), (IId) and (IIe)], suitable compounds include 1-3, 1-13, 1-15, 1-19,
1-22, 1-25, 1-28, 1-31, 1-38,
1-41, 1-44, 1-47, 1-48, 1-49,
1-50, 1-51, 1-53, 1-56, 1-59,
1-60, 1-62, 1-66, 1-68, 1-69,
1-72, 1-75, 1-76, 1-85, 1-96,
1-97, 1-98, 1-107, 1-119, 1-1
22, 1-125, 1-126, 1-128, 1-13
5, 1-142, 1-148, 1-151, 1-16
0, 1-168, 1-169, 1-170, 1-17
3, 1-176, 1-185, 1-186, 1-19
1, 1-193, 1-197, 1-198, 1-19
9, 1-200, 1-204, 1-207, 1-21
6, 1-217, 1-218, 1-219, 1-22
0, 1-221, 1-224, 1-231, 1-24
0, 1-241, 1-242, 1-243, 1-24
4, 1-247, 1-263, 1-264, 1-26
5, 1-266, 1-267, 1-268, 1-26
9, 1-272, 1-275, 1-277, 1-27
8, 1-281, 1-283, 1-284, 1-28
5, 1-286, 1-287, 1-291, 1-29
2, 1-293, 1-294, 1-310, 1-31
1, 1-312, 1-328, 1-346, 1-36
2, 1-363, 1-364, 1-365, 1-38
1, 1-384, 1-400, 1-401, 1-40
2, 1-403, 1-404, 1-405, 1-40
6, 1-414, 1-421, 1-422, 1-42
3, 1-429, 1-435, 1-438, 1-43
9, 1-444, 1-441, 1-442, 1-44
8, 1-457, 1-460, 1-461, 1-46
2, 1-463, 1-464, 1-465, 1-47
1, 1-473, 1-474, 1-480, 1-48
1, 1-482, 1-490, 1-497, 1-49
8, 1-499, 1-500, 1-501, 1-50
2, 1-518, 1-519, 1-520, 1-52
1, 1-528, 1-534, 1-537, 1-55
0, 1-553, 1-554, 1-555, 1-55
6, 1-572, 1-573, 1-574, 1-57
5, 1-576, 1-577, 1-578, 1-57
9, 1-580, 1-581, 1-582, 1-58
3, 1-586, 1-594, 1-596, 1-59
8, 1-618, 2-3, 2-53, 3-2, 3-3,
3-18, 3-19, 4-2, 4-3, 5-2, 5-
3, 6-2, 6-3, 9-1, 9-2, 9-5, 9-
6, 10-1, 10-2, 10-5, 10-6, 11-
1, 11-2, 11-5, 11-6, 12-1, 12-
2, 12-5, 12-6, 13-1, 13-2, 13-
5, 13-6, 14-1, 14-2, 14-5, 14-
6, 15-1, 15-2, 15-5, 15-6, 16-
1, 16-2, 16-5 or 16-6.

Further preferred compounds are 1-3, 1-
13, 1-15, 1-22, 1-28, 1-31, 1-
38, 1-44, 1-51, 1-53, 1-59, 1-
60, 1-62, 1-68, 1-69, 1-75, 1-
76, 1-85, 1-97, 1-98, 1-107, 1
-119, 1-126, 1-128, 1-142, 1-
148, 1-151, 1-160, 1-169, 1-1
70, 1-173, 1-176, 1-191, 1-19
3, 1-197, 1-200, 1-207, 1-22
4, 1-247, 1-269, 1-275, 1-27
7, 1-293, 1-294, 1-312, 1-32
8, 1-346, 1-365, 1-384, 1-40
5, 1-406, 1-414, 1-422, 1-44
1, 1-464, 1-473, 1-480, 1-48
1, 1-482, 1-490, 1-498, 1-50
2, 1-521, 1-537, 1-556, 1-57
2, 1-574, 1-580, 1-581, 1-58
3, 1-586, 1-594, 1-596, 1-59
8, 1-618, 2-3, 3-2, 3-18, 3-1
9, 3-41, 3-83 or 4-2.

Particularly preferred compounds include: Compound No. 1-3: 3- (2-aminoethoxy) -1,
2-benzisoxazole, Compound No. 1-15: 3- (2-aminoethoxy) -5
-Fluoro-1,2-benzisoxazole, Compound No. 1-22: 3- (2-aminoethoxy) -5
-Fluoro-4-methyl-1,2-benzisoxazole, Compound No. 1-31: 3- (2-aminoethylthio)-
5-fluoro-1,2-benzisoxazole, Compound No. 1-53: 3- (2-aminoethoxy) -5
-Chloro-1,2-benzisoxazole, compound No. 1-59: 3- (2-aminoethoxy)-
5,7-dichloro-1,2-benzisoxazole, compound number 1-62: 3- (2-aminoethylthio)-
5-chloro-7-methyl-1,2-benzisoxazole, Compound No. 1-69: 3- (2-aminoethylthio)-
5-chloro-1,2-benzisoxazole, Compound No. 1-85: 3- (2-aminoethoxy) -6
-Chloro-1,2-benzisoxazole, compound number 1-97: 3- (2-aminoethoxy) -7
-Chloro-1,2-benzisoxazole, compound number 1-119: 3- (2-aminoethoxy)-
5-bromo-1,2-benzisoxazole, Compound No. 1-142: 3- (2-aminoethoxy)-
5-methyl-1,2-benzisoxazole, Compound No. 1-151: 3- (2-aminoethylthio)
-5-methyl-1,2-benzisoxazole, compound No. 1-160: 3- (2-aminoethoxy)-
6-methyl-1,2-benzisoxazole, compound number 1-169: 3- (2-aminoethoxy)-
7-methyl-1,2-benzisoxazole, compound number 1-193: 3- (2-aminoethoxy)-
5-methoxy-1,2-benzisoxazole, compound number 1-197: 3- (2-aminoethylthio)
-5-methoxy-1,2-benzisoxazole, compound number 1-224: 3- (2-aminoethoxy)-
5-difluoromethoxy-1,2-benzisoxazole, Compound No. 1-269: 3- (2-aminoethoxy)-
5-fluoro-4-methylthio-1,2-benzisoxazole, compound number 1-422: 3- (2-aminoethoxy)-
5-methoxycarbonyl-1,2-benzisoxazole, compound number 1-521: 3- (2-aminoethoxy)-
5-nitro-1,2-benzisoxazole, compound number 1-537: 3- (2-aminoethylthio)
-5-nitro-1,2-benzisoxazole, compound number 1-572: 3- (2-aminoethoxy)-
4-cyano-1,2-benzisoxazole; or compound number 3-2: 3- (2-aminoethoxy) pyrido [3,2-d] isoxazole.

[0078]

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

[0079]

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[0080]

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[0081]

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[0082]

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[0083]

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[0084]

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[0085]

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[0086] In the above ^{formulas, R 1, R 2, m} , n, ring A and X have the same meanings as described above, R ¹ a is C ₁ -C
₆ alkyl group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆
Alkoxycarbonyl group, a carboxy group, a dithiocarboxy group or a (C ₁ -C ₆ alkylthio) thiocarbonyl group, R ¹ b represents a C ₁ -C ₆ alkyl group, R ³ represents an ester residue, R ³ a represents a C ₁ -C ₄ alkyl group, R ⁴ represents a protected amino group, Y represents a hydroxyl group or a leaving group, Z represents a halogen atom, and m ′ represents an integer of 1-2. .

[0087] C ₁ -C ₆ alkyl group or a C ₁ -C a R ¹ a
C ₁ -C ₆ alkyl moiety, such as ₆ alkylthio group have the same meanings as described above, R ¹ a is, for example, a methyl group,
Ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4- Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,
s-butylthio, t-butylthio _, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methyl Pentylthio group, 2-methylpentylthio group, 1-methylpentylthio group, 3,3-dimethylbutylthio group, 2,2
-Dimethylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 2-ethylbutylthio group, Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, carboxy group , be a dithiocarboxy group or (methylthio) thiocarbonyl group obtained, preferably, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkoxycarbonyl group, a carboxy group or a dithiocarboxy group And more preferably a methyl group, an ethyl group, Thio group, an ethylthio group or a carboxy group.

[0088] C ₁ -C ₆ alkyl group R ¹ b have the same meanings as described above, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an 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, 1,3-dimethylbutyl group, 2,3
-A dimethylbutyl group or a 2-ethylbutyl group,
Preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group.

The ester residue of R ³ is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a pentyl group or a hexyl group. ₁ -C ₆ alkyl group;
Or 2-fluoroethyl group, 2-chloroethyl group, 2-
Bromoethyl group, 2,2-dibromoethyl group, 2,2
2-trichloroethyl group, 3-fluoropropyl group, 4
-Chlorobutyl group, methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, n-butoxymethyl group, t-butoxymethyl group, 1-ethoxy Ethyl group, 1-methyl-1-methoxyethyl group, 1- (isopropoxy) ethyl group, 3-methoxypropyl 4-methoxybutyl group, fluoromethoxymethyl group, 2,2
2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, 3-fluoropropoxymethyl group,
4-chlorobutoxyethyl group, dibromomethoxyethyl group, 2-chloroethoxypropyl group, fluoromethoxybutyl group, 2-methoxyethoxymethyl group, ethoxymethoxyethyl group, methoxyethoxypropyl group, methoxyethoxybutyl group, benzyl group, phenethyl Group, 3-
Phenylpropyl group, 4-phenylbutyl group, α-naphthylmethyl group, β-naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group, 9-anthrylmethyl group, 4-methylbenzyl group 2,4,6-trimethylbenzyl group, 3,4,5
-Trimethylbenzyl group, 4-methoxybenzyl group, 4
-Methoxyphenyldiphenylmethyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, 4-chlorobenzyl group, 4-bromobenzyl group, 4-cyanobenzyl group,
- cyanobenzyl diphenylmethyl group, bis (2-nitrophenyl) such as a methyl group, or a piperonyl group, a substituted C ₁ -C ₄ alkyl group (the substituent is a halogen atom; C ₁
-C ₄ alkoxy group; C ₁ -C ₄ alkoxy group substituted with halogen or C ₁ -C ₄ alkoxy; C ₆ -C
₁₄ aryl groups; or C ₁ -C ₄ alkyl, C ₁ -C ₄
C ₆ -C substituted with 1 to 3 substituents selected from the group consisting of alkoxy, nitro, halogen and cyano
₁₄ aryl group), preferably a C ₁ -C ₄ alkyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2,2-trichloroethyl group, a methoxymethyl group Ethoxymethyl group, fluoromethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, benzyl group, phenethyl group, 4-methylbenzyl group, 2,4,
6-trimethylbenzyl group, 4-methoxybenzyl group,
4-nitrobenzyl group, 4-chlorobenzyl group or 4-
A cyanobenzyl group, more preferably a methyl group, an ethyl group, a 2,2,2-trichloroethyl group, a methoxymethyl group, an ethoxymethyl group, a fluoromethoxymethyl group,
2,2,2-trichloroethoxymethyl group, benzyl group, phenethyl group, 4-methylbenzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, 4-chlorobenzyl group or 4-cyanobenzyl group, particularly Preferably, it is a methyl group or an ethyl group.

[0090] C ₁ -C ₄ alkyl group R ³ a, for example,
It may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group or a t-butyl group, preferably a methyl group or an ethyl group, and more preferably a methyl group. .

The protecting group for the amino group protected by R ⁴ can be generally used without any particular limitation as long as it is a group used as a protecting group for an amino group. Examples thereof include a formyl group, an acetyl group and a propionyl group. C _1- such as a group, butyryl group, isobutyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group
C ₆ alkanoyl group; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluoropropionyl group, 4,4-dichlorobutyryl group, methoxyacetyl group, butoxyacetyl group,
A C ₁ -C ₄ alkanoyl group substituted by halogen or C ₁ -C ₄ alkoxy, such as an ethoxypropionyl group or a propoxybutyryl group; Unsaturated C ₁ -C ₄ alkanoyl group; 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, 4-nitrobenzoyl, 2
Halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ such as -nitrobenzoyl or 6-nitro-α-naphthoyl
₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₆
C _6- which may be substituted by C ₁₀ aryl or nitro;
C ₁₀ Ari - nyl group; a methoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s- butoxycarbonyl, t-
Butoxycarbonyl group, chloromethoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group,
C ₁ -C ₄ alkoxy, which may be substituted with halogen such as 2-trimethylsilylethoxycarbonyl group, 4-tripropylsilylbutoxycarbonyl group or t-butyldimethylsilylpropoxycarbonyl group or tri-C ₁ -C ₄ alkylsilyl. carbonyl group; aryldi such as phthaloyl group; vinyl oxycarbonyl group, C ₂ -C ₅ alkenyloxycarbonyl group such as allyloxycarbonyl group, 1,3-butadienyl oxycarbonyl group or a 2-pentenyl oxycarbonyl group Carbonyl group; benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, α-naphthylmethyl group,
β-naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group or 9
-An aralkyl group such as anthrylmethyl group; or benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthrylmethyloxy carbonyl group, p- methoxy, such as a benzyloxycarbonyl group or a p- nitrobenzyloxycarbonyl group, is substituted with methoxy or nitro be a even better C ₇ -C ₁₅ aralkyloxycarbonyl group, preferably, C ₁ -C ₄ alkanoyl group; a trifluoroacetyl group; methoxyacetyl group; a benzoyl group;
α-naphthoyl group; β-naphthoyl group; anisoyl group;
Nitrobenzoyl group; C ₁ -C ₄ alkoxycarbonyl group; a methoxycarbonyl group; ethoxycarbonyl group; t
-Butoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group; triethylsilylmethoxycarbonyl group; 2-trimethylsilylethoxycarbonyl group; vinyloxycarbonyl group; allyloxycarbonyl group;
A phthaloyl group; a benzyl group; a benzyloxycarbonyl group; or a nitrobenzyloxycarbonyl group, more preferably a formyl group, an acetyl group, a 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-
Butoxycarbonyl group.

The leaving group for 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 a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; A C ₁ -C ₄ alkanesulfonyloxy group such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group or a butanesulfonyloxy group; a trifluoromethanesulfonyloxy group, 2,
2,2-trichloroethanesulfonyloxy group, 3,
A halogeno C ₁ -C ₄ alkanesulfonyloxy group, such as a 3,3, -tribromopropanesulfonyloxy group or a 4,4,4-trifluorobutanesulfonyloxy group; or a benzenesulfonyloxy group, α-naphthyl A C _1- such as a sulfonyloxy group, a β-naphthylsulfonyloxy group, a p-toluenesulfonyloxy group, a 4-t-butylbenzenesulfonyloxy group, a mesitylenesulfonyloxy group or a 6-ethyl-α-naphthylsulfonyloxy group; It may be a C ₆ -C ₁₀ arylsulfonyloxy group optionally having 1 to 3 C ₄ alkyl, preferably a chlorine atom, a bromine atom and an iodine atom; a methanesulfonyloxy group, an ethanesulfonyloxy group and a trifluoro group. Romethanesulfonyloxy group, 2,2,2-trichloroethanesulfonyloxy group A benzenesulfonyloxy group, a toluenesulfonyloxy group or a mesitylenesulfonyloxy group, more preferably a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p- It is a toluenesulfonyloxy group or a mesitylenesulfonyloxy group.

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

The compound (XIII) or compound (XIX) as the starting material compound of the present invention is a known compound or can be produced according to a known method [for example, Abstract, Volume 49,
Pp. 11594 (1955 years) [Chem.Abstr., 49 .11594 ( 19
55).], Tetrahedron, 38, 1457, (1
982) [Tetrahedron, 38 , 1457 (1982)], Japanese Unexamined Patent Publication No. 3-294267, Synthetic Communications, Vol. 9, p. 731 (1979) [Synt
h. Commun., 9 , 731 (1979)]], Journal of Organic Chemistry, 44, 3292 (197).
9) [J. Org. Chem., 44 , 3292 (1979)], Chemische Berichte, Vol. 100, p. 954 (1967) [Chem.
r., 100 , 954 (1967).] etc.].

The compound having the general formula (XVII) is a known compound or can be prepared according to a known method [for example, Synthesis, page 366 (1)
990) [Synthesis, 366 (1990)], Journal of Medicinal Chemistry, 34, 1258 (1991) [J. Med. Chem., 34 , 1258 (1991)]. Further, among the compounds having the general formula (XV), the compound in which Ring A is a pyridyl ring is a known compound or can be produced according to a known method [for example, Journal of・ Medicinal Chemistry, No. 32
Volume, 2116 (1989) [J. Med. Chem., 32 , 2116 (1
989).], Journal of the Chemical Society Section, C, p. 172 (1968) [J. Che
m. Soc. (C), 172 (1968).] etc.].

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

Step A1 is a step of producing a compound having the general formula (XIV) by reacting a compound having the general formula (XIII) with hydroxylamine in an inert solvent in the presence of a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, propanol,
Alcohols such as isopropanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxides such as dimethylsulfoxide or sulfolane, water or It can be a mixed solvent of the above organic solvent and water, preferably ethers, alcohols, amides, sulfoxides or a mixed solvent of these organic solvents and water, more preferably,
Alcohols (particularly methanol or ethanol) or hydrous alcohols (particularly hydrous methanol or hydrous ethanol).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate 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 tert-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Mercaptan alkali metals; 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-
Diazabicyclo [5.4.0] undec-7-ene (D
Organic amines such as BU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithiumalkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates And alkali metal hydroxides and alkali metal alkoxides, more preferably alkali metal hydroxides (particularly sodium hydroxide or potassium hydroxide).

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

The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes 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, after completion of the reaction, the solvent is distilled off, water is added to the obtained residue, the aqueous layer is acidified, and the precipitate is collected by filtration. Solvent (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 or the like, and the solvent is distilled off to obtain the desired compound. The resulting target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, chromatography or salting with an acid.

The step A2 is basically performed in Chemische Berichte, Vol. 100, p. 954 (1967) [Chem.
er., 100 , 954 (1967)]] and a compound represented by the general formula (X
The compound having (IV) is reacted with (1) thionyl chloride, phosgene or its equivalent (such as diphosgene) (preferably thionyl chloride) in an inert solvent, and then (2) reacted with a base in an inert solvent. By doing so, the general formula (XV)
This is a step of producing a compound having

The solvent used in the steps (1) and (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Aliphatic hydrocarbons such as ethers; aromatic hydrocarbons such as benzene, toluene or xylene; 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; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons (particularly methylene chloride, chloro Lum, carbon tetrachloride or dichloroethane), an ether (particularly diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane), is more preferably ethers (particularly diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane).

The base used in the step (2) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; or an alkali metal carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Carbonates; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium Alkali metal alkoxides such as ethoxide, potassium t-butoxide or lithium methoxide; mercaptan alkali metals such as sodium methyl mercaptan or sodium ethyl mercaptan; 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 (DABC
O) or organic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium and butyllithium; or lithium diisopropylamide, lithium dicyclohexylamide And preferably organic amines, more preferably triethylamine, tributylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] nona- 5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU)), particularly preferably triethylamine.

In the reactions of the first and second steps, the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C. .

In the reactions of the first and second steps, the reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, preferably 1 hour.
5 minutes 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 solvent is distilled off, water is poured into the reaction solution, the aqueous layer is acidified, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, After washing with water, drying over anhydrous magnesium sulfate or the like, and the solvent is distilled off, the target compound is obtained. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the step A3, the compound (XV) is reacted with a halogenating agent in an inert solvent or in the absence of a solvent in the presence or absence of a base (preferably in the presence of a base) to give a compound. This is a step of producing (XVI).

The halogenating agent can be, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyiodide or phosphorus pentachloride, preferably phosphorus oxychloride, phosphorus pentachloride or a mixture thereof.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Ethers such as diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons (particularly methylene chloride) or ethers (particularly tetrahydrofuran). It is or dioxane).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride Alkali metal hydrides such as sodium hydroxide 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, 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) It is.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 10 ° C.
C. to 100.degree. The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it 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 according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (eg, benzene, ether,
Ethyl acetate) is added, and the mixture is extracted. The organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step A4 is a step of reacting compound (XVI) with a compound having the general formula (XVII) in an inert solvent in the presence of a base to produce compound (XVIII).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 sulfoxides, such as dimethylsulfoxide or sulfolane, preferably
Ethers, amides or sulfoxides, more preferably ethers (particularly diethyl ether, tetrahydrofuran or dioxane) or amides (particularly dimethylformamide). The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated 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-
Methyl morpholine, 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-diazabicyclo [5.4.0] undec-7-ene (DB
Organic amines such as U); alkyl lithiums such as methyl lithium, ethyl lithium or butyl lithium; lithium alkyl amides 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).

Incidentally, a crown ether such as dibenzo-18-crown-6 may be added in order to carry out the reaction effectively.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 150 ° C, preferably from 0 ° C to 80 ° C. The reaction time depends on the starting compounds, reagents,
Although it varies depending on the reaction temperature, it 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 according to a conventional method. For example, the reaction solution is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. ), Followed by extraction 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step A5 is a step of preparing compound (I) by removing the protecting group for the amino group.

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

[0120] amino-protecting group is, C ₁ -C ₆ alkanoyl group (preferably formyl or acetyl); C ₆ -
A C ₁₀ arylcarbonyl group (preferably a benzoyl group);
It may be substituted by halogen or tri C ₁ -C ₄ alkylsilyl, C ₁ -C ₄ alkoxycarbonyl group (preferably a methoxycarbonyl group, an ethoxycarbonyl group, t-
Butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group or 2,2-dibromo-t-butoxycarbonyl group);
A C ₂ -C ₅ alkenyloxycarbonyl group (preferably a vinyloxycarbonyl group); or a C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted by methoxy or nitro (preferably a benzyloxycarbonyl group, (1 -Phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group), when the acid is used in an inert solvent or an aqueous solvent. It can be removed by processing. In this case, 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.
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. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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; The solvent may be water or a mixed solvent of water and the above-mentioned solvent, preferably, a halogenated hydrocarbon, ether, alcohol, fatty acid or water and the above-mentioned solvent. A mixed solvent of, even more preferably halogenated hydrocarbons (particularly methylene chloride), ethers (particularly tetrahydrofuran or dioxane),
Fatty acids (especially acetic acid) or water or a mixed solvent of water and the above solvent.

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

The reaction time varies depending on the starting compound, solvent or 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 according to 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 water-immiscible solvent (eg, benzene, ether, acetic acid) Ethyl and the like are 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an alkanoyl, arylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aryldicarbonyl, aralkyl or aralkyloxycarbonyl, it may be in an inert solvent or an aqueous solvent. By treating it with a base.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate 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 tert-butoxide or lithium methoxide; sodium methyl mercaptan or sodium ethyl mercaptan Alkali metal salts, preferably alkali metal carbonates (particularly sodium or potassium carbonate), alkali metal hydroxides (particularly sodium hydroxide or potassium hydroxide), alkali metal alkoxides (particularly sodium methoxide). , Sodium ethoxide or potassium tert-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. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 or butanol; dimethyl Amides such as acetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons, ethers, and alcohols Or a mixed solvent of water and the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol Le), or water and a mixed solvent of the above solvents.

The reaction temperature varies depending on the starting compound, solvent or base used, but is usually from -10 ° C to 150 ° C.
And preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, solvent or 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 according to 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 aqueous layer is made alkaline, and the precipitate is collected by filtration, or a water-immiscible solvent (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 like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

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

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

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; Ethers such as diethyl ether, tetrahydrofuran or dioxane; nitriles such as acetonitrile, preferably halogenated hydrocarbons (particularly methylene chloride, chloroform) or nitriles (particularly acetonitrile). .

The reaction temperature varies depending on the starting compound, reagent or solvent, but is usually from -20 ° C to 100 ° C.
Preferably it is 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, reagent, solvent, 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, 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 or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When the amino-protecting group is an allyloxycarbonyl group, a solvent similar to that used in the removal method by catalytic reduction reaction in the case of an aralkyl group or the like using palladium and triphenylphosphine or nickel tetracarbonyl. , Reaction temperature, reaction time and the like.

When the protecting group for the amino group is an aralkyl group or C
If it is ₇ -C ₁₁ aralkyloxycarbonyl group is usually performed in an inert solvent, contacting with a reducing agent (preferably,
The protecting group can be suitably removed by a method of removing the protective group by catalytic reduction in the presence of a catalyst or a method of removing the protective group using an oxidizing agent. In the case of the reaction for removing the protecting group by catalytic reduction, the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, aliphatic hydrocarbons such as hexane or cyclohexane; toluene, benzene Or an aromatic hydrocarbon such as xylene; an ether such as diethyl ether, tetrahydrofuran or dioxane; an ester 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, and ethers. , Esters, alcohols, fatty acids, or a mixed solvent of these organic solvents with water, more preferably alcohols (particularly methanol or alcohol). 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.
It can be palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferably palladium-carbon or Raney-nickel.

Although the pressure of hydrogen is not particularly limited, it is usually 1
To 10 atm, preferably 1 atm.

The reaction temperature varies depending on the starting compound, the solvent, the reducing agent used and the like.
And preferably from 10 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature and the like, but is usually 15 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, after removing the catalyst by filtration, the solvent is distilled off, water is poured into the reaction solution, and the aqueous layer is made alkaline. ), And the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, 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 the reaction. Examples thereof include ketones such as acetone; and halogens such as methylene chloride, chloroform and 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 an organic solvent thereof and water And a mixed solvent.

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

The reaction temperature varies depending on the starting compound, the solvent, the oxidizing agent used and the like, but is usually from 0 ° C. to 150 ° C.
And preferably from 10 ° C to 50 ° C.

The reaction time varies depending on the compound, solvent or oxidizing agent used, 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 according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, water is poured into the reaction solution, and the aqueous layer is made alkaline. And the like, and the mixture is extracted. The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

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

In the step B1, the compound (XV) and the compound of the formula (X)
VIIa) is reacted with a compound (XVI)
IIa).

When Y is a hydroxyl group, basically, Bullin Chemical Society Japan, Vol.
2380 (1967) [Bull. Chem. Soc. Jap., 40 , 23]
80 (1967).] In the presence of a phosphine and an azo compound in an inert solvent according to the Mitsunobu reaction described in
V) with the corresponding compound (XVIIa) by a dehydration condensation reaction.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; , Toluene or xylene; aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons,
Aromatic hydrocarbons or ethers, more preferably ethers (particularly diethyl ether or tetrahydrofuran).

The phosphines used include, for example, tri-C ₁ -C ₆ such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine.
Alkyl phosphines; 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 -6
Tri-C ₆ -C ₁₀ arylphosphine which may have a C ₁ -C ₄ alkyl as a substituent, such as -ethyl-2-naphthylphosphine, and preferably a tri-C ₁ -C ₆ alkylphosphine ( in particular trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or a tri-C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, tri indenyl phosphine or trinaphthylphosphine), and more preferably, tri C ₆ —C ₁₀ arylphosphine (particularly triphenylphosphine).

The azo compound used can be, for example, di-C ₁ -C ₄ alkyl azodicarboxylate such as dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate. Is dimethyl azodicarboxylate or diethyl azodicarboxylate.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 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 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 any insolubles are present, they are removed by filtration and the solvent is distilled off.
Ether, ethyl acetate, etc.) for extraction, washing with water,
After drying over anhydrous magnesium sulfate or the like, the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When Y is a leaving group, compound (XV) and compound (XVII) corresponding to compound (XV) in an inert solvent in the presence of a base
Compound (XVIIIa) can be obtained by reacting a).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 sulfoxides, such as dimethylsulfoxide or sulfolane, preferably
Amides or sulfoxides, more preferably amides (particularly dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate 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; sodium methyl mercaptan or sodium ethyl mercaptan Alkali metals such as mercaptans; 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); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithium such as lithium diisopropylamide or lithium dicyclohexylamide. Alkylamides, preferably alkali metal carbonates, alkali metal hydrides or alkali metal hydroxides,
More preferred are alkali metal hydrides (particularly sodium hydride).

Incidentally, a crown ether such as dibenzo-18-crown-6 may be added in order to carry out the reaction effectively.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 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 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 according to a conventional method. For example, the reaction solution is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate) And the like, and the mixture is 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The method C is a method for separately producing a compound (XV) which is an intermediate of the method A or a starting compound of the method B.

Step C1 is carried out in an inert solvent using a compound of the formula (X)
This is a step of producing a compound having the general formula (XX) by reacting a compound having the formula (IX) with a diazo C ₁ -C ₄ alkane.

The diazo C ₁ -C ₄ alkane can be, for example, diazomethane, diazoethane, diazopropane or diazobutane, preferably diazomethane.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 a mixture of the above solvents It may be a solvent, preferably a halogenated hydrocarbon, an ether, an ester or a mixed solvent of the above solvents, more preferably an ether (particularly diethyl ether), an ester (particularly ethyl acetate) or the above solvent Is a mixed solvent.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 10 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 minutes.
Time, preferably 15 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, after completion of the reaction, the target compound can be obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C2 is a step of producing a compound having the general formula (XXI) by reacting the compound (XX) with hydroxylamine in an inert solvent in the presence of a base.

The solvents and bases used are the same as the solvents and bases mentioned in Step A1.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 10 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 minutes.
Time, preferably 30 minutes 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, after completion of the reaction, the solvent is distilled off,
Water is added to the obtained residue, the aqueous layer is acidified, and the precipitate is collected by filtration, or after the reaction is completed, water is added to the reaction solution to make the aqueous layer acidic, and a water-immiscible solvent (eg, benzene,
The target compound is extracted by adding ether, ethyl acetate, etc.), and the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In step C3, compound (XXI) is reacted with a base in an inert solvent to give compound (XI)
V).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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; sulfoxides such as dimethylsulfoxide or sulfolane; or water, preferably amides, sulfoxides or water, more preferably water. It is.

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride Alkali metal hydrides such as sodium hydroxide 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, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.
4.0] organic amines such as undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithiumalkylamides such as lithium diisopropylamide or lithium dicyclohexylamide. Obtained and preferred are alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides, more preferably alkali metal hydroxides (particularly sodium hydroxide and potassium hydroxide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 10 ° C.
C. to 100.degree. 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 15 minutes 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, after the reaction is completed, the reaction solution is made acidic and the precipitate is collected by filtration. Then, the target compound is extracted, 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. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

[0173] Process D is a method of substituents of the ring A At a intermediate of Method A (XVIII) is prepared compound containing R ¹ a a (XXIII) separately.

In step D1, compound (XXII) is added to halogeno C ₁ -C ₆ alkane, carbon dioxide, carbon disulfide, diC ₁ -C ₆ alkyl disulfide, diC ₁ -C ₆ alkyl carbonates, S-
Reaction of (trifluoromethyl) dibenzothiopheneum trifluoromethanesulfonate or S- (trifluoromethyl) -3,7-dinitrodibenzothiopheneum trifluoromethanesulfonate (preferably halogeno C ₁ -C ₆ alkyl or carbonate Gas) and compound (XXIII).

The halogeno C ₁ -C ₆ alkane can be, for example, methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl iodide, propyl bromide, butyl iodide, pentyl iodide or hexyl iodide, Preferably it is methyl bromide or methyl iodide, more preferably methyl iodide.

The di C ₁ -C ₆ alkyl disulfide can be, for example, dimethyl disulfide, diethyl disulfide, dipropyl disulfide, dibutyl disulfide, dipentyl disulfide or dihexyl disulfide, preferably dimethyl disulfide or diethyl disulfide.

The di C ₁ -C ₆ alkyl carbonate is, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate,
It may be dibutyl carbonate, dis-secondary butyl carbonate, di-tert-butyl carbonate, 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. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 hexamethylphosphorous triamide; or sulfoxides such as dimethylsulfoxide or sulfolane;
Ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).

The base used is, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkyl lithium such as methyl lithium, ethyl lithium, butyl lithium or secondary butyl lithium; It may be a lithium alkyl amide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably an alkyl lithium (particularly butyl lithium ) Or lithium alkylamides (particularly lithium diisopropylamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -100 ° C to 30 ° C, preferably from -70 ° C to 0 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes 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, after the completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound is obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. On the other hand, after completion of the reaction, the target compound of this step can be used in the next step without isolation and purification.

Method E is a compound (XX) in which the substituent of ring A contains a carbamoyl group in the intermediate (XVIII) of method A.
VII) and the following starting compound (XXVIII) of Method F.

Step E1 is a step of reacting compound (XXIV) with a compound having the general formula (XXV) in an inert solvent in the presence of a base to produce compound (XXVI). In addition, the compound in which X is a sulfur atom in the compound (XXVI) is a starting compound (XXVIII) of the method F.

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. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 hexamethylphosphorous triamide; or sulfoxides such as dimethylsulfoxide or sulfolane;
Amides or sulfoxides, more preferably amides (particularly dimethylformamide).

The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride Alkali metal hydrides such as sodium hydroxide 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, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.
4.0] organic amines such as undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithiumalkylamides such as lithium diisopropylamide or lithium dicyclohexylamide. Preferably, they are alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides, more preferably alkali metal carbonates (particularly sodium carbonate, potassium carbonate or lithium carbonate).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 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 30 minutes to 30 hours, preferably 1 hour to 20 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 the completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound is obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the step E2, the compound (X) is dissolved in an inert solvent.
XVI) is reacted with ammonia gas or concentrated aqueous ammonia to produce compound (XXVII).
In the compound (XXVII), the compound in which X is a sulfur atom is the compound in which the substituent of the ring A contains a carbamoyl group in the compound (XVIII).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and 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 hexamethylphosphorous triamide; or dimethylsulfoxide Or sulfoxides such as sulfolane, preferably ethers or alcohols, and more preferably alcohols (particularly Methanol or ethanol).

The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 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 1 hour to 30 hours, preferably 3 hours to 20 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 the completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound is obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the step E3, the compound (X) is dissolved in an inert solvent.
XIV) is condensed with ammonia to give compound (XXVI)
This is a step of separately producing I), and is carried out by a conventional method in peptide synthesis, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method (preferably a mixed acid anhydride method).

In the above method, in the azide method, the compound (XXIV) and hydrazine are treated with an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide in an inert solvent. Formamide), -10 ° C
The reaction is carried out by reacting an amino acid hydrazide produced by reacting at a temperature of from 100 ° C. to 100 ° C. (preferably from 0 ° C. to 50 ° C.) with a nitrite compound, converting it to an azide compound, and then treating it 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 suitably carried out in an inert solvent, the solvents used being amides such as, for example, formamide, dimethylformamide, dimethylacetamide or trimethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; Alternatively, it may be a pyrrolidone such as N-methylpyrrolidone, preferably an amide (particularly dimethylformamide). Also, the two steps of the process (azidation and reaction with ammonia)
Usually, it is performed in one reaction solution. The reaction temperature varies depending on the starting compounds, reagents, and the like. Usually, the azidation step is from -70 ° C to 50 ° C (preferably from -50 ° C to 0 ° C), and the reaction with ammonia is from -70 ° C to The temperature is 50 ° C (preferably -10 ° C to 10 ° C). The time required for the reaction varies depending on the starting compound, reagent, and reaction temperature.
Usually, the azidation step takes 5 minutes to 3 hours (preferably 10 minutes).
Minutes to 1 hour), and the reaction with ammonia is 5 hours to (preferably 10 hours to 5 days). 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 the completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer
The target compound is obtained by drying over anhydrous magnesium sulfate or the like and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The active ester method is carried out by reacting compound (XXIV) with an active esterifying agent in an inert solvent to produce an active ester, and then reacting with ammonia in the inert solvent. 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.Examples include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Halogenated hydrocarbons such as, for example; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; Can be nitriles such as acetonitrile, preferably ethers (especially tetrahydrofuran) or amides (especially dimethylformamide). The active esterifying agent used is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3.
N-hydroxy compounds such as dicarboximide or disulfide compounds such as dipyridyl disulfide, the active esterification reaction being suitable in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. Done in The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -70 ° C to 15 ° C in the active esterification reaction.
0 ° C. (preferably from −10 ° C. to 100 ° C.), and from −20 ° C. to 1 ° C. in the reaction of the active ester compound with ammonia.
00 ° C. (preferably 0 ° C. to 50 ° C.). The time required for the reaction varies depending on the starting compounds, the reagents and the reaction temperature, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours) for both reactions. 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 completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the mixed acid anhydride method, the compound (XXIV) is reacted with a mixed acid anhydride in the presence of a base in an inert solvent to produce a mixed acid anhydride. The reaction is carried out by reacting the substance with ammonia.
The solvent used in the reaction for producing the mixed acid anhydride is as follows:
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting materials to some extent. 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; or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably ethers (especially Tetrahydrofuran). Mixed acid anhydride agents include, for example, C ₁ -C ₄ alkyl halides such as ethyl chlorocarbonate or isobutyl chlorocarbonate, C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride or diethyl cyanophosphoric acid or diphenyl. C such as cyanophosphoric acid
It is a ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ aryl cyano phosphate, preferably a carbonate C ₁ -C ₄ alkyl halide (especially chloroformate isobutyl). The base used is, for example, an alkali metal carbonate 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-diazabicyclo [5.4.0] undec-7
Organic amines such as -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 from -50 ° C to 1 ° C.
00 ° C (preferably -10 ° C to 50 ° C). The reaction time in the reaction for producing the mixed acid anhydride varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours). Solvents used in the reaction of the mixed acid anhydride and ammonia include:
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting materials to some extent. Amides, such as dimethylacetamide or hexamethylphosphoric triamide, preferably ethers, especially tetrahydrofuran. The reaction temperature in the reaction between the mixed acid anhydride and ammonia varies depending on the starting compounds, reagents and the like, but is usually -30 ° C to 100 ° C (preferably 0 ° C to 80 ° C). The reaction time in the reaction between 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 step 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 from which the solvent is distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.)
To extract the target compound. The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The condensation method is carried out in an inert solvent in the presence of a condensing agent.
The reaction is carried out by directly reacting compound (XXIV) with ammonia in the presence of a condensing agent. The condensing agent used can be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide. This reaction can be carried out under the same conditions as in the above-mentioned reaction for producing an active ester. 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 the completion of the reaction, the solvent is distilled off, or water is poured into the residue obtained by distilling the solvent, and a water-immiscible solvent (for example, benzene,
The target compound is extracted by adding ether, ethyl acetate, etc.), and the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method F is a method for separately producing a compound (XXIX) in which the substituent of ring A contains a trifluoromethyl group in the intermediate (XVIII) of method A.

The F1 step is carried out in Chemistry Letters, 8
27 (1992) [Chemistry Letters, 827 (199
2).] The compound (XX) in an inert solvent according to the method described in
VIII) is reacted with tetrabutylammonium dihydrogen trifluoride (TBA ⁺ H ₂ F ₃ ⁻ ) and 1,3-dibromo-5,5-dimethylhydantoin (DBH) to produce compound (XXIX). . The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Hydrogens; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably halogenated hydrocarbons (particularly methylene chloride). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -30 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 10 minutes to 5 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, water is poured into the reaction solution, a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added and extracted, the organic layer is washed with water, dried over anhydrous magnesium sulfate, etc. Is distilled off to obtain the desired compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the method G, the compound (XXXI) in which the substituent of the ring A contains a cyano group in the intermediate (XVIII) of the method A
Is manufactured separately.

In the step G1, the compound (X) is placed in an inert solvent.
XX) is reacted with a dehydrating agent to produce compound (XXXI). The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. 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 methyl acetate or ethyl acetate; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexame Amides such as triphosphorous triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably amides (particularly dimethyl Formamide). The dehydrating agent used is, for example, phosphorus oxychloride, trifluoroacetic anhydride, methanesulfonyl chloride,
Paratoluenesulfonyl chloride or phosphorus pentoxide,
Preferably it is phosphorus oxychloride. The reaction temperature is the starting compound,
Depends on reagents, etc., usually -30 to 100 ° C
And preferably from -10 ° C to 30 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 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, distill off the solvent,
Water is poured into the reaction mixture, and a water-immiscible solvent (eg, 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. Is obtained. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The compound (II) which is an active ingredient of the monoamine oxidase inhibitor is known, or the compound (XVI) is represented by the general formula (XVIIb) HX- (CH ₂ ) _n -R ⁴ a (XVIIb ) (wherein, X represents the same meanings as defined above, R ⁴ a is, in addition to an amino group and a mono--C ₁ -C ₄ alkylamino group is protected, the same significance as R ² a. ) Is reacted in the same manner as in Step A4, and if necessary, the amino- or alkylamino-protecting group is removed in the same manner as in Step A5. Further compounds At a (II), compound X is an oxygen atom, the compound (XVI) and the general formula _{(XVIIc) Y- (CH 2)} n -R 4 a (XVIIc) ( wherein, R ⁴ a and Y is as defined above.)
Is reacted in the same manner as in the step B1, and if necessary, a protecting group for an amino group or an alkylamino group is added to the compound A.
It is also manufactured by removing in the same manner as in the five steps.

The isoxazole derivatives (I) and (II) of the present invention have excellent B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity (especially, they have strong inhibitory activity against B-type monoamine oxidase). Since it has low toxicity, it is useful as a therapeutic or preventive agent for neurological diseases such as Parkinson's disease, depression, and Alzheimer's disease (particularly Parkinson's disease).

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

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxy Cellulose derivatives such as methylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; A salt derivative; a carbonate derivative such as calcium carbonate; a sulfate derivative such as calcium sulfate; a binder (for example, the above-mentioned excipient); Gelatin; polyvinylpyrrolidone;
Disintegrants (eg, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, Talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; luxes such as veegum, gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium benzoate; Carboxylic acid sodium salt; sulfuric acid salt such as sodium sulfate; leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as silicic anhydride and silicic acid hydrate; Starch derivatives etc.), stable (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, sour agents, flavors, etc.), diluents, solvents for injections (eg, water, ethanol, glycerin, etc.). It is manufactured by a well-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 mg per day).
mg), in the case of intravenous administration, the lower limit is 0.1 mg (preferably 1 mg) per day, the upper limit is 500 mg
(Preferably 300 mg) per adult per day
It is desirable to administer from 6 to 6 times depending on the symptoms.

The present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples below, but the scope of the present invention is not limited to these.

[0203]

【Example】

Example 1 3- (2-aminoethoxy) -5-chloro-1,2-benzisoxazole hydrochloride (a) 5-chlorosalicylic acid ethyl ester 5-chlorosalicylic acid (500 g) was added to ethanol (2
L) and concentrated sulfuric acid (40 m
l) was added and the mixture was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed with a 10% saline solution and a 4% aqueous sodium hydrogen carbonate solution, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (514 g, yield: 88%) as a pale yellow oily substance. IR spectrum (KBr) ν _max cm ^-1 : 168
0,1475; NMR spectrum (DMSO-d ₆ ) δ ppm:
1.42 (3H, t, J = 7.3 Hz), 4.43 (2
H, q, J = 7.3 Hz), 6.93 (1H, d, J =
7.3 Hz), 7.35 (1H, dd, J = 7.3H)
z, J = 2.5 Hz), 7.82 (1H, d, J = 2.
5 Hz), 11.80 (1H, s).

(B) 5-chlorosalicylcarbohydroxamic acid Hydroxylamine hydrochloride (197 g) was added to water (400 m
l), and cooled to 5 ° C under potassium hydroxide (54
A 5 g) methanol solution (1.5 L) was added, and a methanol solution (400 ml) of 5-chlorosalicylic acid ethyl ester (500 g) was added dropwise while stirring at the same temperature. After stirring at 5 to 10 ° C for 30 minutes, the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ice water (6 L). (438 g, 93%) were obtained as colorless crystals. Melting point: 216-220 ° C; IR spectrum (KBr) ν _max cm ^-1 : 312
7, 1618, 1577, 1523, 1492, 141
3; NMR spectrum (DMSO-d ₆ ) δ ppm:
6.96 (1H, d, J = 7.3 Hz), 7.43 (1
H, dd, J = 7.3 Hz, J = 2.5 Hz), 9.3
1-9.52 (1H, brs), 10.88-11.0
3 (1H, brs), 11.66-11.87 (1H,
brs).

(C) 5-chloro-3-hydroxy-
1,2-benzisoxazole 5-chlorosalicylcarbohydroxamic acid (216 g)
Was dissolved in tetrahydrofuran (600 ml), and 10
Under stirring at ２０20 ° C., thionyl chloride (100 ml) was added dropwise, followed by stirring at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in dioxane (600 ml).
After cooling to ５5 ° C., triethylamine (383 ml)
Was added dropwise and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the obtained residue was added to ice water (3 L), the pH was adjusted to 2 using concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate. Thus, the target compound (172 g, 88%) was obtained as colorless needles. Melting point: 219-222 ° C; IR spectrum (KBr) ν _max cm ^-1 : 3400
-2000,1613,1560,1516; NMR Spectrum _{(DMSO-d 6) δppm:} 7.
43-7.72 (2H, m), 7.82 (1H, d, J
= 2.5 Hz), 10.78-11.02 (1H, br
s).

(D) 2- (N-tert-butoxycarbonylamino) ethanol 2-Aminoethanol (6.1 g) was dissolved in a mixture of tetrahydrofuran and water (1: 1, 100 ml) and stirred under ice-cooling with stirring. Charly butyl dicarbonate (21.
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, and after washing with water, the organic layer was dried using anhydrous magnesium sulfate, filtered, and then the solvent was distilled off under reduced pressure.
The target compound (15.3 g) was obtained as a colorless oily substance. Rf value (cyclohexane: ethyl acetate = 1: 1):
0.35; NMR spectrum (CDCl ₃ ) δ ppm: 1.45
(9H, s), 2.35-2.50 (1H, brs),
3.29 (2H, q, J = 5.3 Hz), 3.71 (2
H, q, J = 5.3 Hz), 4.85-5.05 (1
H, brs).

(E) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-
To a solution of 1,2-benzoisoxazole triphenylphosphine (0.87 g) in tetrahydrofuran (10 ml), diethyl azodicarboxylate (0.57 g) was added dropwise with stirring under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Next, 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) and 5-chloro-3-hydroxy-1,2-benzisoxazole (0.51 g) were added, and the mixture was stirred for 10 minutes under ice cooling. After doing
The mixture was further stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/1) and crystallized from isopropyl ether to give the desired compound (0.70 g). ) Was obtained as colorless crystals. Melting point: 106-107 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
6,1706, 1611, 1541, 1525; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.50 (2H, t, J = 5.1 Hz), 4.9
5 (1H, brs), 7.37 (1H, d, J = 8.8)
Hz), 7.49 (1H, dd, J = 8.8 Hz, J =
2.0Hz), 7.63 (1H, d, J = 2.0H)
z).

(F) 3- (2-aminoethoxy) -5
-Chloro-1,2-benzisoxazole hydrochloride 3-N- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-1,2-benzisoxazole (0.50 g) 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 1,4-dioxane to give the desired compound (0.38 g) as colorless crystals. Melting point: 217-221 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1612, 1534, 1519; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.33 (2H, t, J = 5.1 Hz), 4.61 (2
H, t, J = 5.1 Hz), 7.73 (2H, d, J =
1.4 Hz), 7.88 (1H, d, J = 1.4H)
z), 8.28 (3H, brs).

Example 2 3- (2-aminoethoxy) -1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzo Isoxazole 3-hydroxy-1,2-benzisoxazole and 2-
(N-tert-butoxycarbonylamino) ethanol was reacted in the same manner as in Example 1 (e) and post-treated to give the target compound in a yield of 68%. Melting point: 106-107 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
6, 1716, 1707, 1615, 1536; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.51 (2H, t, J = 5.1 Hz), 4.9
0-5.05 (1H, brs), 7.26-7.66
(4H, m).

(B) 3- (2-aminoethoxy)-
1,2-Benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole was reacted in the same manner as in Example 1 (f) and worked up. By doing
The target compound was obtained in 98% yield. Melting point: 194-197 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1614, 1541, 1521; NMR spectrum (D ₂ O) δ ppm: 3.60
(2H, t, J = 5.1 Hz), 4.94 (2H, t,
J = 5.1 Hz), 7.41-7.80 (4H, m).

Example 3 3- (3-aminopropoxy) -1,2-benzisoxazole hydrochloride (a) 3- (N-tert-butoxycarbonylamino) propanol 3-aminopropanol (0.75 g) Example 1 ditertiary butyl dicarbonate (2.18 g)
The target compound (1.65 g) was obtained by reacting and post-treating in the same manner as in (d). Rf value (cyclohexane: ethyl acetate = 1: 1):
0.35; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
9 (9H, s), 1.70 (2H, q, J = 5.9H
z), 2.85-2.95 (1H, brs), 3.33
(2H, q, J = 5.9 Hz), 3.70 (2H, q,
J = 5.9 Hz), 4.65-4.90 (1H, br)
s).

(B) 3- (3- (N-tert-butoxycarbonylamino) propoxy) -1,2-benzisoxazole 3-hydroxy-1,2-benzisoxazole and 3-
(N-tert-butoxycarbonylamino) propanol was reacted in the same manner as in Example 1 (e) and worked up to give the target compound in a yield of 75%. Melting point: 59-60 ° C; IR spectrum (KBr) ν _max cm ^-1 : 338
3,1690, 1613, 1539, 1521; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 2.05-2.13 (2H, m),
3.36 (2H, q, J = 6.3 Hz, 4.52 (2
H, t, J = 5.9 Hz), 4.70-4.85 (1
H, brs), 7.25-7.65 (4H, m).

(C) 3- (3-aminopropoxy)-
1,2-Benzisoxazole hydrochloride 3- (3- (N-tert-butoxycarbonylamino) propoxy) -1,2-benzisoxazole is reacted in the same manner as in Example 1 (f), and post-treated. As a result, the target compound was obtained in a yield of 96%. Melting point: 146-147 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1615,1541,1536; NMR spectrum (D ₂ O) δppm: 2.29-
2.36 (2H, m), 3.31 (2H, t, J = 7.
3Hz), 4.59 (2H, t, J = 5.9Hz),
7.40-7.78 (4H, m).

Example 4 3- (4-aminobutoxy) -1,2-benzisoxazole hydrochloride (a) 4- (N-tert-butoxycarbonylamino) butanol 4-aminobutanol (0.89 g) Example 1 ditertiary butyl dicarbonate (2.18 g)
The target compound (1.80 g) was obtained by carrying out the same reaction as in (d) and post-treatment. Rf value (cyclohexane: ethyl acetate = 1: 1):
0.35; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 1.55-1.65 (4H, m),
3.16 (2H, q, J = 5.9 Hz), 3.67 (2
H, q, J = 5.9 Hz), 4.55-4.75 (1
H, brs).

(B) 3- (4- (N-tert-butoxycarbonylamino) butoxy) -1,2-benzisoxazole 3-hydroxy-1,2-benzisoxazole and 4-
(N-tert-butoxycarbonylamino) butanol was reacted in the same manner as in Example 1 (e) and post-treated to obtain the target compound in a yield of 71%. IR spectrum (KBr) ν _max cm ^-1 : 332
1,1701, 1615, 1539, 1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.1
4 (9H, s), 1.62-1.74 (2H, m),
1.91-1.97 (2H, m), 3.15-3.27
(2H, brs), 4.46 (2H, t, J = 6.5H)
z), 4.55-4.70 (1H, brs), 7.24
-7.66 (4H, m).

(C) 3- (4-aminobutoxy)-
1,2-Benzisoxazole hydrochloride 3- (4- (N-tert-butoxycarbonylamino) butoxy) -1,2-benzisoxazole was reacted in the same manner as in Example 1 (f) and worked up. By doing
The target compound was obtained in 97% yield. Melting point: 138-139 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1613, 1541; NMR spectrum (D ₂ O) δ ppm: 1.88-
1.97 (2H, m), 1.99-2.06 (2H,
m), 3.14 (2H, t, J = 7.6 Hz), 4.5
0 (2H, t, J = 6.1 Hz), 7.39-7.78
(4H, m).

Example 5 3- (2-aminoethoxy) -5-fluoro-1,2-
Benzoisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-1,2-benzisoxazole 5-fluoro-3-hydroxy-1,2- Benzoisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e) and post-treated to obtain the target compound in a yield of 60%. IR spectrum (KBr) ν _max cm ^-1 : 333
8, 1707, 1623, 1543, 1534, 150
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z) 4.50 (2H, t, J = 5.1 Hz), 4.88
−5.03 (1H, brs), 7.22−7.42 (3
H, m).

(B) 3- (2-aminoethoxy) -5
-Fluoro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 98% by performing the same reaction and post-treatment. Melting point: 209-211 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1621,1606,1538,1505
NMR spectrum (D ₂ O) δ ppm: 3.59
(2H, t, J = 5.1 Hz), 4.73 (2H, t,
J = 5.1 Hz), 7.42-7.58 (3H, m).

Example 6 3- (2-aminoethoxy) -5-methoxy-1,2-
Benzoisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methoxy-1,2-benzisoxazole 3-hydroxy-5-methoxy-1,2- Benzoisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e) and post-treated to obtain the target compound in a yield of 74%. IR spectrum (KBr) ν _max cm ^-1 : 325
5,1698,1615,1540,1508; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 3.86 (3H, s), 4.50 (2H, t, J
= 5.1 Hz), 4.90-5.05 (1H, br)
s), 6.98 (1H, d, J = 2.6 Hz), 7.1
5 (1H, dd, J = 9.2 Hz, J = 2.6 Hz),
7.33 (1H, d, J = 9.2 Hz).

(B) 3- (2-aminoethoxy) -5
-Methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methoxy-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 96% by carrying out the same reaction and post-treatment. Melting point: 210-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1606,1538,1521,1505
NMR spectrum (D ₂ O) δ ppm: 3.59
(2H, t, J = 5.1 Hz), 3.90 (3H,
s), 4.71 (2H, t, J = 5.1 Hz), 7.2.
2 (1H, d, J = 2.6 Hz), 7.32 (1H, d
d, J = 9.2 Hz, J = 2.6 Hz), 7.48 (1
H, d, J = 9.2 Hz).

Example 7 3- (2-Aminoethoxy) -5-methyl-1,2-benzisoxazole hydrochloride (a) Ethyl 5-methylsalicylate 5-methylsalicylic acid was prepared in the same manner as in Example 1 (a). The target compound was obtained in a yield of 84% by the same reaction and post-treatment. (B) 5-Methylsalicylcarbohydroxamic acid 5-methylsalicylic acid ethyl ester and hydroxylamine hydrochloride are reacted in the same manner as in Example 1 (b) and post-treated to obtain the desired compound in a yield of 94%. Was. Melting point: 172-175 ° C. (decomposition); NMR spectrum (DMSO-d ₆ ) δ ppm:
2.22 (3H, s), 6.78 (1H, d, J = 8.
6 Hz), 7.17 (1H, d, J = 8.6 Hz),
7.50 (1H, s), 9.25 (1H, s), 11.
33 (1H, s), 11.95 (1H, s).

(C) 3-hydroxy-5-methyl-
Example 1 1,2-benzisoxazole 5-methylsalicylcarbohydroxamic acid
The target compound was obtained in a yield of 94% by carrying out the same reaction as in (c) and post-treatment. Melting point: 95-97 ° C; NMR spectrum (CDCl ₃ ) δ ppm: 2.4
5 (3H, s), 7.13-7.43 (3H, m),
9.02-9.15 (1H, brs).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methyl-
1,2-benzisoxazole 3-hydroxy-5-methyl-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e). By post-treatment, the target compound was obtained in a yield of 69%. IR spectrum (KBr) ν _max cm ^-1 : 336
7, 1717, 1614, 1538-1522; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.45 (3H, s), 3.64 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1Hz), 4.90-5.05 (1H, brs),
7.31-7.52 (3H, m).

(E) 3- (2-aminoethoxy) -5
-Methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methyl-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in 97% yield by the same reaction and post-treatment. Melting point: 218-220 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1625, 1612, 1536, 1502
NMR spectrum (DMSO-d ₆ ) δ ppm:
2.43 (3H, s), 3.26-3.41 (2H,
m), 4.60 (2H, t, J = 5.1 Hz), 7.4
8-7.55 (3H, m), 8.32 (3H, br
s).

Example 8 3- (2-Aminoethoxy) -5-nitro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Nitro-1,2-benzisoxazole 3-hydroxy-5-nitro-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). After further reaction at 60 ° C. for 3 hours and post-treatment, the target compound was obtained in a yield of 74%. Melting point: 136-137 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
6,1688,1624,1555,1531; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.67 (2H, q, J = 5.1H
z), 4.55 (2H, t, J = 5.1 Hz), 4.8
7-5.05 (1H, brs), 7.56 (1H, d,
J = 9.2 Hz), 8.46 (1H, dd, J = 9.2)
Hz, J = 2.2 Hz), 8.62 (1H, d, J =
2.2 Hz).

(B) 3- (2-aminoethoxy) -5
-Nitro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-nitro-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 99% by performing the same reaction and post-treatment. Melting point: 228-231 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1620, 1543, 1519; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.36 (2H, t, J = 5.1 Hz), 4.66 (2
H, t, J = 5.1 Hz), 7.93 (2H, d, J =
9.2 Hz), 8.34 (3H, brs), 8.54
(1H, dd, J = 9.2 Hz, J = 2.2 Hz),
8.74 (1H, d, J = 2.2 Hz).

Example 9 3- (2-Aminoethoxy) -7-chloro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7 -Chloro-1,2-benzisoxazole 3-hydroxy-7-chloro-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). The target compound was obtained in a yield of 62% by post-treatment. Melting point: 64-65 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
5,1714,1690,1615,1556,153
8; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.53 (2H, t, J = 5.1 Hz), 4.8
7-5.03 (1H, brs), 7.23 (1H, d
d, J = 8.0 Hz, J = 8.0 Hz), 7.52-
7.58 (2H, m).

(B) 3- (2-aminoethoxy) -7
-Chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-chloro-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 98% by performing the same reaction and post-treatment. Melting point: 198-200 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1616,1599,1541,1516
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.35 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 7.44 (1H, dd, J)
= 8.0 Hz, J = 8.0 Hz), 7.79 (1H,
d, J = 8.0 Hz), 7.83 (1H, d, J = 8.
0 Hz), 8.34 (3H, brs).

Example 10 3- (2-Aminoethoxy) pyrido [3,2-d] isoxazole hydrochloride and 3- (2-aminoethoxy) pyrido [3,2-d] isoxazole dihydrochloride (a) 2 -Chloronicotinic acid methyl ester 2-Chloronicotinic acid (15.75 g) is suspended in ethyl acetate (200 ml), and excess diazomethane (ether solution) is added thereto while stirring at room temperature.
Stirred for minutes. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate. After adding activated carbon, the mixture was filtered, and the solvent was distilled off under reduced pressure to obtain the target compound (15.5 g). (B) 2-Chloropyridine-3-carbohydroxamic acid hydroxylamine hydrochloride (6.75 g) was added to water (25 m
l), an aqueous solution of sodium hydroxide (7.65 g of sodium hydroxide dissolved in 50 ml of water) was added thereto under ice-cooling and stirring, and then 2-chloronicotinic acid methyl ester (15.5 g) was added. Was added and stirred at room temperature for 2.5 hours. Under ice cooling, the pH of the reaction solution was adjusted to 3.5 using 6N hydrochloric acid, allowed to stand at the same temperature for 1 hour,
The precipitated crystals were collected by filtration, washed with water, and then washed with a mixture of methanol and ether (1: 1) to obtain the desired compound (11.0 g). Melting point: 179 ° C; IR spectrum (KBr, Nujol) ν _max cm ^-1
: 3154, 1645, 1580; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.34 (1H, dd, J = 7.5 Hz, J = 5.0 H
z), 7.80 (1H, dd, J = 7.5 Hz, 2.0
Hz), 8.42 (1H, dd, J = 5.0 Hz, J =
2.0Hz), 9.30 (1H, s), 11.00Hz
(1H, s).

(C) 3-hydroxypyrido [3,2-
d] isoxazole 2-chloropyridine-3-carbohydroxamic acid (2.
60 g) in 10% aqueous sodium hydroxide solution (26 ml)
And heated to reflux for 30 minutes. The pH of the reaction solution was adjusted to 2.0 with 6N hydrochloric acid under ice-cooling, and the mixture was allowed to stand at the same temperature for 30 minutes. : 1) to give the desired compound (1.68 g). Melting point: 258 ° C; IR spectrum (KBr, Nujol) ν _max cm ^-1
: 2750-2050, 1620, 1600; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.40 (1H, dd, J = 8.0 Hz, J = 5.0H
z), 8.40-8.70 (2H, m).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) pyrido [3,2-
d] isoxazole 3-hydroxypyrido [3,2-d] isoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e), followed by post-treatment. The compound was obtained in 61% yield. Melting point: 127-128 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
5,1716,1707,1615,1605,153
7; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.54 (2H, t, J = 5.1 Hz), 4.8
5-5.05 (1H, brs), 7.31 (1H, d
d, J = 7.9 Hz, J = 4.6 Hz), 8.06 (1
H, dd, J = 7.9 Hz, J = 1.5 Hz), 8.6
1 (1H, dd, J = 4.6 Hz, J = 1.5 Hz).

(E) 3- (2-Aminoethoxy) pyrido [3,2-d] isoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) pyrido [3,2-d] Isoxazole was reacted in the same manner as in Example 1 (f) and worked up to give the target compound in 99% yield. Melting point: 204-210 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1606, 1538, 1508; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.35 (2H, td, J = 5.1 Hz, J = 5.1H
z), 4.65 (2H, t, J = 5.1 Hz), 7.5
4 (1H, dd, J = 7.9 Hz, J = 4.6 Hz),
8.34 (1H, dd, J = 7.9 Hz, J = 1.5H
z), 8.34 (3H, brs), 8.70 (1H, d
d, J = 4.6 Hz, J = 1.5 Hz).

(F) 3- (2-Aminoethoxy) pyrido [3,2-d] isoxazole hydrochloride 3- (2-Aminoethoxy) pyrido [3,2-d] isoxazole dihydrochloride was added to water (10 ml). Dissolved in 5
1N aqueous sodium hydroxide solution (16 m
l) was added and stirred at the same temperature for 5 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized using a mixed solvent of methanol and water (1: 1) to obtain the desired compound (3.2 g, 94%) as colorless crystals. Was. Melting point: 210-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 301
2,3003,2968,2899,2845,280
3,2752,1636,1615,1606,153
8,1509; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.35 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 7.54 (1H, dd, J)
= 7.9 Hz, J = 4.6 Hz), 8.34 (1H, d
d, J = 7.9 Hz, J = 1.5 Hz), 8.36 (3
H, brs), 8.70 (1H, dd, J = 4.6H)
z, J = 1.5 Hz).

Example 11 3- (2-aminoethoxy) -6-chloro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6 -Chloro-1,2-benzisoxazole 3-hydroxy-6-chloro-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). Then, the target compound was obtained in a yield of 66% by post-treatment. Melting point: 95-96 ° C; IR spectrum (KBr) ν _max cm ^-1 : 339
8, 1698, 1614, 1541, 1519; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.50 (2H, t, J = 5.1 Hz), 4.8
8-5.02 (1H, brs), 7.27 (1H, d
d, J = 8.4 Hz, J = 1.5 Hz), 7.47 (1
H, d, J = 1.5 Hz), 7.55 (1H, d, J =
8.4 Hz).

(B) 3- (2-aminoethoxy) -6
-Chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6-chloro-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in 97% yield by the same reaction and post-treatment. Melting point: 198-202 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1612, 1537; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.1 Hz), 4.62 (2
H, t, J = 5.1 Hz), 7.48 (1H, dd, J)
= 8.4 Hz, J = 1.5 Hz), 7.81 (1H,
d, J = 8.4 Hz), 7.92 (1H, d, J = 1.
5Hz), 8.36 (3H, brs).

Example 12 3- (2-aminoethoxy) -5,7-dichloro-1,
2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5,7-dichloro-1,2-
Benzoisoxazole 3-hydroxy-5,7-dichloro-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e). By treatment, the target compound was obtained in a yield of 68%. Melting point: 94-95 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
9, 1678, 1542, 1524; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.51 (2H, t, J = 5.1 Hz), 4.8
5-5.00 (1H, brs), 7.54 (2H, d,
J = 1.0 Hz).

(B) 3- (2-aminoethoxy)-
Example of 5,7-dichloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5,7-dichloro-1,2-benzisoxazole The target compound was obtained in a 92% yield by reacting and post-treating in the same manner as in 1 (f). Melting point: 198-203 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1600,1541,1514; NMR spectrum (DMSO-d ₆ ) δppm:
3.34 (2H, t, J = 5.1 Hz), 4.63 (2
H, t, J = 5.1 Hz), 7.91 (1H, d, J =
2.0 Hz), 8.03 (1H, d, J = 2.0H)
z), 8.31 (3H, brs).

Example 13 3- (2-Aminoethoxy) -7-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7 -Methyl-1,2-benzisoxazole 3-hydroxy-7-methyl-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). Then, the target compound was obtained in a yield of 66% by post-treatment. Melting point: 54-55 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
2,1713,1699,1615,1539,150
6; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.51 (3H, s), 3.65 (2
H, q, J = 5.1 Hz), 4.51 (2H, t, J =
5.1Hz), 4.90-5.06 (1H, brs),
7.15-7.47 (3H, m).

(B) 3- (2-aminoethoxy) -7
-Methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 96% by carrying out the same reaction and post-treatment. Melting point: 195-197 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1614, 1545, 1520, 1505
NMR spectrum (DMSO-d ₆ ) δ ppm:
2.47 (3H, s), 3.34 (2H, t, J = 5.
1 Hz), 4.62 (2H, t, J = 5.1 Hz),
7.28-7.61 (3H, m).

Example 14 3- (2-Aminoethoxy) -6-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6 -Methyl-1,2-benzisoxazole 3-hydroxy-6-methyl-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). The target compound was obtained in a yield of 64% by post-treatment. Melting point: 128-129 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
1,1718,1708,1629,1613,153
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.50 (3H, s), 3.65 (2
H, q, J = 5.1 Hz), 4.49 (2H, t, J =
5.1Hz), 4.90-5.05 (1H, brs),
7.10 (1H, d, J = 8.0 Hz), 7.23 (1
H, s), 7.50 (1H, d, J = 8.0 Hz).

(B) 3- (2-aminoethoxy) -6
-Methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6-methyl-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 92% by performing the same reaction and post-treatment. Melting point: 207-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1618,1600,1533; NMR Spectrum (DMSO-d ₆₎ δppm:
2.48 (3H, s), 3.33 (2H, t, J = 5.
1 Hz), 4.59 (2H, t, J = 5.1 Hz),
7.23 (1H, d, J = 8.0 Hz), 7.46 (1
H, s), 7.65 (1H, d, J = 8.0 Hz),
8.33 (3H, brs).

Example 15 3- (2-Aminoethoxy) -5-bromo-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Bromo-1,2-benzisoxazole 3-hydroxy-5-bromo-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). The target compound was obtained in 67% yield by post-treatment. Melting point: 123-124 ° C; IR spectrum (KBr) ν _max cm ^-1 : 331
3,1699,1683,1611,1545; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.50 (2H, t, J = 5.1 Hz), 4.8
5-5.00 (1H, brs), 7.33 (1H, d,
J = 8.9 Hz), 7.62 (1H, dd, J = 8.9)
Hz, J = 1.9 Hz), 7.80 (1H, d, J =
1.9 Hz).

(B) 3- (2-aminoethoxy) -5
-Bromo-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound was obtained in a yield of 95% by performing the same reaction and post-treatment. Melting point: 220-224 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1611,1535,1516; NMR Spectrum (DMSO-d ₆₎ δppm:
3.38 (2H, t, J = 5.1 Hz), 4.61 (2
H, t, J = 5.1 Hz), 7.67 (1H, d, J =
8.9 Hz), 7.83 (1H, dd, J = 8.9H)
z, J = 1.9 Hz), 8.02 (1H, d, J = 1.
9 Hz), 8.25 (3H, brs).

Example 16 3,5-Dichloro-1,2-benzisoxazole 5-chloro-3-hydroxy-1,2-benzisoxazole (100 g) was suspended in phosphorus oxychloride (80 ml). Under stirring at room temperature, pyridine (48 ml) was added dropwise over 1 hour, and the mixture was heated under reflux for 5 hours. The reaction solution was added to ice water (500 ml), extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from petroleum ether. Thus, the target compound (102 g, 92%) was obtained as colorless needles. Melting point: 43-44 ° C; IR spectrum (KBr) ν _max cm ^-1 : 146
8, 1419, 1285; NMR spectrum (CDCl ₃ ) δ ppm: 7.5
9 (2H, d, J = 1.5 Hz), 7.70 (1H, b
rs).

Example 17 3- (2-aminoethoxy) -5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) (Ethoxy) -5-fluoro-1,2-benzisoxazole triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (20 ml), and cooled to 5 ° C., and diethyl azodicarboxylate (0.57 g) was added. 15 at the same temperature
Stirred for minutes. Then 5-fluoro-3-hydroxy-
1,2-Benzisoxazole (0.46 g) was added,
After stirring at the same temperature for 15 minutes, N-tert-butoxycarbonylethanolamine (0.48 g) was added, and the mixture was stirred at room temperature for 24 hours. The solvent is distilled off under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (developing agent:
Purification using cyclohexane / ethyl acetate = 9/1) gave the target compound (0.53 g, yield 60%) as a colorless powder. Melting point: 104-105 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
8, 1707, 1623, 1543, 1534, 150
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.46
(9H, s), 3.64 (2H, q, J = 5.1H)
z), 4.50 (2H, t, J = 5.1 Hz), 4.9
5 (1H, brs), 7.22-7.42 (3H,
m).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-
4-Methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylaminoethoxy) -5-fluoro-1,2-benzisoxazole (0.27 g) was added to tetrahydrofuran (10 m
l) and cooled to -70 ° C under a nitrogen atmosphere, and then lithium diisopropylamide (1.1 ml, 1.5M
(Cyclohexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, and then methyl iodide (0.13 g) was added. After stirring at -70 ° C for 15 minutes, the temperature was naturally raised to 0 ° C. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (4.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 9/0). Purification was performed using 1) to obtain the desired compound (0.22 g, yield 94%) as a colorless powder. Melting point: 124-127 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
3,1688,1539,1505; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.50 (3H, d, J = 2.0H
z), 3.65 (2H, q, J = 5.1 Hz), 4.4
9 (2H, t, J = 5.1 Hz), 4.88 (1H, b
rs), 7.15-7.30 (2H, m).

(C) 3- (2-aminoethoxy) -5
-Fluoro-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-4-methyl-1,2-
Benzoisoxazole (0.15 g) was dissolved in a 4N hydrochloric acid / dioxane solution (1.4 ml) and stirred for 15 minutes. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with ethyl acetate (3 ml) to obtain the desired compound (0.13 g, yield 98%) as a colorless powder. Melting point: 213-215 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1630, 1583, 1537, 1505
NMR spectrum (DMSO-d ₆ ) δ ppm:
2.51 (3H, d, J = 2.0 Hz), 3.34 (2
H, q, J = 5.1 Hz), 4.62 (2H, t, J =
5.1 Hz), 7.45-7.55 (2H, m), 8.
33 (3H, brs).

Example 18 3- (2-aminoethoxy) -4-carbamoyl-5
Fluoro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-fluoro-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-1,2-benzisoxazole (0.30 g) was added to tetrahydrofuran (20 m
1) and cooled to -70 ° C under a nitrogen atmosphere. Lithium diisopropylamide (1.4 ml, 1.5 M cyclohexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, then carbon dioxide gas was introduced for 10 minutes, and the temperature was naturally raised to 0 ° C. The reaction solution was poured into ice water (40 ml), washed with diethyl ether (twice with 40 ml), the aqueous layer was separated, and the pH of the solution was adjusted to 4 with potassium phosphate monobasic.
Extracted with ethyl acetate (2 × 40 ml). The organic layer was dried using anhydrous magnesium sulfate, filtered, and then the solvent was distilled off under reduced pressure to obtain the desired compound (0.31 g, yield 90%).
%) As a colorless oil. IR spectrum (KBr) ν _max cm ^-1 : 347
4,3358,3326,3194,1683,167
3,1611,1538,1503; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
8 (9H, s), 3.62 (2H, q, J = 5.1H
z), 4.52 (2H, t, J = 5.1 Hz), 5.2
7. (1H, brs), 6.04 (1H, brs),
40 (1H, brs), 7.34 (1H, t, J = 9.
1 Hz), 7.48 (1 H, dd, J = 9.1 Hz, J
= 3.6 Hz).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-fluoro-1,2-benzisoxazole 3- (2- (N-tert-butoxy) Carbonylamino) ethoxy) -4-carboxy-5-fluoro-1,
2-Benzisoxazole (0.31 g) was dissolved in tetrahydrofuran (20 ml), cooled to 5 ° C., and isobutyl chlorocarbonate (0.14 g) and triethylamine (0.11 g) were added, followed by stirring for 15 minutes. Then
After adding a saturated ammonia / tetrahydrofuran solution (saturated at room temperature, 5 ml) and stirring for 15 minutes, the reaction solution was poured into ice water (40 ml), extracted with diethyl ether (2 times with 40 ml), and the organic layer was dried over anhydrous magnesium sulfate. After drying with filtration and filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/1) to give the target compound (0). .24 g, 78% yield) as a colorless powder. Melting point: 63-65 ° C; IR spectrum (KBr) ν _max cm ^-1 : 347
3,3359,3327,3195,1683,167
3,1612,1538,1503; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
8 (9H, s), 3.62 (2H, q, J = 5.1H
z), 4.52 (2H, t, J = 5.1 Hz), 5.2
7. (1H, brs), 6.04 (1H, brs),
40 (1H, brs), 7.34 (1H, t, J = 9.
5 Hz), 7.48 (1H, dd, J = 9.5 Hz, J
= 3.6 Hz).

(C) 3- (2-aminoethoxy) -4
-Carbamoyl-5-fluoro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-fluoro-
Example 17 (c) was mixed with 1,2-benzisoxazole (25 mg) and a 4N hydrochloric acid / dioxane solution (0.2 ml).
The target compound (20 mg, yield 99%) was obtained as a colorless powder by post-treatment. Melting point: 201-205 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 338
2,3400-2400,1656,1605,159
0,1543; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.1 Hz), 4.62 (2
H, t, J = 5.1 Hz), 7.63 (1H, t, J =
9.5 Hz), 7.77 (1H, dd, J = 9.5H)
z, J = 3.6 Hz), 7.86 (1H, brs),
8.19 (4H, brs).

Example 19 3- (2-Aminoethoxy) -4-cyano-5-fluoro-1,2-benzisoxazole hydrochloride (a) 3- (2-N-tert-butoxycarbonylamino) ethoxy ) -4-Cyano-5-fluoro-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-fluoro-
1,2-Benzisoxazole (0.25 g) was dissolved in dimethylformamide (2.0 ml), phosphorus oxychloride (0.12 g) was added under cooling to 5 ° C, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into ice water (20 ml), extracted with ethyl acetate (twice with 20 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 4/1) to give the desired compound (0.20 g,
(87% yield) as a colorless powder. Melting point: 116-117 ° C; IR spectrum (KBr) ν _max cm ^-1 : 336
8, 2240, 1702, 1532, 1507; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.67 (2H, q, J = 5.1H
z), 4.54 (2H, t, J = 5.1 Hz), 5.0
5 (1H, brs), 7.43 (1H, t, J = 9.5)
Hz), 7.68 (1H, dd, J = 9.5 Hz, J =
3.6 Hz).

(B) 3- (2-aminoethoxy) -4
-Cyano-5-fluoro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-fluoro-1,2-
Benzoisoxazole (0.17 g) and a 4N hydrochloric acid / dioxane solution (1.3 ml) were reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.
12 g, 96% yield) as a colorless powder. Melting point: 190-193 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 2240, 1607, 1541, 1505
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.2 Hz), 4.72 (2
H, t, J = 5.2 Hz), 7.91 (1H, t, J =
9.5 Hz), 8.19 (1H, dd, J = 9.5H)
z, J = 3.7 Hz), 8.30 (3H, brs).

Example 20 3- (2-aminoethoxy) -5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-fluoro-1,
After dissolving 2-benzoisoxazole (0.31 g) in diethyl ether (20 ml) and cooling to 5 ° C., a diazomethane / diethyl ether solution was added dropwise until the reaction solution became yellow, and stirred at the same temperature for 15 minutes. did. The solvent was distilled off under reduced pressure to obtain the desired compound (0.32 g, yield 100%) as an oil. IR spectrum (KBr) ν _max cm ^-1 : 345
7, 1733, 1713, 1541, 1504; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.62 (2H, q, J = 5.1H)
z), 4.01 (3H, s), 4.49 (2H, t, J
= 5.1 Hz), 5.08 (1H, brs), 7.35
(1H, t, J = 9.5 Hz), 7.52 (1H, d
d, J = 9.5 Hz, J = 3.6 Hz).

(B) 3- (2-aminoethoxy) -5
-Fluoro-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-4-methoxycarbonyl-1,2-benzoiso Xazole (0.18g) and 4
N hydrochloric acid / dioxane solution (1.3 ml) was added to Example 17
The target compound (0.15 g, yield 97%) was obtained as a colorless powder by performing the same reaction as in (c) and performing post-treatment. Melting point: 168-170 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1729,1584,1539,1501
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.31 (2H, t, J = 5.1 Hz), 3.96 (3
H, s), 4.62 (2H, t, J = 5.1 Hz),
7.73 (2H, t, J = 9.5 Hz), 7.96 (2
H, dd, J = 9.5 Hz, J = 3.6 Hz), 8.2
3 (3H, brs).

Example 21 3- (2-aminoethoxy) -5-fluoro-4-methylthio-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -5-fluoro-4-methylthio-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-1,2-benzisoxazole (0 .30 g) in tetrahydrofuran (20 m
l) and cooled to -70 ° C under a nitrogen atmosphere.
Lithium diisopropylamide (1.50 ml, 1.5
M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, and then dimethyl disulfide (0.21 g) was added. After the reaction solution was stirred at -70 ° C for 15 minutes, the temperature was raised to 0 ° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice with 40 ml), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 9 /
Purification using 1) gave the desired compound (0.32 g, yield 9).
4%) as a colorless powder. Melting point: 91-92 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
5,1694,1618,1540; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.60 (3H, d, J = 2.1H
z), 3.67 (2H, q, J = 5.1 Hz), 4.5
0 (2H, t, J = 5.1 Hz), 5.04 (1H, b
rs), 7.20-7.30 (2H, m).

(B) 3- (2-aminoethoxy) -5
-Fluoro-4-methylthio-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-fluoro-4-methylthio-1,
2-benzisoxazole (0.18 g) and 4N hydrochloric acid /
Dioxane (1.3 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.1 ml).
(15 g, yield 99%) as a colorless powder. Melting point: 183-185 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3400
-2400, 1617, 1592, 1535; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.57 (3H, d, J = 1.4 Hz), 3.35 (3
H, t, J = 5.1 Hz), 4.64 (2H, t, J =
5.1Hz), 7.59 (1H, t, J = 9.5H)
z), 7.63 (1H, dd, J = 9.5 Hz, J =
3.6 Hz), 8.24 (3H, brs).

Example 22 3- (2-Aminoethoxy) -4-methoxycarbonyl-1,2-benzisoxazole hydrochloride and 3- (2
-Aminoethoxy) -7-methoxycarbonyl-1,2
-Benzisoxazole hydrochloride (a) Dissolve 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole triphenylphosphine (0.95 g) in tetrahydrofuran (20 ml). After cooling to 5 ° C., diethyl azodicarboxylate (0.63 g) was added, and the mixture was stirred at the same temperature for 15 minutes, and then 3-hydroxy-1,2-benzoisoxazole (0.45 g) was added. The mixture was stirred for 15 minutes, then N-tert-butoxycarbonylethanolamine (0.53 g) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane /
Purification was performed using ethyl acetate (9/1) to obtain the target compound (0.63 g, yield 68%) as a colorless powder. Melting point: 106-107 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
6, 1716, 1707, 1615, 1536; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.51 (2H, t, J = 5.1 Hz), 4.9
0-5.05 (1H, brs), 7.26-7.66
(4H, m).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-1,2-benzisoxazole and 3- (2
-(N-tert-butoxycarbonylamino) ethoxy) -7-methoxycarbonyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxa Zol (0.
28 g) was dissolved in tetrahydrofuran (30 ml), cooled to -70 ° C under a nitrogen atmosphere, butyllithium (1.40 ml, 1.6 M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. After introducing carbon dioxide gas into the reaction solution for 10 minutes, the temperature was naturally raised to 0 ° C. The reaction solution was poured into ice water (40 ml) and diethyl ether (40 ml) was added.
, The aqueous layer was separated, the pH was adjusted to 4 with potassium hydroxide, and the mixture was extracted with ethyl acetate (twice with 40 ml), and the organic layer was washed with anhydrous magnesium sulfate. After drying using and filtering, the solvent was distilled off under reduced pressure,
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-1,2-benzisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carboxy -1,
2-Benzisoxazole was used as a colorless, oily mixture (0.
31 g, 92%). Next, the obtained mixture was dissolved in diethyl ether (15 ml), and after cooling to 5 ° C, a diazomethane / diethyl ether solution was added dropwise until the reaction solution turned yellow, and the mixture was stirred at the same temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/1) to obtain the desired 3- (2- (N
-Tert-butoxycarbonylamino) ethoxy)
-4-methoxycarbonyl-1,2-benzisoxazole (0.15 g, 45%) and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-
Methoxycarbonyl-1,2-benzisoxazole (0.08 g, 24%) was each obtained as a colorless powder. Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-1,2-benzisoxazole Melting point: 95-96 ° C; IR spectrum (KBr) ν _max cm ^-1 : 339
7, 1705, 1601, 1533, 1524, 150
3; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.66 (2H, q, J = 5.1H
z), 3.99 (3H, s), 4.51 (2H, t, J
= 5.1 Hz), 5.29 (1H, brs), 7.55
−7.65 (2H, m), 7.85 (1H, d, J =
7.5 Hz). Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methoxycarbonyl-1,2-benzisoxazole Melting point: 90-91 ° C; IR spectrum (KBr) ν _max cm ^-1 : 338
7, 1718, 1693, 1620, 1610, 155
2,1525; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.66 (2H, q, J = 5.1H
z), 4.03 (3H, s), 4.54 (2H, t, J
= 5.1 Hz), 4.96 (1H, brs), 7.37
(1H, t, J = 8.1 Hz), 7.85 (1H, d,
J = 8.1 Hz), 8.23 (3H, d, J = 8.0H)
z).

(C) 3- (2-aminoethoxy) -4
-Methoxycarbonyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-1,2-benzisoxazole (0.10 g) A 4N hydrochloric acid / dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.0%).
8 g, 100%) as a colorless powder. Melting point: 169-172 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1718,1601,1525,1499
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.1 Hz), 3.93 (3
H, s), 4.62 (2H, t, J = 5.1 Hz),
7.75-7.85 (2H, m), 7.95 (1H,
d, J = 8.1 Hz), 8.23 (3H, brs).

(D) 3- (2-aminoethoxy) -7
-Methoxycarbonyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methoxycarbonyl-1,2-benzisoxazole (0.08 g) A 4N hydrochloric acid / dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.0
6 g, 100%) as a colorless powder. Melting point: 211-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1730, 1719, 1618, 160
8,1550,1502; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.36 (2H, t, J = 5.1 Hz), 3.95 (3
H, s), 4.65 (2H, t, J = 5.1 Hz),
7.56 (1H, t, J = 8.0 Hz), 8.10 (1
H, d, J = 8.1 Hz), 8.23 (1H, d, J =
8.1 Hz), 8.30 (3H, brs).

Example 23 3- (2-Aminoethoxy) -4-carbamoyl-1,
2-benzoisoxazole hydrochloride and 3- (2-aminoethoxy) -7-carbamoyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy ) -4-Carbamoyl-1,2-
Benzoisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-Benzisoxazole (0.
55 g) was dissolved in tetrahydrofuran (30 ml), cooled to -70 ° C under a nitrogen atmosphere, butyllithium (3.0 ml, 1.6 M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. After introducing carbon dioxide gas into the reaction solution for 10 minutes, the temperature was naturally raised to 0 ° C. The reaction solution was poured into ice water (40 ml), washed with diethyl ether (twice with 40 ml), the aqueous layer was separated, the pH was adjusted to 4 with potassium potassium phosphate, and the mixture was extracted with ethyl acetate. (2 times with 40 ml), the organic layer was dried using anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-1,2-benzisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carboxy -1,
2-Benzisoxazole was used as a colorless, oily mixture (0.
48g). Next, the obtained mixture was dissolved in tetrahydrofuran (30 ml), and while cooling to 5 ° C., isobutyl chlorocarbonate (0.23 g) and triethylamine (0.18 g) were added. After stirring for 15 minutes, the mixture was saturated with ammonia / tetrahydrofuran. Solution (saturated at room temperature, 5m
l) was added and stirred for 15 minutes. The reaction solution was added to ice water (40
ml), extracted with ethyl acetate (2 in 40 ml).
Times), the organic layer was dried using anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/1). And purified using the desired 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-1,2-benzisoxazole (0.30 g, 47%) and
(2- (N-tert-butoxycarbonylamino)
Ethoxy) -7-carbamoyl-1,2-benzisoxazole (0.17 g, 26%) was each obtained as a colorless powder. Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-1,2-benzisoxazole Melting point: 119-120 ° C; IR spectrum (KBr) ν _max cm ^-1 : 348
8, 3443, 3358, 3196, 1688, 166
3,1610,1592,1533; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
2 (9H, s), 3.70 (2H, q, J = 5.1H
z), 4.62 (2H, t, J = 5.1 Hz), 4.9
3. (1H, brs), 5.91 (1H, brs), 7.
60-7.70 (2H, m), 7.79 (1H, br)
s), 8.14 (1H, d, J = 7.0 Hz). Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-1,2-benzisoxazole Melting point: 151-153 ° C; IR spectrum (KBr) ν _max cm ^-1 : 346
3,3396,3353,3304,3232,318
2,1716,1680,1618,1544; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.67 (2H, q, J = 5.1H
z), 4.54 (2H, t, J = 5.1 Hz), 4.9
7. (1H, brs), 5.95 (1H, brs),
14 (1H, brs), 7.44 (1H, t, J = 7.
0 Hz), 7.83 (1H, d, J = 7.0 Hz),
8.35 (1H, d, J = 7.0 Hz).

(B) 3- (2-aminoethoxy) -4
-Carbamoyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-1,2-benzisoxazole (0.10 g) and 4N hydrochloric acid / Dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.08 g,
100%) as a colorless powder. Melting point: 210-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 338
3,3300-2400,1656,1605,159
0,1543; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.57 (2H, t, J = 5.1 Hz), 4.64 (2
H, t, J = 5.1 Hz), 7.58 (1H, d, J =
7.0 Hz), 7.71 (1H, brs), 7.73
(1H, dd, J = 9.0 Hz, J = 7.0 Hz),
7.79 (1H, d, J = 9.0 Hz), 7.99 (1
H, brs), 8.21 (3H, brs).

(C) 3- (2-aminoethoxy) -7
-Carbamoyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-1,2-benzisoxazole (0.05 g) and 4N hydrochloric acid / Dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.04 g,
100%) as a colorless powder. Melting point: 227-230 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 346
1,3180,3300-2400,1675,161
8,1596,1547; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 7.50 (1H, t, J =
7.0 Hz), 7.77 (1H, brs), 7.83
(1H, brs), 7.95 (1H, d, J = 7.0H)
z), 8.05 (1H, d, J = 7.0 Hz), 8.3
1 (3H, brs).

Example 24 3- (2-Aminoethoxy) -4-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -Cyano-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-1,2-benzisoxazole (0.15 g) was treated with dimethylformamide (1 After cooling to 5 ° C., phosphorus oxychloride (0.09 g) was added, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into ice water (20 ml), extracted with ethyl acetate (twice with 20 ml), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/4).
Purification was performed using 1), and the desired compound (0.13 g, 93
%) As a colorless powder. Melting point: 116-117 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
0, 2232, 1701, 1601, 1530; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.69 (2H, q, J = 5.1H
z), 4.55 (2H, t, J = 5.1 Hz), 5.0
8 (1H, brs), 7.60-7.75 (3H,
m).

(B) 3- (2-aminoethoxy) -4
-Cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-1,2-benzisoxazole (0.10 g) and 4N hydrochloric acid / Dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.08 g,
100%) as a colorless powder. Melting point: 210-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3400
-2400,2234,1601,1538; NMR Spectrum (DMSO-d ₆₎ δppm:
3.35 (2H, t, J = 5.1 Hz), 4.72 (2
H, t, J = 5.1 Hz), 7.87 (1H, t, J =
8.1 Hz), 7.98 (1H, d, J = 8.1H)
z), 8.09 (1H, d, J = 8.1 Hz), 8.2
6 (3H, brs).

Example 25 3- (2-Aminoethoxy) -7-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7 -Cyano-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-1,2-benzisoxazole (0.10 g) was treated with dimethylformamide (1 After cooling to 5 ° C, phosphorus oxychloride (0.06 g) was added, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into ice water (20 ml), extracted with ethyl acetate (twice with 20 ml), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/4).
Purification was performed using 1), and the target compound (0.09 g, 90
%) As a colorless powder. Melting point: 91-92 ° C; IR spectrum (KBr) ν _max cm ^-1 : 343
7,3349,3316,2238,1719,170
1,1688,1621,1607,1546,152
8; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.66 (2H, q, J = 5.1H
z), 4.54 (2H, t, J = 5.1 Hz), 4.9
2 (1H, brs), 7.40 (1H, t, J = 8.0)
Hz), 7.86 (1H, d, J = 8.0 Hz), 7.
90 (1H, d, J = 8.0 Hz).

(B) 3- (2-aminoethoxy) -7
-Cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-cyano-1,2-benzisoxazole (0.07 g) and 4N hydrochloric acid / Dioxane solution (1.0 ml) was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (0.05 g,
100%) as a colorless powder. Melting point: 205-208 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 324
1,3400-2400,2239,1623,160
7,1547; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.36 (2H, t, J = 5.1 Hz), 4.67 (2
H, t, J = 5.1 Hz), 7.61 (1H, t, J =
8.1 Hz), 8.18 (1H, d, J = 8.1H)
z), 8.26 (1H, d, J = 8.1 Hz), 8.3
4 (3H, brs).

Example 26 3- (2-aminoethylthio) -5-fluoro-1,2
-Benzisoxazole hydrochloride (a) 3-chloro-5-fluoro-1,2-benzisoxazole 5-fluoro-3-hydroxyisoxazole (1.
0g) was dissolved in pyridine (0.53 ml), phosphorus oxychloride (0.89 ml) was added, and the mixture was heated under reflux for 8 hours. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography to obtain the target compound (0.8
(5 g, 77%) as a colorless oil. (B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-1,2-benzisoxazole 3-chloro-5-fluoro-1,2-benzisoxazole (0 .83 g) in dimethylformamide (8 ml)
After adding 2-tert-butoxycarbonylaminoethanethiol (0.86 g) and potassium carbonate (0.67 g) under a nitrogen atmosphere, the mixture was stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography to obtain the target compound (1.
21 g, 80%) as a colorless powder. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.41 (2H, t, J = 6.2H)
z), 3.58 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 4.98 (1H, brs), 7.21-
7.51 (3H, m).

(C) 3- (2-aminoethylthio)-
5-Fluoro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-1,2-benzisoxazole (0.20 g) in dioxane (2 ml), 4N hydrochloric acid / dioxane solution (0.8 ml) was added under cooling to 5 ° C., and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol and ethyl acetate to obtain the desired compound (1.40 g) as colorless needles. Melting point: 202-206 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
2,2955,2915,1594,1511,149
3; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 7.1 Hz), 3.53 (2
H, t, J = 7.1 Hz), 7.60-7.86 (3
H, m), 8.22 (3H, brs).

Example 27 3- (2-aminoethylthio) -7-chloro-1,2-
Benzoisoxazole hydrochloride (a) 3,7-Dichloro-1,2-benzisoxazole 7-chloro-3-hydroxy-1,2-benzisoxazole (0.85 g) was prepared in Example 26 ( The target compound (0.73
g, 78%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-chloro-
1,2-benzisoxazole 3,7-dichloro-1,2-benzisoxazole (0.20 g) was reacted in the same manner as in Example 26 (b) and post-treated to give the target compound ( 0.22 g,
63%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.42 (2H, t, J = 6.2H
z), 3.60 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 5.01 (1H, brs), 7.24
(1H, t, J = 9.1 Hz), 7.48 (1H, d,
J = 9.1 Hz), 7.56 (1H, d, J = 9.1H)
z).

(C) 3- (2-aminoethylthio)-
7-chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-chloro-1,2-benzisoxazole (0.15 g) The target compound (0.1
2 g, quant). Melting point: 196-201 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 297
1,909,1592,1502,1492; NMR spectrum (DMSO-d ₆ ) δppm:
3.26 (2H, t, J = 7.1 Hz), 3.56 (2
H, t, J = 7.1 Hz), 7.45 (1H, t, J =
7.9 Hz), 7.79 (1H, d, J = 7.9H)
z), 7.86 (1H, d, J = 7.9 Hz), 8.2
0 (3H, brs).

Example 28 3- (2-aminoethylthio) -7-methyl-1,2-
Benzoisoxazole hydrochloride (a) 3-Chloro-7-methyl-1,2-benzisoxazole 3-hydroxy-7-methyl-1,2-benzisoxazole (0.35 g) was prepared in the Example. The target compound (0.30
g, 77%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-methyl-
1,2-benzisoxazole 3-chloro-7-methyl-1,2-benzisoxazole (0.24 g) was reacted in the same manner as in Example 26 (b) and worked up, Compound (0.24 g,
55%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 2.52 (3H, s), 3.42 (2
H, t, J = 6.2 Hz), 3.58 (2H, td, J)
= 6.2 Hz, J = 6.2 Hz), 5.12 (1H, b
rs), 7.18 (1H, t, J = 9.1 Hz), 7.
33 (1H, d, J = 9.1 Hz), 7.40 (1H,
d, J = 9.1 Hz).

(C) 3- (2-aminoethylthio)-
7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-methyl-1,2-benzisoxazole (0.10 g) The reaction and post-treatment were carried out in the same manner as in Example 26 (c) to give the desired compound (0.0
8 g, quant). Melting point: 198-203 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 298
5,2913,1598,1501; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.51 (3H, s), 3.24 (2H, t, J = 7.
1 Hz), 3.54 (2H, t, J = 7.1 Hz),
7.33 (1H, t, J = 7.4 Hz), 7.52 (1
H, d, J = 7.4 Hz), 7.58 (1H, d, J =
7.4 Hz), 8.22 (3H, brs).

Example 29 3- (2-aminoethylthio) -5,7-dichloro-
1,2-benzisoxazole hydrochloride (a) 3,5,7-trichloro-1,2-benzisoxazole 5,7-dichloro-3-hydroxy-1,2-benzisoxazole (2. 00g) was reacted in the same manner as in Example 26 (a) and worked up to give the target compound (1.81 g, 83%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5,7-dichloro-1,2-benzisoxazole 3,5,7-trichloro-1,2-benzo The target compound (0.25 g, 0.25 g,
68%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.42 (2H, t, J = 6.2H
z), 3.58 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 5.03 (1H, brs), 7.48
(1H, s), 7.56 (1H, s).

(C) 3- (2-aminoethylthio)-
5,7-Dichloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5,7-dichloro-1,2-benzisoxazole (0. 22g) was reacted in the same manner as in Example 26 (c) and worked up to give the desired compound (0.18 g, quant). Melting point: 199-202 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 300
3,2970,2915,1590,1480; NMR spectrum (DMSO-d ₆ ) δppm:
3.25 (1H, t, J = 6.9 Hz), 3.54 (2
H, t, J = 6.9 Hz), 8.00 (1H, s),
8.06 (1H, s), 8.18 (3H, brs).

Example 30 3- (2-aminoethylthio) -7-nitro-1,2-
Benzoisoxazole hydrochloride (a) 3-Chloro-7-nitro-1,2-benzisoxazole 3-hydroxy-7-nitro-1,2-benzisoxazole (1.05 g) was prepared in the Example. The target compound (0.93) was reacted in the same manner as in 26 (a) and post-treated.
g, 80%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-nitro-
1,2-benzisoxazole 3-chloro-7-nitro-1,2-benzisoxazole (0.23 g) was reacted in the same manner as in Example 26 (b) and worked up to obtain the desired compound. Compound (0.20 g,
51%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.48 (2H, t, J = 6.2H)
z), 3.62 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 4.98 (1H, brs), 7.50
(1H, t, J = 9.1 Hz), 7.94 (1H, d,
J = 9.1 Hz), 8.44 (1H, d, J = 9.1H)
z).

(C) 3- (2-aminoethylthio)-
7-nitro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-nitro-1,2-benzisoxazole (0.18 g) The target compound (0.1) was reacted in the same manner as in Example 26 (c) and post-treated.
4 g, quant). Melting point: 193-196 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
0,2924,2882,1620,1589,153
2,1512; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.28 (2H, t, J = 7.1 Hz), 3.61 (2
H, t, J = 7.1 Hz), 7.69 (1H, t, J =
7.9 Hz), 8.24 (3H, brs), 8.29
(1H, d, J = 7.9 Hz), 8.57 (1H, d,
J = 7.9 Hz).

Example 31 3- (2-aminoethylthio) -7-methoxy-1,2
-Benzoisoxazole hydrochloride (a) 3-Chloro-7-methoxy-l, 2-benzisoxazole 3-hydroxy-7-methoxy-l, 2-benzisoxazole (0.80 g) was carried out. The target compound (0.6) was reacted in the same manner as in Example 26 (a) and post-treated.
1 g, 69%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-methoxy-1,2-benzisoxazole 3-chloro-7-methoxy-1,2-benzisoxa Sol (0.26 g) was reacted in the same manner as in Example 26 (b) and worked up to give the target compound (0.25 g).
g, 54%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.42 (2H, t, J = 6.2H)
z), 3.58 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 4.04 (3H, s), 5.02 (1
H, brs), 6.98 (1H, d, J = 9.1H)
z), 7.15 (1H, d, J = 9.1 Hz), 7.2
3 (1H, t, J = 9.1 Hz).

(C) 3- (2-aminoethylthio)-
7-Methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-methoxy-1,2-benzisoxazole (120 mg) was prepared in the Example. The target compound (90) was reacted and post-treated in the same manner as 26 (c).
mg, quant). Melting point: 232-237 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 301
9,2969,2907,1619,1600,151
2; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 7.1 Hz), 3.54 (2
H, t, J = 7.1 Hz), 3.98 (3H, s),
7.27-7.40 (3H, m), 8.21 (3H, b
rs).

Example 32 3- (2-Aminoethylthio) -7-amino-1,2-
Benzoisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-amino-1,2-benzisoxazole 3- (2- (N-tert-butoxy) Carbonylamino) ethylthio) -7-nitro-1,2-benzisoxazole (250 mg) in 90% aqueous acetic acid (2 ml)
And zinc powder (250 mg) was added under ice-cooling and stirring, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure, water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with saturated saline and then dried. Dry using magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (developing agent: ethyl acetate) to obtain the desired compound (23).
0 mg, quant). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.41 (2H, t, J = 6.2H
z), 3.59 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 4.08 (2H, brs), 5.02
(1H, brs), 6.82 (1H, d, J = 8.7H)
z), 6.96 (1H, d, J = 8.7 Hz), 7.1
2 (1H, t, J = 8.7 Hz).

(B) 3- (2-aminoethylthio)-
7-Amino-1,2-benzisoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -7-amino-1,2-benzisoxazole (140 mg) was carried out. The target compound (120) was reacted in the same manner as in Example 26 (c) and post-treated.
mg, quant). Melting point: 157-160 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 303
5,2969,2884,2807,2581,163
1,1614,1570,1521,1504; NMR Spectrum (DMSO-d ₆₎ δppm:
3.24 (2H, t, J = 7.0 Hz), 3.52 (2
H, t, J = 7.0 Hz), 4.05-5.35 (2
H, brs), 6.88 (2H, d, J = 7.9H)
z), 7.12 (1H, t, J = 7.9 Hz), 8.2
3 (3H, brs).

Example 33 3- (2-Aminoethylthio) -5-methoxy-1,2
-Benzisoxazole hydrochloride (a) 3-Chloro-5-methoxy-1,2-benzisoxazole 3-hydroxy-5-methoxy-1,2-benzisoxazole (920 mg) was prepared in Example 26. The same reaction as in (a) and post-treatment give the desired compound (730).
mg, 71%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-methoxy-1,2-benzisoxazole 3-chloro-5-methoxy-1,2-benzisoxa Sol (260 mg) was reacted in the same manner as in Example 26 (b) and post-treated to give the target compound (280 m
g, 61%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.40 (2H, t, J = 6.2H
z), 3.58 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 3.86 (3H, s), 5.02 (1
H, brs), 6.91 (1H, s), 7.18 (1
H, d, J = 9.1 Hz), 7.43 (1H, d, J =
9.1 Hz).

(C) 3- (2-aminoethylthio)-
5-Methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-methoxy-1,2-benzisoxazole (240 mg) was prepared in the Example. The target compound (19) was reacted and post-treated in the same manner as 26 (c).
0 mg, quant). Melting point: 213-217 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
7, 2947, 2883, 1592, 1514, 149
5; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.23 (2H, t, J = 7.1 Hz), 3.52 (2
H, t, J = 7.1 Hz), 3.84 (3H, s),
7.16 (1H, s), 7.32 (1H, d, J = 9.
1 Hz), 7.69 (1H, d, J = 9.1 Hz),
8.17 (3H, brs).

Example 34 3- (2-aminoethylthio) -5-methyl-1,2-
Benzoisoxazole hydrochloride (a) 3-Chloro-5-methyl-1,2-benzisoxazole 3-hydroxy-5-methyl-1,2-benzisoxazole (1.02 g) was prepared in Examples. The target compound (0.81) was reacted and post-treated in the same manner as 26 (a).
g, 71%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-methyl-
1,2-benzisoxazole 3-chloro-5-methyl-1,2-benzisoxazole (90 mg) was reacted in the same manner as in Example 26 (b) and post-treated to give the target compound ( 90mg, 5
6%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 2.46 (3H, s), 3.40 (2
H, t, J = 6.2 Hz), 3.58 (2H, td, J)
= 6.2 Hz, J = 6.2 Hz), 5.02 (1H, b
rs), 7.38 (2H, d, J = 9.1 Hz), 7.
42 (1H, s).

(C) 3- (2-aminoethylthio)-
5-Methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-methyl-1,2-benzisoxazole (80 mg) was prepared in the Example. The target compound (60 m
g, quant). Melting point: 132-135 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 299
6,2919,1600,1592,1497; NMR spectrum (DMSO-d ₆ ) δppm:
2.44 (3H, s), 3.24 (2H, t, J = 7.
1Hz), 3.53 (2H, t, J = 7.1Hz),
7.54 (1H, d, J = 8.5 Hz), 7.55 (1
H, s), 7.65 (1H, d, J = 8.5 Hz),
8.21 (3H, brs).

Example 35 3- (2-aminoethylthio) -5-nitro-1,2-
Benzoisoxazole hydrochloride (a) 3-Chloro-5-nitro-1,2-benzisoxazole 3-hydroxy-5-nitro-1,2-benzisoxazole (1.02 g) was prepared in the Example. The target compound (0.63) was reacted and treated in the same manner as in 26 (a).
g, 56%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-nitro-
1,2-benzisoxazole 3-chloro-5-nitro-1,2-benzisoxazole (560 mg) was reacted in the same manner as in Example 26 (b), and post-treated to give the target compound ( 560 mg,
58%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.47 (2H, t, J = 6.2H
z), 3.62 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 4.96 (1H, brs), 7.64
(1H, d, J = 9.1 Hz), 8.48 (1H, d,
J = 9.1 Hz), 8.56 (1H, s).

(C) 3- (2-aminoethylthio)-
5-Nitro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-nitro-1,2-benzisoxazole (250 mg) was prepared in the Example. The target compound (200) was reacted in the same manner as 26 (c) and subjected to post-treatment.
mg, quant). Melting point: 183-186 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 301
3,2971,2892,1619,1594,153
0; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 7.1 Hz), 3.59 (2
H, t, J = 7.1 Hz), 8.03 (1H, d, J =
9.1 Hz), 8.24 (3H, brs), 8.56
(1H, d, J = 9.1 Hz), 8.72 (1H, d, J = 9.1 Hz)
s).

Example 36 3- (2-Aminoethylthio) -5-amino-1,2-
Benzoisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-amino-1,2-benzisoxazole 3- (2- (N-tert-butoxy) The target compound (140) was reacted with carbonylamino) ethylthio) -5-nitro-1,2-benzisoxazole (150 mg) in the same manner as in Example 32 (a) and post-treated.
mg, quant). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.37 (2H, t, J = 6.2H
z), 3.57 (2H, td, J = 6.2 Hz, J =
6.2 Hz), 3.91 (2H, brs), 5.03
(1H, brs), 6.77 (1H, s), 6.94
(1H, d, J = 8.7 Hz), 7.33 (1H, d,
J = 8.7 Hz).

(B) 3- (2-aminoethylthio)-
5-Amino-1,2-benzisoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-amino-1,2-benzisoxazole (200 mg) was run. The target compound (200) was reacted in the same manner as in Example 26 (c) and post-treated.
mg, quant). Melting point: 201-205 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 304
5,302,2964,2885,1628,158
2,1494; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.26 (2H, t, J = 7.0 Hz), 3.35 −
4.85 (2H, brs), 3.55 (2H, t, J =
7.0 Hz), 7.54 (1H, d, J = 6.5H)
z), 7.56 (1H, s), 7.80 (1H, d, J
= 6.5 Hz), 8.24 (3H, brs).

Example 37 3- (2-aminoethoxy) -1,2-naphtho [2,3
-E] isoxazole hydrochloride (a) 3-hydroxy-1,2-naphtho [2,3-
e] isoxazole 3-hydroxy-2-naphthoic acid (10.0
g) was reacted in the same manner as in Examples 1 (a), 1 (b) and 1 (c), followed by post-treatment to obtain the desired compound (3.1).
g, 31%). IR spectrum (KBr) ν _max cm ^-1 : 304
4,300,1940,2869,2824,274
6,2696, 2661, 223, 1770, 164
5,1618, 1598, 1573, 1521; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.45-7.65 (2H, m), 8.01 (1H,
s), 8.04 (1H, d, J = 8.4 Hz), 8.1.
5 (1H, d, J = 8.4 Hz), 8.43 (1H,
s), 12.67 (1H, brs).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-naphtho [2,3-e] isoxazole 3-hydroxy-1,2-naphtho [2,3- e] The desired compound (0.59 g, 72%) was obtained by reacting isoxazole (0.46 g) with 2- (N-tert-butoxycarbonylamino) ethanol in the same manner as in Example 1 (e) and performing post-treatment. I got Melting point: 148-149 ° C; IR spectrum (KBr) ν _max cm ^-1 : 331
4,1707,1643,1545,1535; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.70 (2H, q, J = 5.1H)
z), 4.59 (2H, t, J = 5.1 Hz), 5.0
1 (1H, brs), 7.33-7.60 (2H,
m), 7.81 (1H, s), 7.94 (1H, d, J
= 8.4 Hz), 8.00 (1H, d, J = 8.4H)
z), 8.22 (1H, s).

(C) 3- (2-aminoethoxy)-
1,2-Naphtho [2,3-e] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-naphtho [2,3-e] isoxazole (0.50 g) Was reacted in the same manner as in Example 1 (f) and post-treated to give the target compound (0.40
g, 99%). Melting point: 207-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1641, 1615, 1545, 151
6,1505; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.39 (2H, q, J = 5.1 Hz), 4.71 (2
H, t, J = 5.1 Hz), 7.50-7.70 (2
H, m), 8.09 (1H, d, J = 8.4 Hz),
8.13 (1H, s), 8.18 (1H, d, J = 8.
4Hz), 8.36 (3H, brs), 8.47 (1
H, s).

Example 38 3- (2-Aminoethylthio) -5-chloro-1,2-
Benzoisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-1,2-benzisoxazole 3,5-dichloro-1,2-benzoiso Xazole (0.53 g) was reacted as in Example 26 (b),
By post-treatment, the target compound (0.63 g, 62
%). Melting point: 95-96 ° C; IR spectrum (KBr) ν _max cm ^-1 : 328
3,1687,1523; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.42 (2H, t, J = 6.3H)
z), 3.58 (2H, q, J = 6.3 Hz), 4.9
8 (1H, brs), 7.47 (1H, d, J = 8.8)
Hz), 7.52 (1H, dd, J = 8.8 Hz, J =
1.5Hz), 7.57 (1H, d, J = 1.5H)
z).

(B) 3- (2-aminoethylthio)-
Implement 5-chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-1,2-benzisoxazole (0.52 g) The target compound (0.41) was reacted and worked up in the same manner as in Example 22 (c).
g, 97%). Melting point: 201-206 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400, 1588, 1524; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.24 (2H, q, J = 7.0 Hz), 3.55 (2
H, t, J = 7.0 Hz), 7.75 (1H, dd, J)
= 8.9 Hz, J = 2.0 Hz), 7.83 (1H,
d, J = 8.9 Hz), 7.95 (1H, d, J = 2.
0 Hz), 8.23 (3H, brs).

Example 39 3- (2-Aminoethylthio) -5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethylthio) -5-fluoro-4-methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-1,2-benzisoxazole ( 0.11 g) was reacted in the same manner as in Example 17 (b) and worked up to give the target compound (0.1
0 g, 91%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 2.55 (3H, s), 3.42 (2
H, t, J = 6.1 Hz), 3.58 (2H, td, J)
= 6.1 Hz, J = 6.1 Hz), 5.02 (1H, b
rs), 7.19-7.34 (2H, m).

(B) 3- (2-aminoethylthio)-
5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-4-methyl-1,2
Example 1-Benzoisoxazole (0.09 g)
The target compound (0.07 g, quant) was obtained by carrying out the same reaction as in (f) and post-treatment. Melting point: 209-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 310
3,2963,2901,1499; NMR Spectrum (DMSO-d ₆₎ δppm:
2.53 (3H, s), 3.26 (2H, t, J = 6.
9Hz), 3.55 (2H, t, J = 6.9Hz),
7.53-7.65 (2H, m), 8.20 (3H, b
rs).

Example 40 3- (2-Aminoethylthio) -5-fluoro-4-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethylthio) -5-fluoro-4-carbamoyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-1,2-benzisoxazole ( 0.30 g) was reacted in the same manner as in Example 18 (a) and worked up to give 3- (2- (N-tert-butoxycarbonylamino) ethylthio)-
5-Fluoro-4-carboxy-1,2-benzisoxazole (0.25 g, 74%) was obtained. Next, the obtained 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-4-carboxy-
By reacting 1,2-benzisoxazole (0.23 g) in the same manner as in Example 18 (b) and performing post-treatment,
The target compound (0.16 g, 70%) was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 3.35 (2H, t, J = 6.1H
z), 3.58 (2H, td, J = 6.1 Hz, J =
6.1 Hz), 5.03 (1H, brs), 6.02
(1H, brs), 6.29 (1H, brs), 7.3
7 (1H, t, J = 8.9 Hz), 7.62 (1H, d
d, J = 3.8 Hz, J = 8.9 Hz).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-4-cyano-1,2-benzisoxazole 3- (2- (N-tert-butoxy) Carbonylamino) ethylthio) -5-fluoro-4-carbamoyl-
By reacting 1,2-benzisoxazole (0.14 g) in the same manner as in Example 19 (a) and performing post-treatment,
The target compound (0.12 g, 92%) was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.46 (2H, t, J = 6.0H)
z), 3.60 (2H, td, J = 6.0 Hz, J =
6.0 Hz), 4.97 (1H, brs), 7.45
(1H, t, J = 8.9 Hz), 7.77 (1H, d
d, J = 3.9 Hz, J = 8.9 Hz).

(C) 3- (2-aminoethylthio)-
5-fluoro-4-cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-fluoro-4-cyano-1,2
Example 1-Benzoisoxazole (0.11 g)
The target compound (0.09 g, quant) was obtained by reacting and post-treating in the same manner as in (f). Melting point: 215-219 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
6,3090,3005,1494; NMR spectrum (DMSO-d ₆ ) δppm:
3.27 (2H, t, J = 6.9 Hz), 3.59 (2
H, t, J = 6.9 Hz), 7.94 (1H, t, J =
9.4 Hz), 8.19 (3H, brs), 8.30
(1H, dd, J = 3.9 Hz, J = 9.4 Hz).

Example 41 3- (2-aminoethoxy) -7-methoxy-1,2-
Benzoisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methoxy-1,2-benzisoxazole 3-hydroxy-7-methoxy-1,2- Benzoisoxazole (0.33 g) was reacted in the same manner as in Example 1 (e) and post-treated to give the target compound (0.39 g).
g, 63%). Melting point: 98-99 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
8, 1708, 1683, 1624, 1615, 154
2,1533,1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.03 (3H, s), 4.51 (2H, t, J
= 5.1 Hz), 4.97 (1H, brs), 6.95
−7.00 (1H, m), 7.15-7.20 (2H,
m).

(B) 3- (2-aminoethoxy) -7
Example 1 -methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methoxy-1,2-benzisoxazole (0.30 g) was prepared. The target compound (0.23) was reacted and post-treated in the same manner as in 1 (f).
g, 96%). Melting point: 208-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 302
2,2983,2909,2840,1627,161
4,1546,1509; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.30 (2H, t, J = 5.1 Hz), 3.97 (3
H, s), 4.61 (2H, t, J = 5.1 Hz),
7.20-7.25 (1H, m), 7.30-7.35
(2H, m), 8.29 (3H, brs).

Example 42 3- (2-Aminoethoxy) -5-methoxycarbonyl-1,2-benzisoxazole hydrochloride (a) 5-bromo-3- (2- (N-tert-butoxycarbonylamino) )) Ethoxy) -1,2-benzisoxazole 5-bromo-3-hydroxy-1,2-benzisoxazole (4.30 g) and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in Example 1. The target compound (4.80 g, 67%) was obtained by reacting and post-treating in the same manner as in (e). Melting point: 123-124 ° C; IR spectrum (KBr) ν _max cm ^-1 : 331
3,1699,1683,1611,1545; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.50 (2H, t, J = 5.1 Hz), 4.9
2 (1H, brs), 7.33 (1H, d, J = 8.9)
Hz), 7.62 (1H, dd, J = 8.9 Hz, J =
1.9 Hz), 7.80 (1H, d, J = 1.9H)
z).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methoxycarbonyl-1,2-benzisoxazole 5-bromo-3- (2- (N-tertiary) Butoxycarbonylamino) ethoxy) -1,2-benzisoxazole (1.00 g) was reacted in the same manner as in Example 22 (b) and worked up to give the target compound (0.27 g).
g, 29%). Melting point: 154-155 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
6,1720,1702,1687,1629,161
1,15477; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.66 (2H, q, J = 5.1H
z), 3.96 (3H, s), 4.53 (2H, t, J
= 5.1 Hz), 4.97 (1H, brs), 7.47
(1H, d, J = 8.8 Hz), 8.24 (1H, d
d, J = 8.8 Hz, J = 1.6 Hz), 8.41 (1
H, d, J = 1.6 Hz).

(C) 3- (2-aminoethoxy) -5
-Methoxycarbonyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methoxycarbonyl-1,2-benzisoxazole (0.20 g) Example 22 (c)
The target compound (0.16 g, 98%) was obtained by reacting in the same manner as described above and performing post-treatment. Melting point: 211-213 ° C; IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1718,1625,1610,1544
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.37 (2H, q, J = 5.1 Hz), 3.91 (3
H, s), 4.63 (2H, t, J = 5.1 Hz),
7.80 (1H, d, J = 8.8 Hz), 8.26 (1
H, dd, J = 8.8 Hz, J = 1.6 Hz), 8.4
4 (1H, d, J = 1.6 Hz).

Example 43 3- (2-aminoethoxy) -5-methylamino-1,
2-benzisoxazole dihydrochloride and 3- (2-aminoethoxy) -5-dimethylamino-1,2-benzisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonyl) Amino) ethoxy) -5-methylamino-1,2-
Benzoisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-dimethylamino-1,2-benzisoxazole 5-amino-3- (2- (N-tert-butoxy) Carbonylamino) ethoxy) -1,2-benzisoxazole (0.88 g) was added to tetrahydrofuran (10 m
l), sodium borohydride (0.66 g) was added thereto while stirring at 5 ° C, and a 37% aqueous solution of formaldehyde (0.99 g) and a 3M sulfuric acid (1.0 ml) solution in tetrahydrofuran (10 ml) were added. At the same temperature
Stir for 5 minutes. After stirring at room temperature for 1.5 hours, the mixture was cooled to 5 ° C., and a 37% aqueous formaldehyde solution (3.0 g) was used.
And sodium borohydride (0.66 g) were further added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was added to ice water (100
ml), extracted with ethyl acetate (2 in 50 ml).
Times), the organic layer was dried using anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 4/1). And purified using
(2- (N-tert-butoxycarbonylamino)
Ethoxy) -5-methylamino-1,2-benzisoxazole (0.49 g, 53%) and 3- (2- (N-
Tertiary butoxycarbonylamino) ethoxy)-
5-Dimethylamino-1,2-benzisoxazole (0.14 g, 15%) was obtained. Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methylamino-1,2-benzisoxazole Melting point: 122-123 ° C; IR spectrum (KBr) ν _max cm ^-1 : 339
2,3317,1695,1673,1636,161
1,1548, 1538, 1523; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.88 (3H, s), 3.64 (2
H, q, J = 5.1 Hz), 3.79 (1H, br)
s), 4.49 (2H, t, J = 5.1 Hz), 4.9.
9 (1H, brs), 6.64 (1H, d, J = 2.3)
Hz), 6.87 (1H, dd, J = 8.9 Hz, J =
2.3 Hz), 7.23 (1H, d, J = 8.9H)
z). Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-dimethylamino-1,2-benzisoxazole IR spectrum (KBr) ν _max cm ^-1 : 338
7, 2979, 2934, 1703, 1547, 152
6,1507; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.97 (6H, s), 3.65 (2
H, m), 4.49 (2H, t, J = 5.1 Hz),
4.99 (1H, brs), 6.78 (1H, d, J =
2.4Hz), 7.10 (1H, dd, J = 9.2H)
z, J = 2.4 Hz), 7.30 (1H, d, J = 9.
2 Hz).

(B) 3- (2-aminoethoxy) -5
-Methylamino-1,2-benzisoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methylamino-1,2-benzisoxazole (0.30 g) Was reacted in the same manner as in Example 1 (f) and post-treated, whereby the target compound (0.2
7g, 99%). Melting point: 240-250 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 303
0,2961,889,2841,2,756,272
0, 2683, 2646, 2609, 2579, 253
5,2506,2479,2421,2379,162
3,1604, 1567, 1544, 1528; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.84 (3H, s), 3.34 (2H, q, J = 5.
1 Hz), 4.61 (2H, t, J = 5.1 Hz),
7.43 (1H, brs), 7.49 (1H, d, J =
8.9 Hz), 7.64 (1H, d, J = 8.9H)
z), 8.34 (3H, brs).

(C) 3- (2-aminoethoxy) -5
-Dimethylamino-1,2-benzisoxazole 2
The hydrochloride was reacted with 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-dimethylamino-1,2-benzisoxazole in the same manner as in Example 1 (f), followed by post-treatment. The desired compound was obtained. Melting point: 150-160 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3500
-3200, 3100-2800, 2700-240
0,1626,1551,1467,1434; NMR Spectrum (DMSO-d ₆₎ δppm:
3.06 (6H, s), 3.34 (2H, dd, J = 1)
0.6 Hz, J = 5.5 Hz), 4.62 (2H, t,
J = 5.5 Hz), 7.8-7.5 (3H, m), 8.
37 (2H, brs).

Example 44 3- (2-Aminoethoxy) -5-difluoromethoxy-1,2-benzosoxazole hydrochloride (a) 5-hydroxy-3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -1,2-benzisoxazole 3,5-dihydroxy-1,2-benzisoxazole (0.50 g) was reacted in the same manner as in Example 1 (e), The desired compound (0.60 g, 62
%). Melting point: 152-153 ° C; IR spectrum (KBr) ν _max cm ^-1 : 328
6,1672,1543,1529; NMR spectrum (CDCl ₃ ) δ ppm: 1.3
8 (9H, s), 3.40 (2H, q, J = 5.1H)
z), 4.34 (2H, t, J = 5.1 Hz), 6.8
8 (1H, d, J = 2.5 Hz), 7.08 (1H, d
d, J = 8.9 Hz, J = 2.5 Hz), 7.42 (1
H, d, J = 8.9 Hz), 9.68 (1H, s).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-difluoromethoxy-1,2-benzisoxazole 5-hydroxy-3- (2- (N-tertiary) Butoxycarbonylamino) ethoxy) -1,2-benzisoxazole (100 mg) was added to dimethylformamide (4
ml) and dissolved in sodium methoxide (90 m
g) was added and stirred at room temperature for 10 minutes, after which chlorodifluoromethane gas was introduced over 20 minutes. The reaction solution was poured into ice water (30 ml) and extracted with ethyl acetate (30 m
The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 9 / Purify using 1)
The target compound (19 mg, 16%) was obtained as a colorless powder. Melting point: 155-156 ° C; IR spectrum (KBr) ν _max cm ^-1 : 332
2,1699,1683,1541; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.51 (2H, t, J = 5.1 Hz), 4.9
4 (1H, brs), 6.52 (1H, t, J = 73.
4 Hz), 7.30-7.50 (3H, m).

(C) 3- (2-aminoethoxy) -5
Example of -difluoromethoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-difluoromethoxy-1,2-benzisoxazole (25 mg) The target compound (2) was reacted and post-treated in the same manner as 1 (f).
0 mg, 95%). Melting point: 162-164 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1618,1599,1544,1497
NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, q, J = 5.1 Hz), 4.63 (2
H, t, J = 5.1 Hz), 4.62 (1H, br)
s), 7.27 (1H, d, J = 73.6 Hz), 7.
54 (1H, dd, J = 9.0 Hz, J = 2.3H
z), 7.58 (1H, d, J = 2.3 Hz), 7.7
5 (1H, d, J = 9.0 Hz), 8.29 (3H, b
rs).

Example 45 3- (2-Aminoethoxy) -7-amino-1,2-benzisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy)- 7-nitro-1,2-benzisoxazole 3-hydroxy-7-nitro-1,2-benzisoxazole (1.80 g) was reacted as in Example 1 (e) and worked up. To give the desired compound (2.20,6)
8%). Melting point: 116-117 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
9,3307,1718,1700,1691,162
8, 1604, 1553; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.67 (2H, q, J = 5.1H
z), 4.57 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 7.46 (1H, t, J = 8.1)
Hz), 7.99 (1H, d, J = 8.1 Hz), 8.
41 (1H, d, J = 8.1 Hz).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-amino-
1,2-Benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-nitro-1,2-benzisoxazole (1.50 g) was prepared according to Example 32 (a). The target compound (1.26
g, 93%). Melting point: 107-108 ° C; IR spectrum (KBr) ν _max cm ^-1 : 343
8,3349,1700,1640,1604; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.1H
z), 4.03 (2H, s), 4.50 (2H, t, J
= 5.1 Hz), 4.98 (1H, brs), 6.79
(1H, d, J = 7.9 Hz), 7.00 (1H, d,
J = 7.9 Hz), 7.07 (1H, t, J = 7.9H)
z).

(C) 3- (2-aminoethoxy) -7
Implement -amino-1,2-benzisoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-amino-1,2-benzisoxazole (0.26 g) The desired compound (0.23 g, 0.23 g,
98%). Melting point: 185-195 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,3026,2870,2583,164
0, 1611, 1582, 1553, 1525, 150
9; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.33 (2H, q, J = 5.1 Hz), 4.59 (2
H, t, J = 5.1 Hz), 6.88 (1H, d, J =
7.9 Hz), 6.97 (1H, d, J = 7.9H)
z), 7.10 (1H, t, J = 7.9 Hz), 8.3
3 (3H, brs).

Example 46 3- (2-aminoethoxy) -7-carboxy-1,2
-Benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole (0.
28g) was reacted in the same manner as in Example 18 (a) and post-treated, then reacted in the same manner as in Example 1 (e) and post-treated to give the desired compound (0.036 g, 14
%). Melting point: 123-126 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
0,3081,3024,2960,2896,171
4,1620,1615,1553,1548,149
5; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.36 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 7.53 (1H, t, J =
7.1 Hz), 8.05 (1H, d, J = 7.1H)
z), 8.18 (1H, d, J = 7.1 Hz), 8.3
2 (3H, brs).

Example 47 3- (2-aminoethoxy) -5-hydroxy-1,2
-Benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-hydroxy-1,2-benzisoxazole (0.20 g) as in Example 1 (f) The target compound (0.16
g, 97%). Melting point: 205-209 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 346
7,3388,3112,3024,2932,161
7,1541,1528,1503; NMR Spectrum (DMSO-d ₆₎ δppm:
3.32 (2H, t, J = 5.1 Hz), 4.57 (2
H, t, J = 5.1 Hz), 7.01 (1H, d, J =
2.5Hz), 7.13 (1H, dd, J = 9.0H)
z, J = 2.5 Hz), 7.45 (1H, d, J = 9.
0 Hz), 8.26 (3H, brs), 9.84 (1
H, s).

Example 48 3- (2-Aminoethoxy) -5-acetoxy-1,2
-Benzisoxazole hydrochloride (a) 5-acetoxy-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole 3- (2- (N-tert-butoxy) Carbonylamino) ethoxy) -5-hydroxy-1,2-benzisoxazole (100 mg) was added to tetrahydrofuran (5 m
l) and triethylamine (4.
4 mg) and acetyl chloride (34 mg) were added, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into ice water (40 ml), extracted with ethyl acetate (twice with 40 ml), the organic layer was dried over anhydrous magnesium sulfate, and filtered.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 9/1) to obtain the desired compound (101 m 2).
g, 88%) as a colorless powder. Melting point: 108-110 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 334
6,1767,1705,1626,1618,154
1,1529; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.34 (3H, s), 3.63 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1 Hz), 4.94 (1H, brs), 7.25
(1H, dd, J = 9.0 Hz, J = 2.2 Hz),
7.39 (1H, d, J = 2.2 Hz), 7.43 (1
H, d, J = 9.0 Hz).

(B) 3- (2-aminoethoxy) -5
-Acetoxy-1,2-benzisoxazole hydrochloride 5-acetoxy-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole (80 mg) was prepared in Example 1 ( The target compound (59 mg,
98%). Melting point: 168-170 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 306
4,3002,2962,2891,2741,174
8, 1726, 1618, 1592, 1545, 151
0; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.31 (3H, s), 3.31 (2H, q, J = 5.
1 Hz), 4.62 (2H, t, J = 5.1 Hz),
7.46 (1H, dd, J = 9.0 Hz, J = 2.2H
z), 7.55 (1H, d, J = 2.2 Hz), 7.7
1 (1H, d, J = 9.0 Hz), 8.27 (3H, b
rs).

Example 49 3- (2-aminoethoxy) -7-methylamino-1,
2-benzisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methylamino-1,2-
Benzoisoxazole 7-amino-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-benzisoxazole (0.88 g) was reacted in the same manner as in Example 43 (a). After the post-treatment, the target compound (0.12
g, 13%). Melting point: 162-164 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
6,3312,1709,1639,1626,155
0,1514; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.99 (3H, d, J = 5.0H
z), 3.63 (2H, q, J = 5.1 Hz), 3.6
3 (1H, q, J = 5.0 Hz), 4.49 (2H,
t, J = 5.1 Hz), 4.98 (1H, brs),
6.64 (1H, d, J = 7.8 Hz), 6.92 (1
H, d, J = 7.8 Hz), 7.15 (1H, t, J =
7.8 Hz).

(B) 3- (2-aminoethoxy) -7
-Methylamino-1,2-benzisoxazole dihydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methylamino-1,2-benzisoxazole (80 mg) was performed. The target compound (72m) was reacted in the same manner as in Example 1 (f) and post-treated.
g, 99%). Melting point: 171-181 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 302
6,2965,2912,2866,2786,273
0,2638,2600,1573,1546,150
4; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.82 (3H, s), 3.33 (2H, q, J = 5.
1 Hz), 4.59 (2H, t, J = 5.1 Hz),
6.65 (1H, d, J = 7.9 Hz), 6.89 (1
H, d, J = 7.9 Hz), 7.16 (1H, t, J =
7.9 Hz), 8.34 (3H, brs).

Example 50 5-Amino-3- (2-aminoethoxy) -1,2-benzisoxazole dihydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy)- 5-Nitro-1,2-benzisoxazole 3-hydroxy-5-nitro-1,2-benzisoxazole (2.70 g) was reacted and worked up as in Example 1 (e). By the target compound (3.60 g,
74%). Melting point: 136-137; IR spectrum (KBr) ν _max cm ^-1 : 334
6,1688,1624,1555,1531; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.67 (2H, q, J = 5.1H
z), 4.55 (2H, t, J = 5.1 Hz), 4.9
5 (1H, brs), 7.56 (1H, d, J = 9.2)
Hz), 8.46 (1H, dd, J = 9.2 Hz, J =
2.2Hz), 8.62 (1H, d, J = 2.2H)
z).

(B) 5-amino-3- (2- (N-tert-butoxycarbonylamino) ethoxy)-
1,2-Benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-nitro-1,2-benzisoxazole (2.00 g) was prepared according to Example 32 (a). The target compound (1.65) can be obtained by reacting and post-treating in the same manner.
g, 91%). Melting point: 134-135; IR spectrum (KBr) ν _max cm ^-1 : 347
0,3442,3384,3360,3325,327
6,1699,1639; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.63 (2H, q, J = 5.1H
z), 3.70 (2H, s), 4.47 (2H, t, J
= 5.1 Hz), 4.95 (1H, brs), 6.83
(1H, d, J = 2.7 Hz), 6.92 (1H, d
d, J = 8.9 Hz, J = 2.7 Hz), 7.23 (1
H, d, J = 8.9 Hz).

(C) 5-amino-3- (2-aminoethoxy) -1,2-benzisoxazole dihydrochloride 5-amino-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -1,2-Benzisoxazole (0.24 g) was reacted in the same manner as in Example 1 (f) and post-treated to give the target compound (0.21 g,
99%). Melting point: 182-202 (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 342
8,3379,2963,2859,2726,266
5,2581,1656,1637,1628,160
9,1549,1507; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.46 (2H, q, J = 5.1 Hz), 4.63 (2
H, t, J = 5.1 Hz), 7.57 (1H, dd, J)
= 8.9 Hz, J = 2.0 Hz), 7.67 (1H,
d, J = 2.0 Hz), 7.93 (1H, d, J = 8.
9 Hz), 8.35 (3H, brs).

Example 51 3- (2-aminoethoxy) -4,7-dimethyl-1,
2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4,7-dimethyl-1,2-
Benzoisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-1,2-benzisoxazole (0.15 g) in tetrahydrofuran (5 ml)
After cooling to −70 ° C. in a nitrogen atmosphere, butyllithium (0.7 ml, 1.6 M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes, and then naturally heated to 0 ° C. After cooling the reaction solution to -70 ° C, methyl iodide (0.
11 g) was added, and the temperature was spontaneously raised to 0 ° C. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (40 m
The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing agent:
Purification using cyclohexane / ethyl acetate = 9/1) gave the target compound (0.12 g, 80%) as a colorless powder. Melting point: 78-79 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
2,1694,1604,1543,1517; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.44 (3H, s), 2.56 (3
H, s), 4.26 (2H, q, J = 5.1 Hz),
4.49 (2H, t, J = 5.1 Hz), 4.90 (1
H, brs), 6.89 (1H, d, J = 7.3H)
z), 7.15 (1H, d, J = 7.3 Hz).

(B) 3- (2-aminoethoxy)-
4,7-dimethyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4,7-dimethyl-1,2-benzisoxazole (0. 10g) was reacted in the same manner as in Example 1 (f) and worked up to give the target compound (0.0
8 g, quant). Melting point: 222-225 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 3300
-2400,1601,1561,1542,1511
NMR spectrum (DMSO-d ₆ ) δ ppm:
2.40 (3H, s), 2.57 (3H, s), 3.3
5 (2H, t, J = 5.1 Hz), 4.60 (2H,
t, J = 5.1 Hz), 7.01 (1H, d, J = 7.
3 Hz), 7.31 (1H, d, J = 7.3 Hz),
8.31 (3H, brs).

Example 52 3- (2-aminoethoxy) -4-methoxy-1,2-
Benzoisoxazole hydrochloride (a) 2-Fluoro-6-methoxybenzoic acid methyl ester 6-Fluorosalicylic acid (5.00 g) is dissolved in dimethylformamide (50 ml), and anhydrous potassium carbonate (6.00 g) is stirred at room temperature. ) And methyl iodide (6.0 m
l) was added and stirred vigorously at room temperature for 12 hours. After completion of the reaction, the reaction solution was diluted with ether, washed with water, and dried using anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (5.80 g, 98%) as an oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.8
6 (3H, s), 3.93 (3H, s), 6.70-
6.80 (2H, m), 7.28-7.37 (1H,
m).

(B) 2-Fluoro-6-methoxybenzohydroxamic acid 2-fluoro-6-methoxybenzoic acid methyl ester and hydroxylamine hydrochloride were reacted in the same manner as in Example 1 (b) and post-treated. , The target compound (yield 44
%). NMR spectrum (CDCl ₃ + MeOH-d ₄ ) δp
pm: 3.92 (3H, s), 6.75-6.86
(2H, m), 7.35-7.45 (1H, m).

(C) 3-hydroxy-4-methoxy-
1,2-Benzisoxazole 2-fluoro-6-methoxybenzohydroxamic acid (2.55 g) and potassium hydroxide (4.50 g) were dissolved in butanol (25 ml), and the mixture was heated under reflux for 4 hours. After completion of the reaction, the reaction solution was acidified, extracted with ethyl acetate, washed with water, and dried using anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from isopropyl ether to obtain the desired compound (2.05 g, 90%). Melting point: 183-185 ° C .; NMR spectrum (CDCl ₃ ) δ ppm: 4.0
2 (3H, s), 6.65 (1H, d, J = 8.2H
z), 6.99 (1H, d, J = 8.2 Hz), 7.5
0 (1H, t, J = 8.2 Hz).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxy-
1,2-Benzisoxazole 3-Hydroxy-4-methoxy-1,2-benzisoxazole was reacted in the same manner as in Example 1 (e) and post-treated to give the target compound (81% yield). ) Got. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, m), 3.96 (3
H, s), 4.50 (2H, t, J = 5.1 Hz),
5.06 (1H, brs), 6.61 (1H, d, J =
8.2 Hz), 7.02 (1H, d, J = 8.2H)
z), 7.43 (1 H, t, J = 8.2 Hz).

(E) 3- (2-aminoethoxy) -4
-Methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxy-1,2-benzisoxazole was prepared in Example 1 (f). The target compound (82% yield) was obtained by post-treatment. Melting point: 193-197 ° C; IR spectrum (KBr) ν _max cm ^-1 : 343
5,3220,2960,1630,1615,153
5,1505; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.2 Hz), 3.92 (3
H, s), 4.60 (2H, t, J = 5.2 Hz),
6.86 (1H, d, J = 8.4 Hz), 7.17 (1
H, d, J = 8.4 Hz), 7.58 (1H, t, J =
8.4 Hz).

Example 53 3- (2-Aminoethoxy) -4-methoxy-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy)- 4-methoxy-1,2-benzisoxazole was reacted in the same manner as in Example 51 (a) and then in Example 1 (f), followed by post-treatment to obtain the target compound. Melting point: 208-211 ° C; IR spectrum (KBr) ν _max cm ^-1 : 316
0,2840,1640,1620,1540,152
0,1510; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.35 (3H, s), 3.33 (2H, t, J = 5.
4Hz), 3.89 (3H, s), 4.59 (2H,
t, J = 5.4 Hz), 6.75 (1H, d, J = 8.
1 Hz), 7.37 (1H, d, J = 8.1 Hz),
8.30 (3H, brs).

Example 54 3- (2-aminoethoxy) -4-fluoro-1,2-
Benzoisoxazole hydrochloride (a) 2,6-difluorobenzohydroxamic acid 2,6-difluorobenzoic acid methyl ester is reacted with hydroxylamine hydrochloride in the same manner as in Example 1 (b), and the post-treatment is carried out. A compound (65% yield) was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm:
7.14-7.25 (2H, m), 7.50-7.60
(1H, m), 9.40 (1H, brs), 11.15
(1H, brs).

(B) 3-hydroxy-4-fluoro-
Example 52: 1,2-benzisoxazole 2,6-difluorobenzohydroxamic acid
The target compound (yield 36%) was obtained by carrying out the same reaction as in (c) and post-treatment. Melting point: 175-178 ° C; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.09 (1H, t, J = 8.5 Hz), 7.40 (1
H, d, J = 8.5 Hz), 7.57-7.65 (1
H, m).

(C) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-
1,2-Benzisoxazole 3-Hydroxy-4-fluoro-1,2-benzisoxazole was reacted in the same manner as in Example 1 (e) and post-treated to give the target compound (yield 67%). ) Got. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
7 (9H, s), 3.65 (2H, m), 4.51 (2
H, t, J = 5.1 Hz), 4.90-5.06 (1
H, brs), 6.91 (1H, t, J = 8.5H)
z), 7.23 (1H, t, J = 8.5 Hz), 7.4
4-7.52 (1H, m).

(D) 3- (2-aminoethoxy) -4
-Fluoro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-1,2-benzisoxazole was prepared according to Example 1 (f). The target compound (yield 75%) was obtained by carrying out the same reaction and post-treatment. Melting point: 230-233 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
5,2970,1635,1620,1545,152
0,1510; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.2 Hz), 4.66 (2
H, t, J = 5.2 Hz), 7.21 (1H, t, J =
8.3 Hz), 7.53 (1H, d, J = 8.3H)
z), 7.68-7.74 (1H, m), 8.35 (3
H, brs).

Example 55 3- (2-Aminoethoxy) -4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3- (2-aminoethoxy) -4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride
(2-aminoethoxy) -4-fluoro-7-methyl-
1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-1,2-benzisoxazole was prepared in Example 51 (a) and then in Example 1. By reacting in the same manner as in (f) and performing post-treatment, 3- (2-aminoethoxy) -4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3- (2-aminoethoxy) ) -4-Fluoro-7-methyl-1,2-benzisoxazole hydrochloride was obtained. (A) 3- (2-aminoethoxy) -4-fluoro-
Data for 5-methyl-1,2-benzisoxazole hydrochloride Melting point: 201-208 ° C; IR spectrum (KBr) ν _max cm ^-1 : 343
0,3305,2840,1645,1615,154
0,1515; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.32 (3H, s), 3.34 (2H, q, J = 5.
0 Hz), 4.64 (2H, t, J = 5.0 Hz),
7.42 (2H, d, J = 8.4 Hz), 7.60 (1
H, t, J = 8.4 Hz), 8.27 (3H, br)
s).

(B) 3- (2-aminoethoxy) -4
Data for -fluoro-7-methyl-1,2-benzisoxazole hydrochloride Melting point: 196-202 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
5,1635,1550,1520; NMR spectrum (DMSO-d ₆ ) δppm:
2.42 (3H, s), 3.35 (2H, t, J = 5.
2Hz), 4.65 (2H, t, J = 5.2Hz),
7.10 (1H, t, J = 8.9 Hz), 7.47−
7.51 (1H, m), 8.32 (3H, brs).

Example 56 3- (2-Aminoethylthio) -5-chloro-7-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethylthio) -5-chloro-7-methyl-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-1,2-benzisoxazole (0.20 g) was prepared in the same manner as in Example 17 (b). The target compound (0.13
g, 62%). NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 2.51 (3H, s), 3.40 (2
H, t, J = 6.3 Hz), 3.58 (2H, q, J =
6.3 Hz), 5.07 (1H, brs), 7.29
(1H, s), 7.36 (1H, s).

(B) 3- (2-aminoethylthio)-
5-chloro-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-7-methyl-1,2-
Benzoisoxazole (0.12 g) was prepared in Example 1 (f).
The target compound (0.10 g, quant.) Was obtained by reacting in the same manner as described above and performing post-treatment. Melting point: 205-208 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 296
6,2927,2848,2802,1481; NMR spectrum (DMSO-d ₆ ) δppm:
2.50 (3H, s), 3.23 (2H, t, J = 6.
9Hz), 3.53 (2H, t, J = 6.9Hz),
7.62 (1H, s), 7.74 (1H, s), 8.1
9 (3H, brs).

Example 57 3- (2-Aminoethylthio) -5-chloro-7-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethylthio) -5-chloro-7-carboxy-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-1,2-benzisoxazole ( 0.51 g) was reacted in the same manner as in Example 18 (a) and worked up to give the desired compound (0.42 g).
g, 72%).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-
7-carbamoyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-7-carboxy-1,
Example 18 was 2-benzoisoxazole (0.20 g).
The target compound (0.17 g, 85%) was obtained by reacting and post-treating in the same manner as in (b). IR spectrum (KBr) ν _max cm ^-1 : 347
1,3354,3143,1693,1678; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.45 (2H, t, J = 6.1H
z), 3.59 (2H, q, J = 6.1 Hz), 4.9
6 (1H, brs), 5.97 (1H, brs), 7.
12 (1H, brs), 7.73 (1H, s), 8.3
4 (1H, s).

(C) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-
7-cyano-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-7-carbamoyl-
By reacting 1,2-benzisoxazole (0.15 g) in the same manner as in Example 19 (a) and performing post-treatment,
The target compound (0.13 g, 90%) was obtained. IR spectrum (KBr) ν _max cm ^-1 : 336
6,2240,1685; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.46 (2H, t, J = 6.2H)
z), 3.60 (2H, q, J = 6.2 Hz), 4.9
6 (1H, brs), 7.81 (1H, s), 7.84
(1H, s).

(D) 3- (2-aminoethylthio)-
5-chloro-7-cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloro-7-cyano-1,2-
Benzoisoxazole (0.12 g) was prepared in Example 1 (f).
The target compound (0.10 g, quant.) Was obtained by reacting in the same manner as described above and performing post-treatment. Melting point: 178-181 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
2,3038,2990,2235,1607,159
8,1588; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.25 (2H, t, J = 7.0 Hz), 3.57 (2
H, t, J = 7.0 Hz), 8.23 (3H, br)
s), 8.42 (1H, s), 8.49 (1H, s).

Example 58 3- (2-Aminoethoxy) -5-chloropyrido [3
2-d] isoxazole hydrochloride (a) 2,5-dichloronicotinic acid methyl ester 2,5-dichloronicotinic acid chloride (5.0 g)
Was dissolved in methanol (30 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ether, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 30).
/ 1) to give the target compound (4.2 g, 86
%). NMR spectrum (CDCl ₃ ) δ ppm: 3.9
8 (3H, s), 8.16 (1H, s), 8.48 (1
H, s).

(B) 2,5-dichloropyridine-3-
Carbohydroxamic acid 2,5-dichloronicotinic acid methyl ester (4.2
g) was reacted in the same manner as in Example 10 (b) and worked up to give the desired compound (3.3 g, 79%). IR spectrum (KBr) ν _max cm ^-1 : 318
7,3073,3058,2985,2906,285
1,1661,1575,1553; NMR spectrum (DMSO-d ₆ ) δppm:
8.11 (1H, s), 8.58 (1H, s), 9.5
0 (1H, s), 11.40 (1H, s).

(C) 3-Hydroxy-5-chloropyrido [3,2-d] isoxazole 2,5-dichloropyridine-3-carbohydroxamic acid (1.5 g) was reacted in the same manner as in Example 10 (c). By post-treatment, the target compound (0.82 g, 66
%). IR spectrum (KBr) ν _max cm ^-1 : 319
3,3166,3069,3055,3003,291
9,2821,2783,2734,2689,263
3,2587,2550,1697,1615,160
2,155,1508; NMR spectrum (DMSO-d ₆ ) δ ppm:
8.40 (1H, s), 8.63 (1H, s), 12.
90 (1H, brs).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloropyrido [3,2-d] isoxazole 3-hydroxy-5-chloropyrido [3,2-d] isoxazole ( 0.20 g) was reacted in the same manner as in Example 1 (e) and worked up to give the target compound (0.27 g).
g, 73%). IR spectrum (KBr) ν _max cm ^-1 : 336
0, 1709, 1701, 1599, 1537, 152
5; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.64 (2H, q, J = 5.2H
z), 4.52 (2H, t, J = 5.2 Hz), 4.9
0 (1H, brs), 8.03 (1H, s), 8.54
(1H, s).

(E) 3- (2-aminoethoxy) -5
-Chloropyrido [3,2-d] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloropyrido [3,2-d] isoxazole (0.21 g) was prepared in Example 1 ( The target compound (0.19) was reacted and post-treated in the same manner as in (f).
g, quant. ) Got. Melting point: 225-230 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 306
5,3036,2978,2900,1604,159
8,1535; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.0 Hz), 4.64 (2
H, t, J = 5.0 Hz), 8.25 (3H, br)
s), 8.50 (1H, s), 8.76 (1H, s).

Example 59 3- (2-Aminoethylthio) -5-chloropyrido [3,2-d] isoxazole hydrochloride (a) 3,5-dichloropyrido [3,2-d] isoxazole 5-chloro-3 -Hydroxypyrido [3,2-d] isoxazole (0.27 g) was reacted in the same manner as in Example 16 and post-treated to give the target compound (0.21 g,
73%). NMR spectrum (CDCl ₃ ) δ ppm: 8.0
8 (1H, s), 8.64 (1H, s).

(B) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloropyrido [3,2-d] isoxazole 3,5-dichloropyrido [3,2-d] isoxazole (0. 10g) was reacted as in Example 26 (b),
By post-treatment, the target compound (0.12 g, 71
%). IR spectrum (KBr) ν _max cm ^-1 : 336
9,1688,1530; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.44 (2H, t, J = 6.3H)
z), 3.59 (2H, q, J = 6.3 Hz), 4.9
7 (1H, brs), 7.95 (1H, s), 8.57
(1H, s).

(C) 3- (2-aminoethylthio)-
Example 1 5-chloropyrido [3,2-d] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-chloropyrido [3,2-d] isoxazole (0.10 g). The target compound (0.0
8g, quant. ) Got. Melting point: 194-198 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 304
0,3001,2909,1586,1515; NMR spectrum (DMSO-d ₆ ) δppm:
3.24 (2H, t, J = 7.1 Hz), 3.55 (2
H, t, J = 7.1 Hz), 8.17 (3H, br)
s), 8.69 (1H, s), 8.79 (1H, s).

Example 60 3- (2-aminoethoxy) -4-methoxycarbonyl-7-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ) Ethoxy) -4-methoxycarbonyl-7
-Methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-1,2-benzisoxazole was prepared in the same manner as in Example 22 (b). The target compound (yield 91%) was obtained by reacting and post-treating. Melting point: 62-64 ° C; IR spectrum (KBr) ν _max cm ^-1 : 338
0, 1715, 1703, 1621, 1591, 153
4,1513; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.56 (3H, s), 3.66 (2
H, q), 3.97 (3H, s), 4.51 (2H,
t, J = 5.1 Hz), 5.33 (1H, brs),
7.35 (1H, d, J = 7.6 Hz), 7.78 (1
H, d, J = 7.6 Hz).

(B) 3- (2-aminoethoxy) -4
-Methoxycarbonyl-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-7-methyl-1,2-benzoiso Xazazole was reacted in the same manner as in Example 17 (c) and worked up to give the target compound (yield 97%). Melting point: 200-202 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 314
8,3003,2953,1699,1608,159
1,1534,1511; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.53 (3H, s), 3.34 (2H, t, J = 5.
1Hz), 3.91 (3H, s), 4.61 (2H,
t, J = 5.1 Hz), 7.59 (1H, d, J = 7.
5 Hz), 7.76 (1H, d, J = 7.5 Hz),
8.19 (3H, brs).

Example 61 3- (2-aminoethoxy) -4-carbamoyl-7-
Methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-7-methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-1,2-benzisoxazole was reacted in the same manner as in Example 23 (a) and post-treated to give the target compound (yield 83%). Melting point: 140-141 ° C; IR spectrum (KBr) ν _max cm ^-1 : 345
1,3351,3199,1705,1675,161
8, 1585, 1539, 1525, 1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
3 (9H, s), 2.56 (3H, s), 3.70 (2
H, q, J = 5.1 Hz), 4.61 (2H, t, J =
5.1Hz), 4.94 (1H, brs), 5.89
(1H, brs), 7.41 (1H, d, J = 7.6H)
z), 7.80 (1H, brs), 8.06 (1H,
d, J = 7.6 Hz).

(B) 3- (2-aminoethoxy) -4
-Carbamoyl-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-7-methyl-1,
2-Benzisoxazole was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound (yield 9).
9%). Melting point: 202-205 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
5,3347,3293,3203,2950,190
1,1687,1659,1608,1581,154
4,1512; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.50 (3H, s), 3.34 (2H, t, J = 5.
1 Hz), 4.64 (2H, t, J = 5.1 Hz),
7.53 (2H, s), 7.64 (1H, brs),
7.92 (1H, brs), 8.22 (3H, br)
s).

Example 62 3- (2-Aminoethoxy) -4-cyano-7-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -4-cyano-7-methyl-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-7-methyl-1,
2-Benzisoxazole was reacted in the same manner as in Example 24 (a) and post-treated to give the target compound (yield 9).
5%). Melting point: 84-85 ° C; IR spectrum (KBr) ν _max cm ^-1 : 345
2,3397,2231,1716,1597,155
2,1541,1509; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.59 (3H, s), 3.68 (2
H, q, J = 5.1 Hz), 4.54 (2H, t, J =
5.1Hz), 5.10 (1H, brs), 7.40
(1H, d, J = 7.4 Hz), 7.54 (1H, d,
J = 7.4 Hz).

(B) 3- (2-aminoethoxy) -4
-Cyano-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-7-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the desired compound (96% yield).
I got Melting point: 208-211 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 309
9,3036,2966,2908,2873,285
0, 2754, 2733, 2232, 1598, 154
2,1514; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.56 (3H, s), 3.39 (2H, t, J = 5.
1 Hz), 4.71 (2H, t, J = 5.1 Hz),
7.68 (1H, d, J = 7.5 Hz), 7.87 (1
H, d, J = 7.5 Hz), 8.26 (3H, br)
s).

Example 63 3- (2-Aminoethoxy) -7-methyl-4-methylthio-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -7-methyl-4-methylthio-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-1,2-benzisoxazole (0 .15 g) in tetrahydrofuran (20 m
l) and cooled to -70 ° C under a nitrogen atmosphere.
Butyl lithium (0.75 ml, 1.6 M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, and then dimethyl disulfide (0.11 g) was added. The reaction solution is -70 ° C
After stirring for 15 minutes, the temperature was raised to 0 ° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice with 40 ml), and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing agent: cyclohexane / ethyl acetate = 9/1) to obtain the desired compound (0.15 g, 88%). Obtained as a colorless powder. Melting point: 85-86 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
6,1699,1627,1589,1549,153
3; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.44 (3H, s), 2.53 (3
H, s), 3.66 (2H, q, J = 5.1 Hz),
4.49 (2H, t, J = 5.1 Hz), 5.07 (1
H, brs), 6.86 (1H, d, J = 7.5H)
z), 7.22 (1H, d, J = 7.5 Hz).

(B) 3- (2-aminoethoxy) -7
-Methyl-4-methylthio-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-methyl-4-methylthio-1,2
-Benzisoxazole was reacted in the same manner as in Example 17 (c) and worked up to give the desired compound (yield 94%).
%). Melting point: 216-218 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 294
0,2917,2883,1629,1593,154
1,1508; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.39 (3H, s), 2.53 (3H, s), 3.3
4 (2H, t, J = 5.1 Hz), 4.61 (2H,
t, J = 5.1 Hz), 7.03 (1H, d, J = 7.
5 Hz), 7.41 (1H, d, J = 7.5 Hz),
8.26 (3H, brs).

Example 64 3- (2-Aminoethoxy) -7-chloro-4-methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -7-chloro-4-methyl-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-chloro-1,2-benzisoxazole was reacted in the same manner as in Example 51 (a), By post-treatment, the target compound was obtained in a yield of 93%. IR spectrum (KBr) ν _max cm ^-1 : 335
5,1691,1605,1551,1536; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.57 (3H, s), 3.65 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1 Hz), 4.87 (1H, brs), 6.94
(1H, d, J = 7.8 Hz), 7.37 (1H, d,
J = 7.8 Hz).

(B) 3- (2-aminoethoxy) -7
-Chloro-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-chloro-4-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 98%. Melting point: 215-218 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 319
4,2967,2892,1606,1540; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.60 (3H, s), 3.35 (2H, t, J = 5.
1 Hz), 4.63 (2H, t, J = 5.1 Hz),
7.17 (1H, d, J = 7.7 Hz), 7.66 (1
H, d, J = 7.7 Hz), 8.24 (3H, br)
s).

Example 65 3- (2-aminoethoxy) -5,7-dichloro-4-
Methyl-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5,7-dichloro-4-methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5,7-chloro-1,2-benzisoxazole was reacted in the same manner as in Example 51 (a), and was post-treated. The target compound was obtained in a yield of 95%. Melting point: 109-111 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
4,1697,1616,1552,1528; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.59 (3H, s), 3.63 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1 Hz), 4.93 (1H, brs), 7.58
(1H, s).

(B) 3- (2-aminoethoxy)-
5,7-dichloro-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5,7-dichloro-4-methyl-1,
2-Benzisoxazole was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound in a yield of 9
Obtained at 9%. Melting point: 222-225 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 306
2,2970,2897,2770,1618,159
6,1542,1521; NMR Spectrum (DMSO-d ₆₎ δppm:
2.56 (3H, s), 3.38 (2H, t, J = 5.
1 Hz), 4.62 (2H, t, J = 5.1 Hz),
7.90 (1H, s), 8.28 (3H, brs).

Example 66 3- (2-aminoethoxy) -7-carbamoyl-5
Chloro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-5-chloro-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-1,2-benzisoxazole is reacted and worked up in the same manner as in Example 18 (a) and then in Example 18 (b). Thereby, the target compound was obtained in a yield of 88%. IR spectrum (KBr) ν _max cm ^-1 : 342
8,3375,3297,3187,1691,165
8, 1620, 1560, 1531; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.66 (2H, q, J = 5.1H
z), 4.53 (2H, t, J = 5.1 Hz), 4.9
4. (1H, brs), 5.99 (1H, brs), 7.
08 (1H, brs), 7.80 (1H, d, J = 2.
1 Hz), 8.31 (1H, d, J = 2.1 Hz).

(B) 3- (2-aminoethoxy) -7
-Carbamoyl-5-chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-carbamoyl-5-chloro-1,
2-Benzisoxazole was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound in a yield of 9
Obtained at 8%. Melting point: 232-237 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 345
0,3339,3290,3238,3164,308
2,3047,3011,2952,2878,284
7,2818,2766,2688,1672,162
6,1608, 1594, 1547, 1520; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.47 (2H, t, J = 5.1 Hz), 4.63 (2
H, t, J = 5.1 Hz), 7.94 (1H, br)
s), 7.97 (1H, brs), 8.03 (1H,
d, J = 2.2 Hz), 8.05 (1H, d, J = 2.
2Hz), 8.33 (3H, brs).

Example 67 3- (2-Aminoethoxy) -5-chloro-7-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -5-chloro-7-cyano-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-7-carbamoyl-1,
2-Benzisoxazole was reacted in the same manner as in Example 24 (a) and worked up to give the target compound in a yield of 9
Obtained at 2%. Melting point: 141-143 ° C; IR spectrum (KBr) ν _max cm ^-1 : 336
4,2244,1684,1609,1547,152
7; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.62 (2H, q, J = 5.1H
z), 4.53 (2H, t, J = 5.1 Hz) <4.9.
0 (1H, brs), 7.81 (1H, d, J = 2.2)
Hz), 7.88 (1H, d, J = 2.2 Hz).

(B) 3- (2-aminoethoxy) -5
-Chloro-7-cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-7-cyano-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 94%. Melting point 211-214 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 307
0, 3047, 2943, 2878, 2810, 276
9,2739,2685,2637,2243,161
1,1586,1548,1507; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 8.32 (1H, d, J =
2.2Hz), 8.39 (3H, brs), 8.48
(1H, d, J = 2.2 Hz).

Example 68 3- (2-Aminoethoxy) pyrido [2,3-d] isoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) pyrido [2,3- d] isoxazole 3-Hydroxypyrido [2,3-d] isoxazole was reacted in the same manner as in Example 1 (e) and worked up to give the target compound in a yield of 63%. Melting point: 94-95 ° C; IR spectrum (KBr) ν _max cm ^-1 : 337
4,3247,1754,1698,1678,158
7,1529; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
4 (9H, s), 3.68 (2H, q, J = 5.1H
z), 4.59 (2H, t, J = 5.1 Hz), 5.1
2 (1H, brs), 7.50 (1H, dd, J = 8.
6 Hz, J = 4.4 Hz), 7.81 (1 H, dd, J
= 8.6 Hz, J = 1.4 Hz), 8.68 (1H, d
d, J = 4.4 Hz, J = 1.4 Hz).

(B) 3- (2-Aminoethoxy) pyrido [2,3-d] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) pyrido [2,3-d] isoxazole Was reacted in the same manner as in Example 1 (f) and post-treated to obtain the target compound in a yield of 89%. Melting point: 217-222 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 307
0, 3020, 2980, 2911, 2870, 278
3,2700,2658,2601,1631,158
6,1541; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.35 (2H, t, J = 5.1 Hz), 4.72 (2
H, t, J = 5.1 Hz), 7.73 (1H, dd, J)
= 8.6 Hz, J = 4.4 Hz), 8.21 (1H,
d, J = 8.6 Hz), 8.32 (3H, brs),
8.73 (1H, d, J = 4.4 Hz).

Example 69 3- (2-Aminoethoxy) -4-trifluoromethylpyrido [3,2-d] isoxazole hydrochloride (a) 4-trifluoromethylnicotinic acid N-oxide 4-trifluoromethyl Nicotinic acid (5.00 g) was dissolved in a mixture of acetic acid (20 ml) and 31% aqueous hydrogen peroxide (5 ml), and the mixture was heated and stirred at 100 ° C. for 10 hours. The solvent was distilled off under reduced pressure, and the target compound (5.40 g, quant) was obtained.
Was obtained as a solid. Melting point: 210-215 ° C. (decomposition); NMR spectrum (CDCl ₃ ) δ ppm: 7.6
1 (1H, d, J = 6.9 Hz), 8.32 (1H,
d, J = 6.9 Hz), 8.56 (1H, s). (B) 2-Chloro-4-trifluoromethylnicotinic acid methyl ester To 4-trifluoromethylnicotinic acid N-oxide (2.00 g), phosphorus oxychloride (4.0 ml) and phosphorus pentachloride (4.0 g) were added. In addition, the mixture was heated and stirred at 100 ° C. for 4 hours. The phosphorus oxychloride was distilled off under reduced pressure, and methanol (30 ml) was added to the obtained residue under ice-cooling.
Stirred for 0 minutes. The reaction mixture was made alkaline by adding aqueous sodium bicarbonate, extracted with ether, washed with water, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing agent: hexane / ethyl acetate = 9 /
Purification was performed using 1), and the desired compound (310 mg, 14
%) As an oil. NMR spectrum (CDCl ₃ ) δ ppm: 4.01
(3H, s), 7.54 (1H, d, J = 5.3H
z), 8.65 (1H, d, J = 5.3 Hz).

(C) 3-Hydroxy-4-trifluoromethylpyrido [3,2-d] isoxazole 2-chloro-4-trifluoromethylnicotinic acid methyl ester (300 mg) was added to hydroxylamine hydrochloride (4
50 mg) and an aqueous solution (5 ml) of sodium hydroxide (520 mg) were added at room temperature, and the mixture was stirred at room temperature for 5 days. The reaction solution was acidified by adding dilute hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried using anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain the desired compound (180 mg, 67%) as a solid. Melting point: 196-202 ° C .; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.81 (1H, d, J = 4.9 Hz), 8.88 (1
H, d, J = 4.9 Hz), 13.30 (1H, br)
s).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-trifluoromethylpyrido [3,2-d] isoxazole 3-hydroxy-4-trifluoromethylpyrido 3,
2-d] isoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared according to Example 1 (e).
The reaction was carried out in the same manner as described above, and post-treatment was performed to obtain a solid target compound in a yield of 75%. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.65 (2H, q, J = 5.2H
z), 4.55 (2H, t, J = 5.2 Hz), 4.9
0 (1H, brs), 7.56 (1H, d, J = 4.9)
Hz), 8.77 (1H, d, J = 4.9 Hz).

(E) 3- (2-aminoethoxy) -4
-Trifluoromethylpyrido [3,2-d] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-trifluoromethylpyrido [3
2-d] isoxazole was reacted in the same manner as in Example 1 (f) and worked up to give the target compound in a yield of 96%. Melting point: 203-207 ° C; IR spectrum (KBr) ν _max cm ^-1 : 310
0,2970,1600,1540; NMR spectrum (DMSO-d ₆ ) δppm:
3.34 (2H, t, J = 5.5 Hz), 4.71 (2
H, t, J = 5.5 Hz), 7.94 (1H, d, J =
4.8 Hz), 8.26 (3H, brs), 8.97
(1H, d, J = 4.8 Hz).

Example 70 3- (2-Aminoethoxy) -7-trifluoromethyl-1,2-benzisoxazole hydrochloride (a) 2-fluoro-3-trifluoromethylbenzoic acid methyl ester 2-fluoro -3-Trifluoromethylbenzoic acid was reacted in the same manner as in Example 52 (a) and post-treated to give the target compound as an oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.9
6 (3H, s), 7.31 (1H, t, J = 5.0H)
z), 7.79 (1H, t, J = 5.0 Hz), 8.1
8 (1H, t, J = 5.0 Hz).

(B) 2-Fluoro-3-trifluoromethylbenzohydroxamic acid 2-fluoro-3-trifluoromethylbenzoic acid methyl ester was reacted in the same manner as in Example 52 (b), and post-treated. The desired compound was obtained. NMR spectrum (DMSO-d ₆ ) δ ppm:
7.46 (1H, t, J = 5.0 Hz), 7.82 (2
H, m).

(C) 3-Hydroxy-7-trifluoromethyl-1,2-benzisoxazole 2-fluoro-3-trifluoromethylbenzohydroxamic acid was reacted in the same manner as in Example 52 (c). By treatment, a solid target compound was obtained. Melting point: 204-207 ° C; NMR spectrum (DMSO-d ₆ ) δ ppm:
7.54 (1H, t, J = 7.6 Hz), 7.98 (1
H, d, J = 7.6 Hz), 8.09 (1H, d, J =
7.6 Hz), 12.80 (1H, brs).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-trifluoromethyl-1,2-benzisoxazole 3-hydroxy-7-trifluoromethyl-1,2 -Benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were reacted in the same manner as in Example 1 (e) and post-treated to obtain a solid target compound in a yield of 65%. . NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 3.65 (2H, q, J = 5.2H
z), 4.54 (2H, t, J = 5.2 Hz), 4.5
2 (1H, brs), 7.39 (1H, t, J = 7.6)
Hz), 7.79 (1H, d, J = 7.6 Hz), 7.
85 (1H, d, J = 7.6 Hz).

(E) 3- (2-aminoethoxy) -7
Example 1 was performed using -trifluoromethyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -7-trifluoromethyl-1,2-benzisoxazole. The target compound was obtained in a yield of 77% by reacting and post-treating in the same manner as in (f). Melting point: 190-194 ° C; IR spectrum (KBr) ν _max cm ^-1 : 297
0,2905,1615,1555,1510; NMR Spectrum (DMSO-d _6): 3.37
(2H, t, J = 5.1 Hz), 4.68 (2H, t,
J = 5.1 Hz), 7.62 (1H, t, J = 7.6H)
z), 8.09 (1H, d, J = 7.6 Hz), 8.1
6 (1H, d, J = 7.6 Hz), 8.44 (3H, b
rs).

Example 71 3- (2-Aminoethoxy) -4-chloro-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4 -Chloro-1,2-benzisoxazole 3-hydroxy-4-chloro-1,2-benzisoxazole and 2- (N-tert-butoxycarbonylamino) ethanol were prepared in the same manner as in Example 1 (e). React
By post-treatment, the target compound was obtained in a yield of 63%. Melting point: 110-111 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
7, 1691, 1607, 1537; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.66 (2H, q, J = 5.1H
z), 4.51 (2H, t, J = 5.1 Hz), 4.9
9 (1H, brs), 7.23 (1H, d, J = 7.6)
Hz), 7.34 (1H, d, J = 8.4 Hz), 7.
44 (1H, dd, J = 8.4 Hz, J = 7.6H
z).

(B) 3- (2-aminoethoxy) -4
-Chloro-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-1,2-benzisoxazole was prepared according to Example 17 (c). The target compound was obtained in a yield of 99% by the same reaction and post-treatment. Melting point: 221-226 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 344
0, 3070, 3006, 2969, 2898, 161
0, 1538, 1515; NMR spectrum (DMSO-d ₆ ) δ ppm: 3.
35 (2H, t, J = 5.4 Hz), 4.65 (2H,
t, J = 5.4 Hz), 7.42-7.49 (1H,
m), 7.62-7.71 (2H, m), 8.23 (3
H, brs).

Example 72 3- (2-Aminoethoxy) -6-methylpyrido [3
2-d] isoxazole hydrochloride (a) 2-chloro-6-methylnicotinic acid ethyl ester 2-chloro-6-methylnicotinic acid was reacted in the same manner as in Example 1 (a), followed by post-treatment to obtain the objective compound. The compound was obtained as an oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.4
1 (3H, t, J = 7.2 Hz), 2.59 (3H,
s), 4.41 (2H, q, J = 7.2 Hz), 7.1
6 (1H, d, J = 7.2 Hz), 8.08 (1H,
d, J = 7.2 Hz).

(B) 2-Chloro-6-methylpyridine-3-carbohydroxamic acid Ethyl 2-chloro-6-methylnicotinic acid was reacted in the same manner as in Example 10 (b) and post-treated. The target compound was obtained as a powder. NMR spectrum (DMSO-d ₆ ) δ ppm:
2.51 (3H, s), 7.33 (1H, d, J = 7.
8 Hz), 7.75 (1 H, d, J = 7.8 Hz).

(C) 3-Hydroxy-6-methylpyrido [3,2-d] isoxazole 2-chloro-6-methylpyridine-3-carbohydroxamic acid was reacted in the same manner as in Example 10 (c) and worked up. As a result, the target compound was obtained as a powder. IR spectrum (KBr) ν _max cm ^-1 : 298
5,2907,2739,2559,1663,161
0, 1595, 1561, 1541; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.60 (3H, s), 7.30 (1H, d, J = 8.
0 Hz), 8.14 (1H, d, J = 8.0 Hz).

(D) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6-methylpyrido [3,2-d] isoxazole 3-hydroxy-6-methylpyrido [3,2-d] isoxazole 2- (N-tert-butoxycarbonylamino) ethanol was reacted in the same manner as in Example 1 (e) and post-treated to obtain the target compound in a yield of 71%. Melting point: 151-152 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
2,1718,1708,1614,1609,153
4; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.69 (3H, s), 3.64 (2
H, q, J = 5.1 Hz), 4.51 (2H, t, J =
5.1 Hz), 4.94 (1H, brs), 7.15
(1H, d, J = 8.0 Hz), 7.90 (1H, d,
J = 8.0 Hz).

(E) 3- (2-aminoethoxy) -6
-Methylpyrido [3,2-d] isoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -6-methylpyrido [3,2-d] isoxazole was prepared in the same manner as in Example 1 (f). The target compound was obtained in 97% yield by reacting and post-treating. Melting point: 209-213 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 342
6,3063,3000,2938,1669,160
9,1565,1536,1506; NMR Spectrum (DMSO-d ₆₎ δppm:
2.63 (3H, s), 3.30-3.40 (2H,
m), 4.62 (2H, t, J = 5.1 Hz), 7.4
0 (1H, d, J = 8.0 Hz), 8.18 (1H,
d, J = 8.0 Hz), 8.29 (3H, brs).

Example 73 3- (2-Aminoethoxy) -5-chloro-4-methyl-1,2-benzisoxazole hydrochloride and 3- (2
-Aminoethoxy) -5-chloro-7-methyl-1,2
-Benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-4-methyl-
1,2-benzisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5
-Chloro-7-methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-1,2-benzisoxazole was prepared in Example 17 (b ), And post-treated to give 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-4-methyl-1,2-benzisoxazole in a yield of 40. 3%
-(2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-7-methyl-1,2-benzisoxazole was obtained in a yield of 37%. Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-4-methyl-1,2-benzisoxazole Melting point: 140-141 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
1,1688,1615,1601,1537; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.62 (3H, s), 3.66 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1 Hz), 4.88 (1H, brs), 7.19
(1H, d, J = 8.8 Hz), 8.83 (1H, d,
J = 8.8 Hz). Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-7-methyl-1,2-benzisoxazole Melting point: 94-95 ° C; IR spectrum (KBr) ν _max cm ^-1 : 333
3,1686, 1611, 1539; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.48 (3H, s), 3.63 (2
H, q, J = 5.1 Hz), 4.49 (2H, t, J =
5.1 Hz), 4.94 (1H, brs), 7.29
(1H, d, J = 1.8 Hz), 7.44 (1H, d,
J = 1.8 Hz).

(B) 3- (2-aminoethoxy) -5
-Chloro-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-4-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 99%. Melting point: 223-226 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 345
1,3009,2970,1645,1618,160
5,1536; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.62 (3H, s), 3.34 (2H, t, J = 5.
1 Hz), 4.63 (2H, t, J = 5.1 Hz),
7.52 (1H, d, J = 8.9 Hz), 7.68 (1
H, d, J = 8.9 Hz), 8.28 (3H, br)
s).

(C) 3- (2-aminoethoxy) -5
-Chloro-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-chloro-7-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 98%. Melting point: 208-211 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 342
8, 3056, 2966, 2894, 2770, 160
8,1541,1517; NMR Spectrum (DMSO-d ₆₎ δppm:
2.46 (3H, s), 3.34 (2H, t, J = 5.
1 Hz), 4.60 (2H, t, J = 5.1 Hz),
7.59 (1H, d, J = 1.8 Hz), 7.69 (1
H, d, J = 1.8 Hz), 8.32 (3H, br)
s).

Example 74 3- (2-Aminoethoxy) -5-bromo-4-methyl-1,2-benzisoxazole hydrochloride and 3- (2
-Aminoethoxy) -5-bromo-7-methyl-1,2
-Benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-4-methyl-
1,2-benzisoxazole and 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5
-Bromo-7-methyl-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-1,2-benzisoxazole was prepared in Example 17 (b ), And post-treated to give 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-4-methyl-1,2-benzisoxazole in a yield of 7. %
(2- (N-tert-butoxycarbonylamino)
Ethoxy) -5-chloro-7-methyl-1,2-benzisoxazole was obtained in a yield of 68%. Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-4-methyl-1,2-benzisoxazole Melting point: 140-141 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
0,1688, 1618, 1595, 1538; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.64 (3H, s), 3.66 (2
H, q, J = 5.1 Hz), 4.50 (2H, t, J =
5.1 Hz), 4.88 (1H, brs), 7.14
(1H, d, J = 8.8 Hz), 7.63 (1H, d,
J = 8.8 Hz). Physical data of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-7-methyl-1,2-benzisoxazole Melting point: 79-80 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
0,1692,1612,1535; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.48 (3H, s), 3.65 (2
H, q, J = 5.1 Hz), 4.49 (2H, t, J =
5.1 Hz), 4.95 (1H, brs), 7.29
(1H, d, J = 1.8 Hz), 7.44 (1H, d,
J = 1.8 Hz).

(B) 3- (2-aminoethoxy) -5
-Bromo-4-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-4-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and post-treated to give the target compound in a yield of 96%. Melting point: 208-212 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
6,3000,1615,1599,1535; NMR Spectrum (DMSO-d ₆₎ δppm:
2.64 (3H, s), 3.34 (2H, t, J = 5.
1 Hz), 4.63 (2H, t, J = 5.1 Hz),
7.46 (1H, d, J = 8.9 Hz), 7.82 (1
H, d, J = 8.9 Hz), 8.24 (3H, br)
s).

(C) 3- (2-aminoethoxy) -5
-Bromo-7-methyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-7-methyl-1,2-benzisoxazole Was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 98%. Melting point: 212-215 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 333
9, 3054, 2968, 2925, 2892, 160
6,1546,1516; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.46 (3H, s), 3.33 (2H, t, J = 5.
1 Hz), 4.60 (2H, t, J = 5.1 Hz),
7.70 (1H, d, J = 1.8 Hz), 7.82 (1
H, d, J = 1.8 Hz), 8.28 (3H, br)
s).

Example 75 3- (2-aminoethoxy) -4,5-dimethyl-1,
2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4,5-dimethyl-1,2-
Benzoisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methyl-1,2-benzisoxazole is reacted in the same manner as in Example 51 (a) and worked up. As a result, the target compound was obtained in a yield of 73%. Melting point: 125-126 ° C; IR spectrum (KBr) ν _max cm ^-1 : 335
2,1694,1678,1620,1609,153
9; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 2.33 (3H, s), 2.51 (3
H, s), 3.65 (2H, q, J = 5.1 Hz),
4.49 (2H, t, J = 5.1 Hz), 4.90 (1
H, brs), 7.13 (1H, d, J = 8.5H)
z), 7.29 (1H, d, J = 8.5 Hz).

(B) 3- (2-aminoethoxy)-
Example of 4,5-dimethyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4,5-dimethyl-1,2-benzisoxazole The target compound was obtained in a yield of 96% by reacting in the same manner as in 17 (c) and performing post-treatment. Melting point: 180-183 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 343
4,2971,924,2751,1643,161
2,1538; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.32 (3H, s), 2.51 (3H, s), 3.3
4 (2H, t, J = 5.1 Hz), 4.61 (2H,
t, J = 5.1 Hz), 7.31 (1H, d, J = 8.
5Hz), 7.43 (1H, d, J = 8.5Hz),
8.28 (3H, brs).

Example 76 3- (2-Aminoethoxy) -4-methyl-5-methoxy-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) Ethoxy) -4-methyl-5-methoxy-
1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-methoxy-1,2-benzisoxazole was reacted in the same manner as in Example 51 (a), By post-treatment, the target compound was obtained in a yield of 88%. Melting point: 137-138 ° C; IR spectrum (KBr) ν _max cm ^-1 : 336
1,1689,1618,1538; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
5 (9H, s), 2.46 (3H, s), 3.65 (2
H, q, J = 5.1 Hz), 3.87 (3H, s),
4.48 (2H, t, J = 5.1 Hz), 4.90 (1
H, brs), 7.12 (1H, d, J = 8.9H)
z), 7.18 (1H, d, J = 8.9 Hz).

(B) 3- (2-aminoethoxy) -4
-Methyl-5-methoxy-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methyl-5-methoxy-1,2-
Benzoisoxazole was reacted in the same manner as in Example 17 (c) and worked up to give the target compound in a yield of 99%.
I got it. Melting point: 173-176 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 342
3,3008,2971,2920,2842,161
7, 1601, 1536, 1500; NMR spectrum (DMSO-d ₆ ) δ ppm:
2.44 (3H, s), 3.35 (2H, t, J = 5.
1 Hz), 3.84 (3H, s), 4.60 (2H,
t, J = 5.1 Hz), 7.35 (1H, d, J = 9.
0 Hz), 7.40 (1H, d, J = 9.0 Hz),
8.32 (3H, brs).

Example 77 3- (2-Aminoethoxy) -5-carbamoyl-1,
2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-carbamoyl-1,2-
Benzoisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-bromo-1,2-benzisoxazole was reacted in the same manner as in Example 23 (a) and worked up. As a result, the target compound was obtained in a yield of 12%. Melting point: 178-180 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
8,3197,1717,1672,1624,159
9,1543; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.53 (2H, t, J = 5.1 Hz), 5.0
0 (1H, brs), 5.50-6.50 (2H, br)
s), 7.49 (1H, d, J = 8.8 Hz), 8.0
4 (1H, d, J = 8.8 Hz), 8.16 (1H,
s).

(B) 3- (2-aminoethoxy) -5
-Carbamoyl-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-carbamoyl-1,2-benzisoxazole as in Example 17 (c) The target compound was obtained in a yield of 96% by the same reaction and post-treatment. Melting point: 218-222 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 342
9,3353,3317,3195,2977,290
1,1671,1622,1596,1546,150
1; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.33 (2H, t, J = 5.1 Hz), 4.64 (2
H, t, J = 5.1 Hz), 7.51 (1H, s),
7.72 (1H, d, J = 8.8 Hz), 8.18 (1
H, s), 8.21 (1H, d, J = 8.8 Hz),
8.31 (3H, brs), 8.40 (1H, s).

Example 78 3- (2-Aminoethoxy) -5-cyano-1,2-benzisoxazole hydrochloride (a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5 -Cyano-1,2-benzisoxazole 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-carbamoyl-1,2-benzisoxazole was prepared in the same manner as in Example 24 (a). By reacting and post-treating, the target compound was obtained in a yield of 92%. Melting point: 138-140 ° C; IR spectrum (KBr) ν _max cm ^-1 : 334
9,2233,1717,1708,1623,160
5,1540,1527; NMR spectrum (CDCl ₃ ) δ ppm: 1.4
6 (9H, s), 3.65 (2H, q, J = 5.1H
z), 4.53 (2H, t, J = 5.1 Hz), 4.9
3 (1H, brs), 7.56 (1H, d, J = 8.8)
Hz), 7.79 (1H, d, J = 8.8 Hz), 8.
04 (1H, s).

(B) 3- (2-aminoethoxy) -5
-Cyano-1,2-benzisoxazole hydrochloride 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-cyano-1,2-benzisoxazole was prepared according to Example 17 (c). The target compound was obtained in a yield of 96% by the same reaction and post-treatment. Melting point: 212-216 ° C (decomposition); IR spectrum (KBr) ν _max cm ^-1 : 317
1,3096,3058,3029,2953,223
9, 1624, 1601, 1544, 1518; NMR spectrum (DMSO-d ₆ ) δ ppm:
3.34 (2H, t, J = 5.1 Hz), 4.65 (2
H, t, J = 5.1 Hz), 7.91 (1H, d, J =
8.8 Hz), 8.12 (1H, d, J = 8.8H)
z), 8.35 (3H, brs), 8.43 (1H,
s).

Test Example 1 Monoamine oxidase inhibitory activity Biochemical Pharmacology, Vol. 12, 143
9 (1963) [Biochem. Pharmacol., 12 , 1439 (196
3).] And Journal of Neurochemistry,
35, 109 (1980) [J. Neurochem., 35 ,
109 (1980).]]. Mouse brain crude mitochondrial preparation (30 μg protein)
In 30 μl, 210 μl of a phosphate buffer (pH 7.4) and a test compound (dissolved in 10% DMSO-water) 30
μl was added and preincubated at 38 ° C. for 20 minutes. Then, for the measurement of B-type monoamine oxidase inhibitory activity, ¹⁴ C-2-phenylethylamine (PEA,
(Final concentration: 20 μM) or for the measurement of type A monoamine oxidase inhibitory activity, ¹⁴ C-5-hydroxytryptamine (5-HT, final concentration: 100 μM) was added.
The reaction was performed at 38 ° C. for 20 minutes. 2N-HCl (200μ
After stopping the reaction by adding l), the metabolite by the enzymatic reaction labeled with ¹⁴ C was dissolved in a solvent (ethyl acetate: toluene =
1: 1), and the ¹⁴ C radioactivity was measured with a liquid scintillation counter to determine the concentration (IC ₅₀ ) of the compound that reduced the control ¹⁴ C radioactivity by 50%. Table 17 shows the results.

[0408]

[Table 17] Monoamine oxidase inhibitory activity Example No. B-type monoamine oxidase inhibitory activity (IC ₅₀ ) 1 ^*) 0.37 nM 2 1.85 nM 5 ^*) 1.35 nM 6 ^*) 5.60 nM 7 ^*) 0.56 nM 8 ^*) 0.56 nM 9 20.0 nM 10 (e) 10.2 nM 10 (f) 13 0.5 nM 11 2.8 nM 12 26.5 nM 13 27.5 nM 14 21.5 nM 15 ^*) 0.32 nM 17 4.2 nM 21 4.7 nM 24 6.8 nM 26 2.7 nM 33 4.5 nM 34 2.2 nM 3359 0.0 nM 38 2.95 nM 42 18.0 nM 44 6.0 nM 56 6.6 nM Compound A ^**) 2.35 μM Compound B ^***) 4.70 μM *) Compared with A-type monoamine oxidase inhibitory activity, B-type monoamine oxidase inhibitory activity was shown to be 4500 to 5500 times stronger. **) 3- (2-N-methylamino) ethoxy-1,2-benzisoxazole ***) 3- (2-N, N'-dimethylamino) ethoxy-1,2-benzoisoxazole Formulation Example 1 Hard Capsules Each of the standard bisected hard gelatin capsules is 100m
g of powdered compound of Example 1, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate are filled to prepare a unit capsule, washed and dried to obtain a hard capsule.

[0409]

The isoxazole derivatives (I) and (II) of the present invention have excellent B-type monoamine oxidase inhibitory activity and A-type monoamine oxidase inhibitory activity (particularly, they have strong inhibitory activity against B-type monoamine oxidase). It has low toxicity and is useful as a therapeutic or preventive agent for neurological diseases such as Parkinson's disease, depression and Alzheimer's disease (particularly Parkinson's disease).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 25/16 A61P 25/16 25/24 25/24 25/28 25/28 C07D 498/04 101 C07D 498/04 101 103 103 103 105 105 513/04 301 513/04 301 (72) Inventor Yuichi Aizawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Masao Kitsuzuka 1-2-2 Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo Co., Ltd. (72) Inventor Kenji Yoshimi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Isao Kaneko 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kazuo Koyama 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-B-47-6302 (JP, B2) (58) Fields surveyed (Int .Cl. ⁷ , DB name) C07D 261/20 C07D 498/04 C07D 513/04 CA (STN) REGISTRY (STN)

Claims (38)

(57) [Claims] 1. A compound of the general formula [Wherein, R ¹ represents a hydrogen atom; a halogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₄ alkyl group substituted with halogen or C ₁ -C ₄ alkoxy; a C ₁ -C ₆ alkoxy group; Halogeno C ₁
-C ₆ alkoxy group; a hydroxyl group; C ₁ -C ₆ alkylthio group; an amino group; a mono C ₁ -C ₆ alkylamino group; di-C ₁ -C ₆ alkylamino group; C ₁ -C ₆ alkanoyl group; C ₁ - C ₆ -alkanoylamino group; C ₁ -C ₆ alkanoyloxy group; C ₁ -C ₆ alkoxycarbonyl group; carboxy group; (C ₁ -C ₆ alkylthio) thiocarbonyl group; carbamoyl group; mono C ₁ -C ₆
An alkylcarbamoyl group; a di-C ₁ -C ₆ alkylcarbamoyl group; a nitro group; or a cyano group, R ² represents an amino group, m represents an integer of 1 to 3, and n represents an integer of 1 to 6. And ring A is a phenyl ring fused with isoxazole or a naphthyl ring fused with isoxazole, or one or two heteroatoms selected from a heteroatom group consisting of oxygen, nitrogen and sulfur atoms fused with isoxazole Including 5
And X represents an oxygen atom or a sulfur atom. However, when m represents an integer of 2 to 3, R ¹ represents the same or different groups. Or a pharmacologically acceptable salt thereof. 2. The method according to claim 1, wherein R ¹ is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, -Chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₁ -C ₄ alkoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy Group, trichloromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, amino group, mono C ₁ -C ₄ alkylamino group, di-C ₁ -C ₄ alkylamino group, formyl group, acetyl group, formylamino group, acetylamino group, C ₁ -C ₄ A Kanoiruokishi group,
C ₁ -C ₄ alkoxycarbonyl group, carboxy group, (methylthio) thiocarbonyl group, (ethylthio) thiocarbonyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, nitro group or cyano group Or a pharmacologically acceptable salt thereof. 3. The method according to claim 1, wherein R ¹ is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, , 2,2-trifluoroethyl group,
Methoxymethyl group, methoxyethyl group, C ₁ -C ₄ alkoxy group, difluoromethoxy group, hydroxyl group, C ₁ -C ₄ alkylthio group, amino group, methylamino group, ethylamino group,
Dimethylamino, diethylamino, formyl, acetyl, formylamino, acetylamino, C ₁ -C
₄ alkoxycarbonyl group, carboxy group, carbamoyl group, methyl carbamoyl group, ethyl carbamoyl group,
An isoxazole derivative which is a dimethylcarbamoyl group, a diethylcarbamoyl group, a nitro group or a cyano group, or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1, wherein R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a difluoromethoxy group, a hydroxyl group. , Methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, formyloxy, acetyloxy,
An isoxazole derivative which is a methoxycarbonyl group, an ethoxycarbonyl group, a carboxy group, a carbamoyl group, a nitro group or a cyano group, or a pharmaceutically acceptable salt thereof. 5. The method according to claim 1, wherein R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group,
An isoxazole derivative which is a methylthio group, a difluoromethoxy group, a methoxycarbonyl group, a nitro group or a cyano group, or a pharmaceutically acceptable salt thereof. 6. The isoxazole derivative according to claim 1, wherein m 2 is 2, or a pharmaceutically acceptable salt thereof. 7. The isoxazole derivative according to claim 1, wherein m is 1, or a pharmaceutically acceptable salt thereof. 8. The isoxazole derivative according to claim 1, wherein n is 2 to 4, or a pharmacologically acceptable salt thereof. 9. The isoxazole derivative according to claim 1, wherein n is 2 or a pharmaceutically acceptable salt thereof. 10. The method according to claim 1, wherein ring A is a phenyl ring, a naphthyl ring, a furyl ring, a thienyl ring, a pyrrolyl ring, an imidazolyl ring, a pyrazolyl ring, a thiazolyl ring, or an isothiazolyl ring. Ring, oxazolyl ring, isoxazolyl ring, pyridyl ring, pyrazinyl ring,
An isoxazole derivative having a pyrimidinyl ring or a pyridazinyl ring, or a pharmaceutically acceptable salt thereof. 11. The isoxazole derivative according to claim 1, wherein ring A is a phenyl ring, a naphthyl ring or a pyridyl ring, or a pharmaceutically acceptable salt thereof. 12. The isoxazole derivative according to claim 1, wherein ring A is a phenyl ring or a pyridyl ring, or a pharmaceutically acceptable salt thereof. 13. The isoxazole derivative according to claim 1, wherein ring A 1 is a phenyl ring, or a pharmaceutically acceptable salt thereof. 14. The isoxazole derivative according to claim 1, wherein X 1 is an oxygen atom, or a pharmacologically acceptable salt thereof. 15. A method comprising the steps of: 3- (2-aminoethoxy) -1,
2-benzisoxazole or a pharmacologically acceptable salt thereof. (16) 3- (2-aminoethoxy) -5-
Fluoro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. (17) 3- (2-aminoethoxy) -5-
Fluoro-4-methyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. (18) 3- (2-aminoethylthio) -5
-Fluoro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. (19) 3- (2-aminoethoxy) -5-
Chloro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 20. 3- (2-aminoethoxy) -5,
7-Dichloro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 21. 3- (2-aminoethylthio) -5
-Chloro-7-methyl-1,2-benzoisoxazole or a pharmaceutically acceptable salt thereof. 22. 3- (2-aminoethylthio) -5
-Chloro-1,2-benzoisoxazole or a pharmacologically acceptable salt thereof. 23. 3- (2-aminoethoxy) -6-
Chloro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 24. 3- (2-aminoethoxy) -7-
Chloro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 25. 3- (2-aminoethoxy) -5-
Bromo-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 26. 3- (2-aminoethoxy) -5-
Methyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 27. 3- (2-aminoethylthio) -5
-Methyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 28. 3- (2-aminoethoxy) -6-
Methyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 29. 3- (2-aminoethoxy) -7-
Methyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 30. 3- (2-aminoethoxy) -5-
Methoxy-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 31. 3- (2-aminoethylthio) -5
-Methoxy-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 32. 3- (2-aminoethoxy) -5-
Difluoromethoxy-1,2-benzisoxazole or a pharmaceutically acceptable salt thereof. 33. 3- (2-aminoethoxy) -5-
Fluoro-4-methylthio-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 34. 3- (2-aminoethoxy) -5-
Methoxycarbonyl-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 35. 3- (2-aminoethoxy) -5-
Nitro-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 36. 3- (2-aminoethylthio) -5
-Nitro-1,2-benzoisoxazole or a pharmacologically acceptable salt thereof. 37. 3- (2-aminoethoxy) -4-
Cyano-1,2-benzisoxazole or a pharmacologically acceptable salt thereof. 38. 3- (2-Aminoethoxy) pyrido [3,2-d] isoxazole or a pharmaceutically acceptable salt thereof.