JP3411262B2 - New spiro compounds - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is useful in the field of medicine. More specifically, the novel spiro compound of the present invention is useful as a neuropeptide Y receptor antagonist as a therapeutic agent for various cardiovascular diseases, central nervous system diseases, metabolic diseases and the like.

[0002]

2. Description of the Related Art Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acids and was first isolated from pig brain by Tatemoto et al. In 1982 [Nature (N
Nature, 296, 659 (1982)].
NPY is widely distributed in the central and peripheral nervous systems, and as one of the most abundant peptides in the nervous system,
It controls various functions in the living body. That is, NP
Y acts as an appetite promoting substance in the center, and significantly promotes fat accumulation through the secretion of various hormones or the action of the nervous system. Based on these effects, it is known that continuous intracerebroventricular administration of NPY induces obesity and insulin resistance [International Journal of Ovecity (International Jo
19: 517 (1995); Endocrinology (Endocri).
vol.133, p. 1753 (1993).
Year)]. In addition, it is known to have other central actions such as depression, anxiety, schizophrenia, pain and dementia [Drugs, 52, 371 (199).
6)]. Furthermore, in the periphery, NPY coexists with norepinephrine at the sympathetic nerve endings and is associated with sympathetic tone. Peripheral administration of NPY is known to cause vasoconstriction and potentiate the effects of other vasoconstrictors, including norepinephrine [British Journal of Pharmacology.
urn of of Pharmacology), 95
Vol., 419 (1988)]. It has also been reported to promote cardiac hypertrophy associated with the enhancement of the sympathetic nervous system [Proceeding National Academic Science USA].
nal Academic Science US
A), 97, 1595 (2000)].

[0003] In addition, it has been reported that they are involved in secretion of sex hormones and growth hormones, sex and reproductive functions, digestive tract motility, bronchoconstriction, inflammation and preference for alcohol [Life Science (Life Science).
e), 55, 551 (1994); The Journal of Allergy and Clinical Immunology (The Journal of Allergy).
and Immunology), Volume 101, S34
Page 5 (1998); Nature, 3
96, 366 (1998)]. NPY has a wide variety of pharmacological actions through its receptors, which are partially common to its analogs, peptide YY and pancreatic polypeptide. It is known that the pharmacological action of these NPYs is elicited through the interaction of at least five types of receptors alone or through the interaction [Trends in Neurosc.
20), p. 294 (1997)]. N
As a central action through the PY Y1 receptor, a remarkable appetite-promoting action has been reported [Endocrinology (E
137, 3177 (1996): Endocrinology (Endocrinology).
141), 1011 (2000)
Year)]. Furthermore, involvement in anxiety and pain has been reported [Nature, 259, 528 (1993); Brain Research (Brain R).
research, 859, 361 (2000)
Year)]. In the periphery, a blood pressure-increasing action via a powerful vasoconstrictor action has been reported [FEBS Letters, 362, 192,
(1995): Nature Medicine (Natur)
e Medicine, vol. 4, p. 722 (1998)
Year)].

It is known that the action of NPY Y2 receptors inhibits the release of various neurotransmitters at nerve endings [British Journal of Pharmacology.
l of Pharmacology), Volume 102, 4
Page 1 (1991): Synapse 2
Vol., 299 (1988)]. In the periphery, it is involved in the contraction of blood vessels or vas deferens as a control or direct action of these neurotransmitters [The Journal of Pharmacology and Experimental Therapeutics (The Journal of
f Pharmacology and Experi
Mental Therapeutics), 261
Volume, 863 (1992); British Journal of Pharmacology (British Jou).
rnal of Pharmacology), 100
Vol. 190, p. 190]. In adipose tissue, suppression of lipolytic action is known [Endocrinology, 131,
1970 (1992)]. Furthermore, in the digestive tract,
It has been reported to inhibit ion secretion [British Journal of Pharmacology (Brit
ish Journal of Pharmacolo
gy), 101, 247 (1990)]. on the other hand,
Central effects such as memory and anxiety are also known [Brain Research, 503.
Volume 73 (1989): Peptids.
es), vol. 19, p. 359 (1998)]. NPY
The Y3 receptor is mainly expressed in the brainstem and heart, and is reported to be involved in the control of blood pressure and heart rate [The Journal of Pharmacology and.
Experimental Therapeutics (The J
individual of Pharmacology an
d Experiential Therapeutic
s), 258, 633 (1991); Peptides, 11, 545 (1990).
Year)]. Furthermore, it is known to be involved in the secretion of catecholamines in the adrenal gland [The Journal of Pharmacology and Experimental Therapeutics (The Journal of P
harmology and Experimen
tal Therapeutics), 244, 46
Page 8 (1988); Life Science (Life)
Science), Volume 50, PL7 page (1992)
Year)].

The NPY Y4 receptor has a particularly high affinity for pancreatic polypeptide, and its pharmacological effect has been reported to be the suppression of exocrine pancreas and gastrointestinal motility [Gastroenterology (Gastroentero).
85), 1411 (1983)]. In addition, it is known to promote the secretion of sex hormones in the central nervous system [Endocrinology (Endocrin
vol., 140, 5171 (1999)
Year)]. As an action mediated by the NPY Y5 receptor, a fat accumulation action including an appetite promoting effect is remarkable [Nature, 382, 168 (1996).
Year); American Journal of Phys
ii, 277, R1428 (1999)
Year)]. In addition, central effects such as involvement in convulsions and epilepsy or involvement in pain and withdrawal symptoms associated with discontinuation of morphine administration have been reported [Nature Medicine (Nat
ure Medicine, Volume 3, pp. 761 (199)
7 years); Proceeding National Academic Science USA (Proceeding)
National Academic Science
USA, 96, 13518 (1999); The Journal of Pharmacology and Experimental Therapeutics (The Jou.
rnal of Pharmacology and
Experimental Therapeutic
s), 284, 633 (1998)]. Further, in the periphery, diuretic action and hypoglycemic action have been reported [British Journal of Pharmacology (British Journal of Pharmacology.
), 120, 1335 pages (1998)
Year); Endocrinology (Endocrinology)
y), 139, 3018 (1998)]. It has also been reported to promote cardiac hypertrophy associated with the enhancement of the sympathetic nervous system [Proceedin National Academic Science USA].
g National Academic Science
Ce USA, 97, 1595 (2000)].

The function of NPY is expressed by binding to NPY receptors present in the central or peripheral nervous system. Therefore, by inhibiting the binding of NPY to the NPY receptor, the action expression of NPY can be blocked. As a result, NPY is a substance that antagonizes NPY receptor binding.
Diseases associated with, such as hypertension, kidney disease, heart disease,
Cardiovascular diseases such as vasospasm, such as bulimia, depression,
Central diseases such as anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, for example, metabolic diseases such as obesity, diabetes, hormonal abnormalities, sexual and reproductive dysfunction, digestive tract It can be expected to be useful in the prevention or treatment of movement disorders, respiratory diseases, inflammation, glaucoma, etc. [Trends in Pharmacological Science]
Science), vol. 15, p. 153 (1994)
Year); Life Science (Life Science)
e), 55, 551 (1994); Drugs, 52, 371 (1996); The Journal of Allergies and Clinical Immunology (The Journal of Al).
lergy and Immunology), 101
Volume, S 345 (1998); Nature
Re), 396, 366 (1998); The Journal of Pharmacology and Experimental Therapeutics (The Journal).
l of Pharmacology and Exp
eriental Therapeutics), 28
Volume 4, p. 633 (1998); Trends in Pharmacological Science (Trends in P)
pharmacological Science), 2
Volume 0, p. 104 (1999); Proceeding National Academic Acad.
(emic Science USA), Vol. 97, 159
P. 5 (2000)]. In addition, recently, according to the studies conducted by the present inventors, it was found that certain NPY receptor antagonists are useful in the prevention or treatment of hypercholesterolemia, hyperlipidemia, arteriosclerosis ( International publication WO99 / 2
7965).

[0007]

The object of the present invention is to provide an NP
It is to provide a novel drug having a Y-antagonism.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have made general formula (I)

[Chemical 15] [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Means an aryl group or a heteroaryl group; n is 0
Or 1 means; Q means a single bond or a carbonyl group; T, U, V and W are each independently selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group. A methine group which may have a substituent or a nitrogen atom, of which at least 2
Is a methine group; X is a methine group or a nitrogen atom; Y is an imino group optionally substituted with a lower alkyl group or an oxygen atom.
They have a PY antagonistic action and have been found to be useful as a therapeutic agent for various diseases involving NPY, and completed the present invention.

The compound (I) of the present invention is used in various diseases involving NPY, such as hypertension, kidney disease, heart disease, vasospasm, arteriosclerosis, and other cardiovascular diseases such as bulimia nervosa and depression. , Anxiety, convulsions, epilepsy, dementia, pain,
Alcoholism, central diseases such as withdrawal symptoms associated with drug withdrawal, such as obesity, diabetes, hormonal abnormalities, hypercholesterolemia, hyperlipidemia and other metabolic diseases, sexual and reproductive dysfunction such as digestion It is useful as a therapeutic agent for digestive system diseases such as tube movement disorder, respiratory system diseases, inflammation and glaucoma. In particular, the compound (I) of the present invention is useful as a therapeutic agent for hyperphagia, obesity, diabetes and the like. The present invention relates to a compound represented by the general formula (I), a salt or ester thereof, and a method for producing the same and use thereof. Furthermore, the present invention provides an intermediate for producing a compound represented by the general formula (I), that is,
General formula (VI-1)

[Chemical 16] [Wherein, t, u, v and w each independently have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and an optionally protected hydroxyl group. A methine group or a nitrogen atom, at least two of which mean the methine group].

The meanings of the terms used in the present specification will be described below, and the present invention will be described in more detail.
The “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. "Lower alkyl group" means
It means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group. , Isopentyl group, hexyl group, isohexyl group and the like. The “halo lower alkyl group” means the above lower alkyl group in which any substitutable position is substituted with one or more, preferably 1 to 3 the same or different halogen atoms, for example, a fluoromethyl group, Difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1,2-
Examples thereof include a difluoroethyl group, a chloromethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a bromomethyl group and an iodomethyl group. The “hydroxy lower alkyl group” means the lower alkyl group in which any substitutable position is substituted with one or more, preferably one or two hydroxyl groups, and examples thereof include a hydroxymethyl group and a 2-hydroxyethyl group. A 1-hydroxy-1-methylethyl group,
Examples include 1,2-dihydroxyethyl group and 3-hydroxypropyl group. "Cyclo lower alkyl group" means
It means a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The "lower alkenyl group" means a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 3-butenyl group. Group, 2-butenyl group, 1-
Butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group,
Examples thereof include a 2-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a 3-methyl-2-butenyl group and a 4-pentenyl group. The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, isobutoxy group. Group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like. The “halo lower alkoxy group” means the above lower alkoxy group in which any substitutable position is substituted with 1 or 2 or more, preferably 1 to 3 the same or different halogen atoms, for example, a fluoromethoxy group, Difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,2-difluoroethoxy group, chloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, bromomethoxy group, iodomethoxy group, etc. Can be mentioned. The "lower alkylthio group" means a linear or branched alkylthio group having 1 to 6 carbon atoms, and includes, for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, sec-butylthio group, isobutyl. Thio group, t
Examples thereof include an ert-butylthio group, a pentylthio group, an isopentylthio group, a hexylthio group and an isohexylthio group. The "lower alkanoyl group" means an alkanoyl group having the above lower alkyl group, that is, an alkanoyl group having 2 to 7 carbon atoms, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, Examples thereof include pivaloyl group.
The “lower alkoxycarbonyl group” means an alkoxycarbonyl group having the above lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group. Base,
Butoxycarbonyl group, isobutoxycarbonyl group, t
Examples include ert-butoxycarbonyl group and pentyloxycarbonyl group.

The "lower alkylene group which may be substituted with an oxo group" is a linear or branched alkylene group having 2 to 6 carbon atoms in which any substitutable position is 1
Or two or more, preferably one, which may be substituted with an oxo group, such as ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, 1-oxoethylene group, 1-oxo group. Examples thereof include trimethylene group, 2-oxotrimethylene group, 1-oxotetramethylene group, and 2-oxotetramethylene group. Examples of the "aryl group" include a phenyl group and a naphthyl group. The "heteroaryl group" is a 5- or 6-membered mono- or hetero-member containing 1 or 2 or more, preferably 1 to 3 heteroatoms selected from the same or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom. A condensed aromatic aromatic heterocyclic group in which the cyclic aromatic heterocyclic group or the monocyclic aromatic heterocyclic group is condensed with the aryl group, or the same or different monocyclic aromatic heterocyclic groups are condensed with each other. Means a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, Tetrazolyl group, oxadiazolyl group,
1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group,
1,2,4-triazinyl group, 1,3,5-triazinyl group, indolyl group, benzofuranyl group, benzothienyl group, benzimidazolyl group, benzoxazolyl group,
Benzisoxazolyl group, benzothiazolyl group, benzisothiazolyl group, indazolyl group, purinyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, pyrido [3 2-b] pyridyl group and the like. The "lower alkylamino group" means an amino group mono-substituted with the lower alkyl group, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group,
Examples thereof include sec-butylamino group and tert-butylamino group. The “di-lower alkylamino group” means an amino group which is di-substituted with the same or different lower alkyl group, for example, dimethylamino group, diethylamino group, ethylmethylamino group, dipropylamino group, methylpropylamino group. , Diisopropylamino group and the like.

The "salt" of the compound represented by the general formula (I) means a pharmaceutically acceptable conventional salt, for example, when it has a carboxyl group, a base addition salt or amino group at the carboxyl group. Alternatively, when it has a basic heterocyclic group, salts of acid addition salts in the basic heterocyclic group can be mentioned. Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; for example ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine Examples thereof include salts, diethanolamine salts, triethanolamine salts, procaine salts, and organic amine salts such as N, N′-dibenzylethylenediamine salt. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetic acid salts; for example, methanesulfonic acid salts, isethionic acid salts, benzenesulfonic acid salts, sulfonic acid salts such as p-toluenesulfonic acid salts, and the like. The "ester" of the compound represented by the general formula (I) means, for example, a pharmaceutically acceptable conventional one in the case of having a carboxyl group, such as a methyl group, an ethyl group, a propyl group. , Isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, ester with lower alkyl group such as cyclopentyl group, benzyl group, phenethyl group, etc. With an aralkyl group, an allyl group, an ester with a lower alkenyl group such as 2-butenyl group, an ester with a lower alkoxy lower alkyl group such as a methoxymethyl group, a 2-methoxyethyl group and a 2-ethoxyethyl group, acetoxy Methyl group, pivaloyloxymethyl group, 1-pivaloyloxy Esters with a lower alkanoyloxy-lower alkyl groups such as ethyl group,
Esters with lower alkoxycarbonyl lower alkyl groups such as methoxycarbonylmethyl group and isopropoxycarbonylmethyl group, esters with lower carboxy lower alkyl groups such as carboxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1- (cyclohexyloxy (Carbonyloxy) ethyl group and other lower alkoxycarbonyloxy lower alkyl group, carbamoyloxymethyl group and other carbamoyloxy lower alkyl group, phthalidyl group, and (5-methyl-2
(5-substituted-2-oxo-1,3-dioxole-such as -oxo-1,3-dioxol-4-yl) methyl group
Examples thereof include esters with 4-yl) methyl groups. The “treatment agent” means a drug provided for the purpose of treating and / or preventing various diseases.

In order to more specifically disclose the compound of the present invention represented by the general formula (I), various symbols used in the formula (I) will be described in more detail with reference to preferable specific examples thereof. . Ar ¹ is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, a lower alkenyl group,
A lower alkoxy group, a halo-lower alkoxy group, consisting of lower alkylthio group, a carboxyl group, a lower alkanoyl group, lower alkoxycarbonyl group, a group represented by optionally substituted lower alkylene group, and -Q-Ar ² by an oxo group It means an aryl group or a heteroaryl group which may have a substituent selected from the group. "Halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl group, lower alkanoyl group, Lower alkoxycarbonyl group, lower alkylene group optionally substituted with oxo group and -Q
The "aryl group or heteroaryl group which may have a substituent selected from the group consisting of a group represented by -Ar ² " is an unsubstituted aryl group or heteroaryl group, or It means the aryl group or the heteroaryl group having a substituent at any substitutable position, and the substituent is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group,
Cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group,
Carboxyl group, a lower alkanoyl group, lower alkoxycarbonyl group, from the group consisting of groups represented by may be substituted with an oxo group lower alkylene group, and -Q-Ar ^2, same or different one or more, preferably Can be selected 1 or 2.

As the halogen atom for the substituent, for example, a fluorine atom, a chlorine atom and the like are preferable. As the lower alkyl group as the substituent, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group and the like are preferable. As the halo lower alkyl group for the substituent, for example, a difluoromethyl group, a trifluoromethyl group and the like are preferable. Examples of the hydroxy lower alkyl group as the substituent include a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy- group.
A 1-methylethyl group and the like are preferable. As the cyclo-lower alkyl group as the substituent, for example, a cyclopropyl group, a cyclobutyl group and the like are preferable. Examples of the lower alkenyl group as the substituent include vinyl group, 1-propenyl group, 2
A -methyl-1-propenyl group and the like are preferable. As the lower alkoxy group as the substituent, for example, a methoxy group, an ethoxy group and the like are preferable. As the halo lower alkoxy group as the substituent, for example, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are preferable. As the lower alkylthio group as the substituent, for example, methylthio group, ethylthio group and the like are preferable. As the lower alkanoyl group for the substituent, for example, an acetyl group, a propionyl group and the like are preferable. The lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group. The lower alkylene group which may be substituted with an oxo group as the substituent is, for example, preferably a 1-oxotetramethylene group. In the group represented by -Q-Ar ² of the substituent, Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, It means an aryl group or a heteroaryl group which may have a substituent selected from the group consisting of a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group;
Q means a single bond or a carbonyl group.

"Halogen atom, cyano group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group,
An aryl group or a heteroaryl which may have a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group. The "group" means an unsubstituted aryl group or heteroaryl group, or an aryl group or heteroaryl group having a substituent at any substitutable position, and the substituent is halogen. Atom, cyano group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, halo lower alkoxy group, lower alkylamino group, di lower alkylamino group,
From the group consisting of a lower alkanoyl group and an aryl group, 1 or 2 or more, preferably 1 or 2, which are the same or different, can be selected. As the halogen atom of the substituent,
For example, a fluorine atom and a chlorine atom are suitable. As the lower alkyl group as the substituent, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group and the like are preferable. As the halo lower alkyl group for the substituent, for example, a difluoromethyl group, a trifluoromethyl group and the like are preferable. The hydroxy lower alkyl group as the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group. As the lower alkoxy group as the substituent, for example, a methoxy group, an ethoxy group and the like are preferable. As the halo lower alkoxy group as the substituent, for example, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are preferable. As the lower alkylamino group for the substituent, for example, methylamino group, ethylamino group and the like are preferable. As the di-lower alkylamino group for the substituent, for example, a dimethylamino group, a diethylamino group and the like are preferable. As the lower alkanoyl group for the substituent, for example, an acetyl group, a propionyl group and the like are preferable. As the aryl group as the substituent, for example, a phenyl group and the like are preferable.

As the substituent of Ar ² , for example, a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a hydroxyl group, a halo lower alkoxy group and the like are preferable. The aryl group of Ar ² is preferably a phenyl group or the like, and the heteroaryl group is preferably an imidazolyl group, a pyridyl group, a benzofuranyl group or a quinolyl group. Therefore, -Q-
Examples of the group represented by Ar ² include a phenyl group and 2-
Fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group,
2,4-difluorophenyl group, 3,5-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-cyanophenyl group, 3
-Cyanophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-fluoro-5-methylphenyl group, 3-fluoromethylphenyl group, 2-trifluoro Methylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group,
3-methoxyphenyl group, 4-methoxyphenyl group, 3
-Fluoro-5-methoxyphenyl group, 3-fluoromethoxyphenyl group, 3-difluoromethoxyphenyl group, 3- (2-hydroxyethyl) phenyl group, 3-hydroxymethylphenyl group, 3- (1-hydroxy-1)
-Methylethyl) phenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-imidazolyl group,
1-ethyl-2-imidazolyl group, 1,2,4-thiadiazol-5-yl group, 1,3,4-thiadiazole-
2-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-ethyl-4-pyridyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 4-benzo [b] furanyl group, 5- Benzo [b] furanyl group, 7-benzo [b]
A furanyl group, a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, a 5-quinolyl group, a 6-quinolyl group, an 8-quinolyl group, a benzoyl group, a 2-pyridylcarbonyl group and the like, among which a phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 3,5-difluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-cyanophenyl group, 3-trifluoromethylphenyl group, 3-difluoromethoxyphenyl group , 3-
(2-hydroxyethyl) phenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 1-ethyl-
2-imidazolyl group, 2-pyridyl group, 7-benzo [b] furanyl group, 2-quinolyl group, 3-quinolyl group,
A benzoyl group, a 2-pyridylcarbonyl group and the like are preferable.

As the substituent of Ar ¹ , for example, a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkenyl group, a lower alkanoyl group, a lower alkylene group which may be substituted with an oxo group, —Q-Ar ² The group represented by and the like are preferable. Examples of the aryl group of Ar ¹ include a phenyl group and the like, and examples of the heteroaryl group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, 1, 2,
3-triazolyl group, 1,2,4-thiadiazolyl group,
Pyridyl group, pyrazinyl group, pyrimidinyl group, 1, 2,
A 4-triazinyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group, a pyrido [3,2-b] pyridyl group and the like are preferable.

Therefore, as Ar ¹ , for example, 3-
Fluorophenyl group, 4-fluorophenyl group, 3,4
-Difluorophenyl group, 3-chlorophenyl group, 4-
Chlorophenyl group, 3,4-dichlorophenyl group, 4-
Acetylphenyl group, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl group, 4-acetyl-3-trifluoromethylphenyl group, 4- (1-ethyl-2-imidazolyl) phenyl group, 3 -(2-pyridyl) phenyl group, 3- (4-pyridyl) phenyl group, 4- (2-pyridyl) phenyl group, 4- (3-pyridyl) phenyl group, 4- (2-ethyl-4-pyridyl) Phenyl group, 4
-(4-pyrimidinyl) phenyl group, 4-benzoylphenyl group, 4- (2-pyridylcarbonyl) phenyl group, 1-phenyl-3-pyrrolyl group, 1-phenyl-4
-Imidazolyl group, 1- (2-fluorophenyl) -4
-Imidazolyl group, 1- (3-fluorophenyl) -4
-Imidazolyl group, 1- (4-fluorophenyl) -4
-Imidazolyl group, 1- (2,3-difluorophenyl) -4-imidazolyl group, 1- (2,4-difluorophenyl) -4-imidazolyl group, 1- (3,5-difluorophenyl) -4-imidazolyl group Group, 1- (3-chlorophenyl) -4-imidazolyl group, 1- (2-cyanophenyl) -4-imidazolyl group, 1- (3-cyanophenyl) -4-imidazolyl group, 1- (4-cyanophenyl ) -4-Imidazolyl group, 1- (3-trifluoromethylphenyl) -4-imidazolyl group, 1- [3-
(2-Hydroxyethyl) phenyl] -4-imidazolyl group, 1- [3- (1-hydroxy-1-methylethyl) phenyl] -4-imidazolyl group, 1- (3-methoxyphenyl) -4-imidazolyl group , 1- (2-difluoromethoxyphenyl) -4-imidazolyl group, 1-
(3-Difluoromethoxyphenyl) -4-imidazolyl group, 1- (4-difluoromethoxyphenyl) -4-
Imidazolyl group, 1- (2-pyridyl) -4-imidazolyl group, 1- (4-benzo [b] furanyl) -4-imidazolyl group, 1- (5-benzo [b] furanyl) -4-
Imidazolyl group, 1- (7-benzo [b] furanyl)-
4-imidazolyl group, 1- (2-quinolyl) -4-imidazolyl group, 1- (3-quinolyl) -4-imidazolyl group, 1- (4-quinolyl) -4-imidazolyl group, 1-
(5-quinolyl) -4-imidazolyl group, 1- (6-quinolyl) -4-imidazolyl group, 1- (8-quinolyl)
-4-imidazolyl group, 1-phenyl-3-pyrazolyl group, 5-phenyl-3-pyrazolyl group, 1-phenyl-
4-pyrazolyl group, 1- (2-fluorophenyl) -3
-Pyrazolyl group, 5- (2-fluorophenyl) -3-
Pyrazolyl group, 5- (3-fluorophenyl) -3-pyrazolyl group, 1- (3-fluorophenyl) -4-pyrazolyl group, 1- (4-fluorophenyl) -3-pyrazolyl group, 5- (4- Fluorophenyl) -3-pyrazolyl group, 5- (2-chlorophenyl) -3-pyrazolyl group, 5- (3-chlorophenyl) -3-pyrazolyl group,
5- (4-chlorophenyl) -3-pyrazolyl group, 5-
(2-difluoromethoxyphenyl) -3-pyrazolyl group, 5- (3-difluoromethoxyphenyl) -3-pyrazolyl group, 2-methyl-5-phenyl-3-pyrazolyl group, 5- (2-pyridyl) -3 -Pyrazolyl group, 5-
(2-quinolyl) -3-pyrazolyl group, 5- (3-quinolyl) -3-pyrazolyl group, 4-phenyl-2-thiazolyl group, 5-phenyl-2-thiazolyl group, 5- (3-
Chlorophenyl) -2-thiazolyl group, 5- (4-chlorophenyl) -2-thiazolyl group, 5- (4-methoxyphenyl) -2-thiazolyl group, 5- (2-pyridyl)
-2-thiazolyl group, 2-phenyl-4-thiazolyl group, 4-phenyl-2-oxazolyl group, 5-phenyl-2-oxazolyl group, 4- (2-fluoromethoxyphenyl) -2-oxazolyl group, 4- (3-Fluoromethoxyphenyl) -2-oxazolyl group, 5-phenyl-3-isoxazolyl group, 3-phenyl-5-isoxazolyl group, 3- (2-chlorophenyl) -5-isoxazolyl group, 3- (3-chlorophenyl ) -5-Isoxazolyl group, 3- (4-chlorophenyl) -5-
Isoxazolyl group, 3- (2-pyridyl) -5-isoxazolyl group, 2-phenyl-1,2,3-triazol-4-yl group, 5-phenyl-1,2,4-thiadiazol-3-yl group, 5-phenyl-1,3,4-thiadiazol-2-yl group, 5- (3-chlorophenyl) -1,3,4-thiadiazol-2-yl group, 5-
(2-Pyridyl) -1,3,4-thiadiazole-2-
Yl group, 5- (2-ethyl-4-pyridyl) -1,3,
4-thiadiazol-2-yl group, 5-phenyl-2-
Pyridyl group, 6-phenyl-3-pyridyl group, 2-phenyl-4-pyridyl group, 5- (2-pyridyl) -2-pyridyl group, 5-benzoyl-2-pyridyl group, 6-benzoyl-3-pyridyl group Group, 5-chloro-2-pyrazinyl group, 5- (2-methyl-1-propenyl) -2-pyrazinyl group, 5-acetyl-2-pyrazinyl group, 5-propionyl-2-pyrazinyl group, 5-phenyl- 2-pyrazinyl group, 5- (3-hydroxyphenyl) -2-pyrazinyl group, 5- (4-hydroxyphenyl) -2-pyrazinyl group, 5- (1,2,4-thiadiazol-5-yl) -2 -Pyrazinyl group, 5- (1,3,4-thiadiazol-2-yl) -2-pyrazinyl group, 5- (2-pyridyl) -2-pyrazinyl group, 5- (3-pyridyl)-
2-pyrazinyl group, 5- (5-pyrimidinyl) -2-pyrazinyl group, 5- (3-quinolyl) -2-pyrazinyl group, 5-benzoyl-2-pyrazinyl group, 5- (2-pyridylcarbonyl) -2 -Pyrazinyl group, 5-acetyl-2-pyrimidinyl group, 5-acetyl-3-methyl-2
-Pyrimidinyl group, 4-phenyl-2-pyrimidinyl group, 5-phenyl-2-pyrimidinyl group, 6-phenyl-4-pyrimidinyl group, 2-phenyl-5-pyrimidinyl group, 5- (2-fluorophenyl) -2 -Pyrimidinyl group, 5- (3-fluorophenyl) -2-pyrimidinyl group, 5- (4-fluorophenyl) -2-pyrimidinyl group, 5- (2-chlorophenyl) -2-pyrimidinyl group, 5- (3- Chlorophenyl) -2-pyrimidinyl group, 5- (4-chlorophenyl) -2-pyrimidinyl group, 5- (2-methylphenyl) -2-pyrimidinyl group, 5- (3-methylphenyl) -2-pyrimidinyl group, 5 -(2-fluoromethylphenyl) -2-pyrimidinyl group, 5- (3-fluoromethylphenyl) -2-
Pyrimidinyl group, 5- (2-trifluoromethylphenyl) -2-pyrimidinyl group, 5- (3-trifluoromethylphenyl) -2-pyrimidinyl group, 5- (4-trifluoromethylphenyl) -2-pyrimidinyl group , 5-
(2-hydroxymethylphenyl) -2-pyrimidinyl group, 5- (3-hydroxymethylphenyl) -2-pyrimidinyl group, 5- (2-hydroxyphenyl) -2-pyrimidinyl group, 5- (3-hydroxyphenyl) -2-
Pyrimidinyl group, 5- (2-methoxyphenyl) -2-
Pyrimidinyl group, 5- (3-methoxyphenyl) -2-
Pyrimidinyl group, 5- (4-methoxyphenyl) -2-
Pyrimidinyl group, 5- (2-fluoromethoxyphenyl) -2-pyrimidinyl group, 5- (3-fluoromethoxyphenyl) -2-pyrimidinyl group, 5- (2-fluoro-5-methylphenyl) -2-pyrimidinyl group , 5-
(3-Fluoro-5-methoxyphenyl) -2-pyrimidinyl group, 6-phenyl-3-pyridazinyl group, 6-phenyl-1,2,4-triazin-3-yl group, 5-chloro-2-benzooxa Zolyl group, 5-fluoro-2-
Benzothiazolyl group, 4-methyl-2-benzothiazolyl group, 2-methyl-5-benzothiazolyl group, 4-methoxy-2-benzothiazolyl group, 3-quinolyl group, 6-
Quinolyl group, 7-methyl-2-quinolyl group, 2-methyl-6-quinolyl group, 6-chloro-2-quinoxalinyl group, pyrido [3,2-b] pyridin-2-yl group, 7-
Chloropyrido [3,2-b] pyridin-2-yl group, 7
-Methylpyrido [3,2-b] pyridin-2-yl group,
7-trifluoromethylpyrido [3,2-b] pyridin-2-yl group, 7-difluoromethoxypyrido [3,2]
-B] pyridin-2-yl group, 7-acetylpyrido [3,2-b] pyridin-2-yl group, and the like, among which, 3,4-dichlorophenyl group, 4-acetylphenyl group, 5-oxo-5 , 6,7,8-Tetrahydro-2
-Naphthyl group, 4-acetyl-3-trifluoromethylphenyl group, 4- (1-ethyl-2-imidazolyl) phenyl group, 4-benzoylphenyl group, 4- (2-pyridylcarbonyl) phenyl group, 1-phenyl -3-Pyrrolyl group, 1-phenyl-4-imidazolyl group, 1- (2
-Fluorophenyl) -4-imidazolyl group, 1-
(3,5-Difluorophenyl) -4-imidazolyl group, 1- (3-chlorophenyl) -4-imidazolyl group, 1- (3-cyanophenyl) -4-imidazolyl group, 1- [3- (2-hydroxy Ethyl) phenyl]-
4-imidazolyl group, 1- (3-difluoromethoxyphenyl) -4-imidazolyl group, 1- (7-benzo [b] furanyl) -4-imidazolyl group, 1- (2-quinolyl) -4-imidazolyl group, 1- (3-quinolyl)
-4-imidazolyl group, 1-phenyl-3-pyrazolyl group, 5-phenyl-3-pyrazolyl group, 1-phenyl-
4-pyrazolyl group, 1- (3-fluorophenyl) -4
-Pyrazolyl group, 1- (4-fluorophenyl) -3-
A pyrazolyl group, a 5- (4-chlorophenyl) -3-pyrazolyl group, a 5- (3-quinolyl) -3-pyrazolyl group,
5-phenyl-2-thiazolyl group, 3-phenyl-5-
Isoxazolyl group, 5- (2-methyl-1-propenyl) -2-pyrazinyl group, 1-phenyl-3-pyrazolyl group, 5-phenyl-2-pyrazinyl group, 5- (3-hydroxyphenyl) -2-pyrazinyl group Group, 5- (4-hydroxyphenyl) -2-pyrazinyl group, 5- (2-pyridyl) -2-pyrazinyl group, 5-benzoyl-2-pyrazinyl group, 5-phenyl-2-pyrimidinyl group, 5-
(2-fluorophenyl) -2-pyrimidinyl group, 5-
(3-fluorophenyl) -2-pyrimidinyl group, 5-
(3-chlorophenyl) -2-pyrimidinyl group, 5-
(3-trifluoromethylphenyl) -2-pyrimidinyl group, 5-chloro-2-benzoxazolyl group, 4-methyl-2-benzothiazolyl group, 7-methyl-2-quinolyl group, 7-trifluoromethylpyryl Do [3,2-b]
Pyridin-2-yl group and the like are preferable, and particularly 1-phenyl-3-pyrazolyl group, 5-phenyl-3-pyrazolyl group, 5-phenyl-2-pyrazinyl group, 5- (3-hydroxyphenyl) -2 -Pyrazinyl group, 5- (4-hydroxyphenyl) -2-pyrazinyl group, 5-phenyl-
2-pyrimidinyl group, 5- (2-fluorophenyl)-
2-pyrimidinyl group, 5- (3-fluorophenyl)-
A 2-pyrimidinyl group, a 7-trifluoromethylpyrido [3,2-b] pyridin-2-yl group and the like are preferable.

N means 0 or 1, with 0 being preferred. T, U, V and W are each independently a methine group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, or a nitrogen atom. , At least two of them
Means the methine group. The “methine group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group” means an unsubstituted methine group or a methine group having a substituent. ,
The substituent can be selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group. As the halogen atom for the substituent, for example, a fluorine atom, a chlorine atom and the like are preferable. As the lower alkyl group as the substituent, for example, a methyl group, an ethyl group and the like are preferable. As the lower alkoxy group as the substituent, for example, a methoxy group, an ethoxy group and the like are preferable. As the substituent, for example, a halogen atom or the like is suitable.

As a preferred embodiment of T, U, V and W, for example, T, U, V and W are each independently
When the substituent is more preferably a methine group which may have a halogen atom; or when any one of T, U, V and W is a nitrogen atom. X means a methine group or a nitrogen atom. Y means an imino group optionally substituted with a lower alkyl group or an oxygen atom. The "imino group which may be substituted with a lower alkyl group" means an unsubstituted imino group or an imino group substituted with a lower alkyl group. As the lower alkyl group, for example, methyl group, ethyl group and the like are preferable. As Y, an unsubstituted imino group or an oxygen atom is preferable, and an oxygen atom is particularly preferable. More specifically, the formula (1
5)

[Chemical 17] As the group represented by, for example, the following formula (16)

[Chemical 18] And the like.

Among the compounds represented by the general formula (I), for example, the general formula (Ia)

[Chemical 19] [Wherein R ¹ represents a hydrogen atom or a halogen atom, and A 1
r ¹ has the above meaning] or a compound represented by the general formula (Ib)

[Chemical 20] Compounds represented by [wherein Ar ¹ , T, U, V and W have the above-mentioned meanings] are suitable. General formula (I-
Among the compounds represented by a), for example, the aryl group of Ar ¹ is a phenyl group, or the heteroaryl group of Ar ¹ is an imidazolyl group, a pyrazolyl group, an isoxazolyl group, a 1,2,4-thiadiazolyl group, a pyrazinyl group. Group, pyrimidinyl group, quinolyl group or pyrido [3,2-
The compound etc. which are b] pyridyl groups are suitable. Among the compounds represented by formula (Ib), for example, the aryl group of Ar ¹ is a phenyl group, or the heteroaryl group of Ar ¹ is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group. A compound which is an isoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-thiadiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a 1,2,4-triazinyl group is preferable. Further, among the compounds represented by the general formula (Ib), for example, a compound in which any one of T, U, V and W is a nitrogen atom, etc., more preferably V is a nitrogen atom and T Compounds in which each of U, W and W is an unsubstituted methine group are preferred.

The compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers and geometric isomers or tautomers depending on the form of the substituents.
The compounds of the present invention also include all these stereoisomers, tautomers and mixtures thereof. For example, the general formula (I
The compound represented by general formula (I-1b) is

[Chemical 21] And a general formula (I-2b) represented by

[Chemical formula 22] Although there are cis stereoisomers represented by, the trans isomer is more preferable.

Various crystals, hydrates and solvates of the compounds of the present invention are also within the scope of the present invention. Furthermore, prodrugs of the compounds of the invention are also within the scope of the invention. Generally, such prodrugs are functional derivatives of the compounds of this invention that can be readily converted in vivo to the required compound. Therefore, in the method for treating various diseases according to the present invention, the term “administration” refers to not only the administration of the specified compound but also the administration of the compound to the specified compound in vivo after administration to the patient. Including administration. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier,
1985, the entire disclosure of which is incorporated herein by reference. Metabolites of these compounds include active compounds produced by subjecting the compounds of the invention to the biological milieu and are within the scope of the invention.

Therefore, specific examples of the compound represented by the general formula (I) include, for example, N- (4-benzoylphenyl) -3-oxospiro [isoindoline-1,
4'-piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isoindoline-1,4'-piperidine] -1'-carboxamide, N- (7-methyl -2-quinolyl) -3-oxospiro [isoindoline-1,4'-piperidine]
-1'-carboxamide, N- (4-benzoylphenyl) -2-methyl-3-oxospiro [isoindoline-1,4'-piperidine] -1'-carboxamide, N
-(4-benzoylphenyl) -3,4-dihydro-3
-Oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-phenyl-2-pyrazinyl)
Spiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-N-
(7-Methyl-2-quinolyl) -3-oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1'-
Carboxamide, N- (4-acetylphenyl) -3,
4-dihydro-3-oxospiro [isoquinoline-1
(2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- [1- (2-
Quinolyl) -4-imidazolyl] spiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-oxo-5,6,7, 8-Tetrahydro-2-naphthyl) spiro [isoquinoline-1 (2H), 4′-piperidine]
-1'-carboxamide, 3,4-dihydro-N- [5
-(2-Methyl-1-propenyl) -2-pyrazinyl]
-3-Oxospiro [isoquinoline-1 (2H), 4 '
-Piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (3-phenyl-5-isoxazolyl) spiro [isoquinoline-1 (2H), 4'-
Piperidine] -1'-carboxamide, N- [1- (7
-Benzo [b] furanyl) -4-imidazolyl] -3,
4-dihydro-3-oxospiro [isoquinoline-1
(2H), 4'-piperidine] -1'-carboxamide, N- [1- (3-difluoromethoxyphenyl)-
4-Imidazolyl] -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'-piperidine]
-1'-carboxamide, 3,4-dihydro-3-oxo-N- [4- (2-pyridylcarbonyl) phenyl]
Spiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, N- (3,4-dichlorophenyl) -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'- Piperidine] -1'-
Carboxamide, N- [1- (3-chlorophenyl)-
4-Imidazolyl] -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'-piperidine]
-1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-phenyl-2-thiazolyl) spiro [isoquinoline-1 (2H), 4'-piperidine] -1'-
Carboxamide, 3,4-dihydro-3-oxo-N-
[5- (2-Pyridyl) -2-pyrazinyl] spiro [isoquinoline-1 (2H), 4'-piperidine] -1'-
Carboxamide, 3,4-dihydro-N- (4-methyl-2-benzothiazolyl) -3-oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, N- (5-chloro-2 -Benzoxazolyl) -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, N- (4-benzoylphenyl) -3-oxospiro [isobenzofuran -1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N-
(5-Phenyl-2-pyrazinyl) -spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- (7-methyl-2-quinolyl) -3
-Oxospiro [isobenzofuran-1 (3H), 4 '
-Piperidine] -1'-carboxamide, 3-oxo-
N- (3-phenyl-5-isoxazolyl) spiro [isobenzofuran-1 (3H), 4'-piperidine]
-1'-carboxamide, 3-oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridin-2-yl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1 '-Carboxamide, 3-oxo-N-
(5-Phenyl-2-pyrimidinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- [1- (3-quinolyl) -4-imidazolyl] spiro [Isobenzofuran-
1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl-3-pyrazolyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'- Carboxamide, N- [5- (4-
Chlorophenyl) -3-pyrazolyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- [5-
(3-quinolyl) -3-pyrazolyl] spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- [5- (3-fluorophenyl)-
2-Pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- [5- (3-trifluoromethylphenyl) -2-pyrimidinyl] Spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-
Carboxamide, N- [5- (3-chlorophenyl)-
2-pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- (7-difluoromethoxypyrido [3,3
2-b] pyridin-2-yl) -3-oxospiro [isobenzofuran-1 (3H), 4′-piperidine]-
1'-carboxamide, 3-oxo-N- (5-phenyl-1,2,4-thiadiazol-3-yl) spiro [isobenzofuran-1 (3H), 4'-piperidine]
-1'-carboxamide, N- {1- [3- (2-hydroxyethyl) phenyl] -4-imidazolyl} -3-
Oxospiro [isobenzofuran-1 (3H), 4'-
Piperidine] -1'-carboxamide, N- [4- (1
-Ethyl-2-imidazolyl) phenyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- [1- (3-methoxyphenyl) -4-imidazolyl]- 3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 6-fluoro-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H ), 4'-piperidine]-
1'-carboxamide, 6-fluoro-3-oxo-N
-(5-Phenyl-2-pyrimidinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-
Carboxamide, 5-fluoro-3-oxo-N- (5
-Phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 5-fluoro-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [iso Benzofuran-1
(3H), 4'-piperidine] -1'-carboxamide, N- (4-benzoylphenyl) -3,4-dihydro-3-oxospiro [1H-2-benzopyran-1,
4'-piperidine] -1'-carboxamide, 3,4-
Dihydro-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [1H-2-benzopyran-1,4'-
Piperidine] -1'-carboxamide, N- (5-benzoyl-2-pyrazinyl) -3,4-dihydro-3-oxospiro [1H-2-benzopyran-1,4'-piperidine] -1'-carboxamide, trans -N- (4
-Benzoylphenyl) -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran]-
4-carboxamide, trans-3'-oxo-N-
(5-Phenyl-2-pyrazinyl) spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran] -4-
Carboxamide, trans-3′-oxo-N- (1-
Phenyl-4-imidazolyl) spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-3′-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [cyclohexane-
1,1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3′-oxospiro [cyclohexane-1,1 ′ (3′H) -Isobenzofuran] -4-carboxamide, trans-3′-oxo-N- (5-phenyl-3-pyrazolyl) spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran]
-4-carboxamide, trans-N- [1- (2-fluorophenyl) -4-imidazolyl] -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxamide, trans -N-
(4-acetyl-3-trifluoromethylphenyl)-
3'-oxospiro [cyclohexane-1,1 '(3'
H) -isobenzofuran] -4-carboxamide, trans-3′-oxo-N- [1- (3-quinolyl) -4.
-Imidazolyl] spiro [cyclohexane-1,1 '
(3′H) -isobenzofuran] -4-carboxamide, trans-N- [1- (3-cyanophenyl) -4
-Imidazolyl] -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [4-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [4-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (3-phenyl-
5-isoxazolyl) spiro [4-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [4-aza Isobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- (4-benzoylphenyl)
-3-oxospiro [6-azaisobenzofuran-1
(3H), 1′-Cyclohexane] -4′-carboxamide, N- [5- (4-hydroxyphenyl) -2-pyrazinyl] -3-oxospiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide, N- [5- (3-hydroxyphenyl) -2-pyrazinyl] -3-oxospiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide, 4-fluoro-3-oxo-N- (5-phenyl-
2-pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 7
-Fluoro-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide, 6-ethyl-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide , 6-hydroxy-
3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, trans-3-oxo-
N- (5-phenyl-2-pyrimidinyl) spiro [5-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5-
(3-Fluorophenyl) -2-pyrimidinyl] -3-
Oxospiro [5-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [5- (2-fluorophenyl)-
2-Pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane]-
4'-carboxamide, trans-3-oxo-N-
(4-Phenyl-2-oxazolyl) spiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5-
(2-Methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H),
1'-cyclohexane] -4'-carboxamide, trans-N- [5- (3-methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N- [5- (3-fluoromethoxyphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'- Carboxamide, trans-N
-[5- (3-Fluoromethylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N- [5- (3-fluoro-5
-Methoxyphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H),
1'-cyclohexane] -4'-carboxamide, trans-N- [5- (2-fluoro-5-methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1 '-Cyclohexane] -4'-carboxamide, trans-N- [4-
(3-Fluoromethoxyphenyl) -2-oxazolyl] -3-oxospiro [5-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5- (3-hydroxymethylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H) , 1'-Cyclohexane] -4'-carboxamide, trans-N-
[5- (3-Hydroxyphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (5-phenyl-
2-Pyrimidinyl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5- (3-fluoromethylphenyl) -2-pyrimidinyl] -3- Oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N-
[5- (3-Fluoromethoxyphenyl) -2-pyrimidinyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (6-Phenyl-1,2,4-triazin-3-yl) spiro [6-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5-
(2-Difluoromethoxyphenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5- (3-difluoromethoxyphenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H) , 1'-Cyclohexane] -4'-carboxamide, trans-N-
[5- (3-Fluorophenyl) -3-pyrazolyl]-
3-oxospiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [5- (4-fluorophenyl)-
3-Pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane]-
4'-carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3-oxospiro [7-azaisobenzofuran-1 (3H), 1′-
Cyclohexane] -4'-carboxamide, trans-
3-oxo-N- [2-phenyl-4-pyridyl] spiro [7-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3
-Oxo-N- (1-phenyl-4-pyrazolyl) spiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-3
-Oxo-N- (1-phenyl-3-pyrrolyl) spiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N-
[1- (4-fluorophenyl) -3-pyrazolyl]-
3-oxospiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (1-phenyl-3-
Pyrazolyl) spiro [4-azaisobenzofuran-1
(3H), 1′-Cyclohexane] -4′-carboxamide, trans-3-oxo-N- (1-phenyl-4
-Pyrazolyl) spiro [4-azaisobenzofuran-1
(3H), 1′-Cyclohexane] -4′-carboxamide, trans-N- [1- (3-fluorophenyl)
-4-Pyrazolyl] -3-oxospiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane]-
4'-carboxamide, trans-3-oxo-N-
(1-Phenyl-3-pyrazolyl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane]
-4'-carboxamide, trans-N- [1- (4-
Fluorophenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1′-
Cyclohexane] -4'-carboxamide, trans-
N- [1- (2-fluorophenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (5-phenyl-
1,2,4-thiadiazol-3-yl) spiro [6-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (5-phenyl-3-isoxazolyl) spiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-3-
Oxo-N- (6-phenyl-3-pyridyl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-
Oxo-N- (2-phenyl-3-thiazolyl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide or trans-3
-Oxo-N- (2-phenyl-1,2,3-triazol-4-yl) spiro [6-azaisobenzofuran-
1 (3H), 1′-cyclohexane] -4′-carboxamide and the like, among which 3-oxo-N- (5-
Phenyl-2-pyrazinyl) -spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide, 3-oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridine -2-yl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1 '
-Carboxamide, N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-
Carboxamide, trans-3′-oxo-N- (5-
Phenyl-2-pyrimidinyl) spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-3′-oxo-N- [1- (3
-Quinolyl) -4-imidazolyl] spiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-
Carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N −
[5- (2-fluorophenyl) -2-pyrimidinyl]
-3-Oxospiro [5-azaisobenzofuran-1
(3H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3-oxospiro [7-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (1-phenyl-4-pyrazolyl) spiro [4-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-3-oxo-N- (1-phenyl-3-pyrazolyl) spiro [6-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide or trans-3-oxo-N- (2-phenyl-1,2,3-triazole-
4-yl) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide and the like are preferable.

Next, the method for producing the compound according to the present invention will be described.
Explain. The compound (I) of the present invention can be produced, for example, by the following production
Can be manufactured by the method or the method shown in the examples.
It However, the method for producing the compound (I) of the present invention is not limited to these reactions.
It is not limited to the example.Manufacturing method 1 General formula (II)

[Chemical formula 23] [ ^Wherein Ar ^1p is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group,
Substituted by a lower alkenyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group and a group represented by -Q ^p -Ar ^2p and an optionally protected oxo group. Optionally an lower alkylene group, a hydroxy lower alkyl group, and an aryl group which may have a substituent selected from the group consisting of a carboxyl group, or a heteroaryl group; Ar ^2p is a halogen atom, a cyano group , A lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, a di lower alkylamino group,
A lower alkanoyl group and an aryl group, and an optionally protected aryl group or heteroaryl group, which may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group and a lower alkylamino group. Ar ³ represents a phenyl group which may be substituted with a halogen atom or a nitro group; Q ^p represents a single bond or an optionally protected carbonyl group] and a compound represented by the general formula: (III)

[Chemical formula 24] [Wherein n, t, u, v, w and Y have the above-mentioned meanings], and the compound represented by the general formula (IV-
1)

[Chemical 25] [Wherein Ar ^1p , n, t, u, v, w, and Y have the above-mentioned meanings], and a protecting group is removed as necessary to give a compound of the general formula (I-1)

[Chemical formula 26] A compound represented by the formula: wherein Ar ¹ , n, T, U, V, W and Y have the above-mentioned meanings can be produced.

This production method is a method for producing a compound represented by the general formula (I), wherein X in the formula is a nitrogen atom, that is, a compound represented by the general formula (I-1). is there. In the above reaction, when an amino group, a hydroxyl group, a carboxyl group, an oxo group, a carbonyl group or the like which does not participate in the reaction is present in the reaction material, the amino group, the hydroxyl group, the carboxyl group, the oxo group or the carbonyl group is an amino group. After protecting with a protecting group for a group, a protecting group for a hydroxyl group, a protecting group for a carboxyl group, or a protecting group for an oxo group or a carbonyl group, the reaction can be carried out and the protecting group can be removed after the reaction. Examples of the “amino group-protecting group” include aralkyl groups such as benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group and trityl group;
For example, lower alkanoyl group such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group; for example, benzoyl group; arylalkanoyl group, for example, phenylacetyl group, phenoxyacetyl group; for example, methoxycarbonyl group, ethoxycarbonyl group, propyloxy group Carbonyl group, lower alkoxycarbonyl group such as tert-butoxycarbonyl group; for example, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group,
Aralkyloxycarbonyl groups such as phenethyloxycarbonyl group; for example, lower alkylsilyl groups such as trimethylsilyl group, tert-butyldimethylsilyl group and the like, particularly acetyl group, pivaloyl group, benzoyl group, ethoxycarbonyl group, tert-butoxycarbonyl group. A group and the like are preferable. Examples of the “hydroxyl-protecting group” include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; Methoxymethyl group,
Lower alkoxymethyl group such as 2-methoxyethoxymethyl group; eg tetrahydropyranyl group; eg trimethylsilylethoxymethyl group; eg benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o
Aralkyl groups such as -nitrobenzyl group, p-nitrobenzyl group and trityl group; examples thereof include acyl groups such as formyl group and acetyl group, and particularly methyl group, methoxymethyl group, tetrahydropyranyl group, trityl group, trimethylsilyl group. Ethoxymethyl group, tert-butyldimethylsilyl group, acetyl group and the like are preferable. Examples of the "carboxyl protecting group" include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group; a lower haloalkyl group such as a 2,2,2-trichloroethyl group; Lower alkenyl groups such as 2-propenyl group; for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, aralkyl group such as trityl group and the like, particularly methyl group, ethyl group, tert-butyl group. A group, 2-propenyl group, benzyl group, p-methoxybenzyl group, benzhydryl group and the like are preferable.

Examples of the "protecting group for oxo group or carbonyl group" include acetals and ketals such as ethylene ketal, trimethylene ketal and dimethyl ketal. The compound represented by the general formula (II) and the general formula (II
The reaction with the compound represented by I
The compound (III) is used in an equimolar to excess mol, preferably equimolar to 1.5 mol, relative to 1 mol of I). The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like or a mixed solvent thereof and the like are suitable.
Further, the above reaction is preferably carried out in the presence of a base,
As the base, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or an inorganic base such as sodium hydroxide or potassium hydroxide can be used. The amount of the base used is usually equimolar to excess mol, preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (II). The reaction temperature is usually -30 ° C to 2
The temperature is 00 ° C, preferably 20 ° C to 100 ° C. The reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours. After completion of the reaction, usual treatment can be carried out to obtain a crude product of the compound represented by the general formula (IV-1). The general formula (I
The compound represented by V-1) is purified according to a conventional method, or is optionally combined with a reaction for removing a protective group of an amino group, a hydroxyl group, a carboxyl group, an oxo group and a carbonyl group without purification. The compound of general formula (I-1) can be produced by carrying out the above.

The method of removing the protecting group varies depending on the type of the protecting group, the stability of the target compound (I-1), and the like. For example, the method described in the literature [Protective Groups in Organic Synthesis (Protective)
Groups in Organic Synthes
is), T.I. W. Green (TW Greene)
Written by John Wiley & Sons (1981)
Year))] or a method analogous thereto, for example, solvolysis using an acid or a base, that is, for example 0.01
A molar to large excess of acid, preferably trifluoroacetic acid,
Formic acid, hydrochloric acid or the like, or a method of reacting an equimolar or large excess of a base, preferably potassium hydroxide, calcium hydroxide or the like; chemical reduction using a metal hydride complex or a palladium-carbon catalyst, Raney nickel catalyst, etc. It is carried out by catalytic reduction or the like.

[0030]Manufacturing method 2 General formula (V)

[Chemical 27] [Wherein Ar ^1p has the above-mentioned meaning] and a compound of the general formula (VI)

[Chemical 28] [Wherein n, t, u, v, w and Y have the above-mentioned meanings] and reacted with a carboxylic acid or a reactive derivative thereof to give a compound of the general formula (IV-2)

[Chemical 29] ^{Wherein, Ar 1p, n, t,} u, v, is w and Y have the meanings given above] and a compound represented by, by removing the protecting group as necessary, general formula (I-2)

[Chemical 30] A compound represented by the formula: wherein Ar ¹ , n, T, U, V, W and Y have the above-mentioned meanings can be produced. This production method is a method for producing a compound represented by the general formula (I), in which X in the formula is a methine group, that is, a compound represented by the general formula (I-2). The reaction between the compound represented by the general formula (V) and the carboxylic acid represented by the general formula (VI) is usually carried out by reacting 1 mol of the compound represented by the general formula (V) with the general formula (VI). The carboxylic acid represented by the formula (1) is used in an amount of 0.5 mol to excess mol, preferably 1 mol to 1.5 mol.

The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine and the like or a mixed solvent thereof and the like are suitable. Further, the above reaction is preferably carried out in the presence of a condensing agent, and examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide,
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3
-Ethylcarbodiimide hydrochloride, benzotriazole-
1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromotris- (dimethylamino) phosphonium hexafluorophosphate, diphenylphosphoric acid azide, 1,1 '-Carbonyldiimidazole or the like can be used. The condensing agent is usually, relative to 1 mol of the compound represented by the general formula (VI),
1 mol to excess mol, preferably 1 mol to 1.5
Molar can be used. The reaction temperature is usually -50.
C. to 100.degree. C., preferably -20.degree. C. to 50.degree. The reaction time is generally 30 minutes to 7 days, preferably 1 hour to 24 hours.

Instead of the carboxylic acid represented by the general formula (VI), a reactive derivative of the carboxylic acid is reacted with a compound represented by the general formula (V) to give a compound represented by the general formula (I-
The compound represented by 2) can also be produced. Examples of the reactive derivative of the carboxylic acid represented by the general formula (VI) include acid halides, mixed acid anhydrides, active esters, active amides and the like. The acid halide of the carboxylic acid of the general formula (VI) can be obtained by reacting the carboxylic acid of the general formula (VI) with a halogenating agent according to a conventional method. Examples of the halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride,
Phosphorus tribromide, oxalyl chloride, phosgene, etc. are used. Mixed acid anhydrides of carboxylic acids of general formula (VI) are
It can be obtained by reacting the carboxylic acid of the general formula (VI) with an alkyl chlorocarbonate such as ethyl chlorocarbonate; an aliphatic carboxylic acid chloride such as pivaloyl chloride according to a conventional method. The active ester of the carboxylic acid of the general formula (VI) is obtained by using the carboxylic acid of the general formula (VI) according to a conventional method, for example, N, N′-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-.
In the presence of a condensing agent such as ethylcarbodiimide, for example, N-
N-hydroxy compounds such as hydroxysuccinimide, N-hydroxyphthalimide and 1-hydroxybenzotriazole; phenol compounds such as 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol and pentachlorophenol It can be obtained by reacting. The activated amide of the carboxylic acid of the general formula (VI) is obtained by using the carboxylic acid of the general formula (VI) according to a conventional method, for example, 1,1′-carbonyldiimidazole, 1,1′-carbonylbis (2-methylimidazole) and the like. It can be obtained by reacting with. The reaction of the compound represented by the general formula (V) with the reactive derivative of the carboxylic acid represented by the general formula (VI) is generally carried out in a proportion of 1 mol of the compound represented by the general formula (V). Formula (V
It is carried out using 0.5 mol to an excess mol, preferably 1 mol to 1.5 mol, of the reactive derivative of the carboxylic acid represented by I).

The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine and the like or a mixed solvent thereof and the like are suitable. Further, the above-mentioned reaction proceeds even in the absence of a base, but it is preferable to carry out in the presence of a base so that the reaction proceeds more smoothly.
As the base, for example, an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate can be used. . Usually, the base is preferably used in an amount of 1 mol to excess mol per 1 mol of the compound represented by the general formula (V). When the base is liquid, the base can be used as a solvent and a base. The reaction temperature is usually -50.
C. to 100.degree. C., preferably -20.degree. C. to 50.degree. The reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours. After completion of the reaction, when a protecting group is present in the product, after removing the protecting group or when the protecting group is not present in the product, ordinary treatment is carried out as it is to give a compound of the general formula (I-2). It can be manufactured. Removal of the protecting group, post-treatment, and the like can be carried out according to the method described in the above Production Method 1. The compound of formula (I-1) or (I-2) can be easily isolated and purified by a conventional separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography and the like. These compounds can be converted into pharmaceutically acceptable salts or esters by a conventional method, and conversely, the conversion of a salt or an ester into a free compound can be performed by a conventional method.

As the compound represented by the general formula (II), (III), (V) or (VI), for example, a commercially available product is used, or the method described in the literature [JP-A-6-263737,
US Pat. No. 3,301,857, Journal of Organic Chemistry (J. Org. Che
m. ), 40, 1427 (1975), International Publication WO95 / 28389, etc.] or a method according to these methods, or by appropriately combining the following methods or the methods described in Examples, etc. It can be manufactured. Manufacturing method A

[Chemical 31] [Wherein, L ¹ represents a halogen atom, and Ar ^1p and A ¹
r ³ has the above meaning] This production method is a method for producing a compound represented by the general formula (II). According to this production method, the compound represented by the general formula (II) can be produced by reacting the compound represented by the general formula (V) with the compound represented by the general formula 1 . The reaction between compound (V) and compound 1 is usually carried out using 0.5 mol to excess mol of compound 1 , preferably equimolar to 1.5 mol, per 1 mol of compound (V). The reaction is usually carried out in an inert solvent, and examples of the inert solvent include methylene chloride, chloroform, tetrahydrofuran, ethyl ether, benzene,
Toluene, dimethylformamide and the like or a mixed solvent thereof and the like are preferable. Further, the above reaction is preferably carried out in the presence of a base, and examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, or sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid. potassium,
Inorganic bases such as sodium hydrogen carbonate can be used. The base is usually, relative to 1 mol of the compound (V),
It is preferable to use an equimolar or excess molar amount. When the base is liquid, the base can be used as a solvent and a base. The reaction temperature is generally -78 ° C to 100 ° C, preferably -20 ° C to 50 ° C. The reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.

The compound represented by the general formula 1 may be a commercially available product, or can be produced by appropriately combining known methods, methods described in the examples, or methods analogous thereto, as necessary. Manufacturing method B

[Chemical 32] [Wherein P ¹ represents a protecting group for an amino group; R ¹⁰ represents a hydrogen atom, a nitro group, a lower alkyl group or a lower alkoxy group; L ¹ , t, u, v and w have the above-mentioned meanings] This method is a method for producing the compound represented by the general formula (III-1). According to this production method, the compound represented by the general formula (III-1)
The compound represented by the general formula is obtained by subjecting the compound represented by the general formula 2 and the compound represented by the general formula 3 to a dehydration condensation reaction.
4 , the compound 4 is reacted with the compound represented by the general formula 5 in the presence of a base to give the compound represented by the general formula 6 , and then the compound 6 is subjected to an intramolecular Heck reaction. The compound 7 can be produced by subjecting it to cyclization to give a compound represented by the general formula 7 , then subjecting the compound 7 to a reduction reaction, and further removing the amino-protecting group P ¹ if necessary.

Examples of the amino group-protecting group represented by P ¹ include the amino group-protecting groups described in the above Production Method 1. The step of producing compound 4 by subjecting compound 2 and compound 3 to a dehydration condensation reaction is usually performed in an inert solvent such as benzene or toluene. The reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, and the reaction time is usually from 30 minutes to 24 hours. The step of producing compound 6 from compound 4 is usually carried out in an inert solvent such as benzene, toluene, methylene chloride, chloroform, acetonitrile, dimethylformamide, etc., in a base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc. In the presence of. The reaction temperature is usually 0 ° C.
To the boiling point of the solvent used for the reaction, and the reaction time is usually preferably 30 minutes to 24 hours. The step of producing the compound 7 from the compound 6 can be applied to the so-called intramolecular Heck reaction, which is well known in the field of organic chemistry. Specifically, the step is usually
For example, in an inert solvent such as benzene, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, N-methylpyrrolidone, etc., for example, palladium catalysts such as palladium acetate, palladium chloride, etc., phosphine ligands such as triphenylphosphine, tri-2-furylphosphine, etc., And in the presence of a base such as potassium carbonate or triethylamine, and optionally an additive such as tetraethylammonium chloride. The reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, and the reaction time is usually from 30 minutes to 24 hours. As the reduction method in the step of producing compound (III-1) from compound 7 , for example, catalytic reduction is preferable.

The catalytic reduction reaction is usually carried out in an inert solvent such as methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide and acetic acid in the presence of a catalyst such as a palladium-carbon catalyst at 1 atm to 50 atm. It is carried out under atmospheric hydrogen pressure. The reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, and the reaction time is usually from 30 minutes to 24 hours. After the reaction, if a protecting group is present in the product, the compound (III
-1) can be manufactured. The removal of the protecting group can be carried out according to the method described in the above Production method 1. This step can also be carried out by removing the protecting group of compound 7 and then subjecting the produced compound to a reduction reaction.

The compound represented by the general formula 2 , 3, or 5 may be a commercially available product, or may be produced by appropriately combining a known method, a method described in the examples, or a method analogous thereto, if necessary. it can. Manufacturing method C

[Chemical 33] [Wherein L ² represents a hydrogen atom or a halogen atom; P
h represents a phenyl group; Y ¹ represents an imino group substituted with an oxygen atom or a lower alkyl group or an aryl group; t, u, v and w have the above meanings]

This production method is a method for producing the compound represented by the general formula (VI-1). The compound represented by the general formula (VI-1) is a novel compound not described in the literature. According to the present production method, the compound is obtained by lithiation of the compound represented by the general formula 8 , followed by lactonization by reacting the compound represented by the formula 9 with the compound, and then acidifying the compound for deketalization reaction. subjected to the general formula 10 compounds represented by it, 1) after the introduction of a methylene group to the compound 10, the compound represented by the general formula 11 performs hydroboration, finally the compound 11
Or by 2) subjecting compound 10 to a reduction reaction to give a compound represented by general formula 12 , and then introducing a leaving group into compound 12 and cyanating it. It can be produced by preparing a compound represented by the formula 13 and finally hydrolyzing the cyano group of the compound 13 . The lithiation reaction in the step of producing compound 10 from compound 8 is generally carried out by reacting compound 8 with, for example, n-butyllithium, lithium 2,2,6,6-tetramethyl in an inert solvent such as tetrahydrofuran or diethyl ether. It can be performed by reacting an organolithium reagent such as piperidide. The reaction temperature is generally -120 ° C to 0 ° C, preferably -100 ° C to -50 ° C,
The reaction time is usually preferably 1 hour to 4 hours. The reaction between the formed lithio compound and the ketone represented by the formula 9 is usually carried out in an inert solvent such as tetrahydrofuran or diethyl ether. The reaction temperature is usually -100.
C. to room temperature are preferable, and the reaction time is usually preferably 10 minutes to 2 hours. The compound produced by the above reaction can be lactonized by treating it with an acid such as hydrochloric acid or sulfuric acid. The reaction temperature is
Usually, it is preferably 0 ° C. to the boiling point of the solvent used for the reaction, and the reaction time is usually preferably 30 minutes to 8 hours. The lactone product produced in the above reaction was prepared according to a conventional method.
Compound 10 can be produced by subjecting it to a deketalization reaction. The reaction temperature is usually preferably 50 ° C. to the boiling point of the solvent used in the reaction, and the reaction time is usually preferably 1 hour to 24 hours.

In the step of producing compound 11 from compound 10, the method of converting an oxo group into a hydroxymethyl group, which is well known in the field of organic chemistry per se, can be applied, and usually, for example, benzene, toluene, methylene chloride. After a methylene group is introduced into the compound 10 by an action of, for example, methylenetriphenylphosphorane in the compound 10 in an inert solvent such as chloroform, acetonitrile, tetrahydrofuran, dimethylformamide, etc., a hydroboration reaction is carried out. It can be done by attaching to. In both the step of introducing a methylene group and the step of subjecting to a hydroboration reaction, the reaction temperature is usually preferably 0 ° C. to the boiling point of the solvent used in the reaction, and the reaction time is
Generally, 30 minutes to 8 hours is preferable. In the step of producing compound (VI-1) from compound 11, the method of oxidizing a hydroxymethyl group to a carboxyl group, which is well known in the field of organic chemistry per se, can be applied. Usually, for example, benzene, toluene, chloride It can be carried out in an inert solvent such as methylene, chloroform, acetonitrile or dimethylformamide using, for example, sodium periodate and a catalytic amount of an oxidizing agent such as ruthenium chloride. The reaction temperature is usually preferably 0 ° C. to the boiling point of the solvent used in the reaction, and the reaction time is usually preferably 30 minutes to 8 hours. The step of producing compound 12 from compound 10 is
A method well known in the field of organic chemistry per se, which can be applied to a method for reducing an oxo group to a hydroxyl group, is usually used in an inert solvent such as water, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof, such as hydrogenation. It can be carried out using a reducing agent such as sodium borohydride or lithium borohydride. The reaction temperature is usually -20 ° C to 50 ° C.
C. is preferable, and the reaction time is usually preferably 10 minutes to 4 hours. In the step of producing compound 13 from compound 12, the method of converting a hydroxyl group into a cyano group, which is well known in the field of organic chemistry per se, can be applied, and usually, in the presence of a base such as triethylamine or pyridine, for example, After converting the hydroxyl group into a leaving group by acting methanesulfonyl chloride, p-toluenesulfonyl chloride, etc., the resulting compound is added to cyanide such as sodium cyanide, potassium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide, etc. It can be carried out by reacting a compound.

The step of converting a hydroxyl group into a leaving group is usually
For example, it is carried out in an inert solvent such as methylene chloride, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dimethylformamide, and the reaction temperature is usually -2.
The temperature is preferably 0 ° C. to room temperature, and the reaction time is usually preferably 10 minutes to 8 hours. The step of reacting the cyan compound is usually carried out in an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone or dimethylsulfoxide, and the reaction temperature is usually preferably 50 ° C to 120 ° C, and the reaction time is preferably Is usually preferred from 2 hours to 24 hours. In the step of producing the compound (VI-1) by hydrolyzing the cyano group of the compound 13 , the hydrolysis reaction of the cyano group, which is well known in the field of organic chemistry per se, can be applied, and usually, for example, methanol, ethanol. , Tetrahydrofuran, dioxane, in a solvent such as water or a mixed solvent thereof, for example, an acid such as hydrochloric acid or sulfuric acid, or for example sodium hydroxide, potassium hydroxide,
It can be carried out using a base such as calcium hydroxide.
The reaction temperature is usually preferably 50 ° C to the boiling point of the solvent used in the reaction, and the reaction time is usually 1 hour to 4 hours.
8 hours is preferred.

The compound represented by the general formula (VI-1) includes the general formula (VI-1-a) or the general formula (VI-1-).
b)

[Chemical 34] There are two types of stereoisomers represented by the formula: [wherein t, u, v and w have the above-mentioned meanings], and a mixture thereof is used for usual separation means such as chromatography and fractional recrystallization. These stereoisomers can be separated by adding Further, the stereoisomers of the compound represented by the general formula 11 , 12, or 13 are separated, and the isomer is used as an intermediate raw material for the general formula (VI-1-a) or the general formula (V
The compound represented by I-1-b) can be produced. In addition, the compound represented by the general formula 8 or formula 9 may be a commercially available product, or can be produced by appropriately combining known methods, methods described in the examples, or methods similar thereto as necessary. The usefulness of the compound of the present invention as a medicine is shown by, for example, NP in the following pharmacological test examples.
It is proved by showing Y antagonistic activity.

[0043]Pharmacological test example 1 (NPY binding inhibition test) CDNA sequence encoding human NPY Y5 receptor [Country
International patent application WO96 / 16542]]
Current vectors pcDNA3, pRc / RSV (in vitro
Jen) and pCI-neo (Promega)
I've roasted. The resulting expression vector is
Quality Law [Proceeding of the National Aka
Demy of Science of the United
States of America (Proceedings)
of the nationalacademy of
  sciences of the uniteds
States of America), 84, 741
See page 3 (1987)].
7, CHO and LM (tk-) (American type
Culture collection), N
PY Y5 receptor expressing cells were obtained. NPY Y5 receptor
A membrane preparation prepared from cells expressing
20,000 cpm [¹²⁵I] Peptide YY (N
Assay buffer (10 mM chloride)
Magnesium, 1 mM Phenylmethylsulfonylful
Olide, 0.1% bacitracin and 0.5% bovine serum
25 mM Tris buffer, pH 7.
4) After incubation at 25 ° C for 2 hours in
It was filtered with a lath filter GF / C. 0.3% BSA
After washing with 5 mM Tris buffer, pH 7.4 containing
The radioactivity on the glass filter was determined. Non-specific binding
Was measured in the presence of 1 μM peptide YY and
50% inhibitory concentration of test compound for tied YY binding
(IC_FiftyValue) was calculated [End Clinology (End
ocrinology), 131, 2090 (19)
1992)]]. The results are shown in Table 1.

[Table 1] As shown above, the compounds of the present invention potently inhibited the binding of peptide YY (a substance homologous to NPY) to the NPY Y5 receptor.

[0044]Pharmacological test example 2 (bPP-induced intake
Antagonistic test for eating behavior) Under pentobarbital anesthesia (50 mg / kg intraperitoneal single dose
Administration), male SD rats (7-8 weeks old, 200-300)
g) Stereotactically fixed chronic guide cannula in the right ventricle
(Outer diameter 0.8 mm, inner diameter 0.5 mm, length 10 mm)
Inserted and fixed with dental resin. Beyond the guide cannula
The position of the end is 0.9 mm behind bregma, and the median line
1.2 mm to the right and 1.5 mm deep from the brain surface
When the needle is inserted, the tip of the needle is about 2 mm, which is the guide cannula.
It came out from the tip of the to reach the lateral ventricle. About a week
Bovine Pancreatic Polypeptide After a Recovery Period of
(BPP, 5 μg / 10 μL / head, 0.05%
0.01M, pH 7.4 Phosphate containing serum albumin
Buffered saline) was administered into the lateral ventricle. The test compound is
0.5% methylcellulose aqueous solution 2 hours before bPP administration
Suspended in liquid and administered orally, and food intake 2 hours after bPP administration
Was measured. The compound of the present invention was administered to bP administered intraventricularly.
Significantly suppresses an increase in food intake due to P (a homologous substance to NPY)
Controlled.

The compound represented by the general formula (I) can be administered orally or parenterally, and by formulating into a form suitable for such administration, various diseases associated with NPY, That is, for example, cardiovascular diseases such as hypertension, kidney disease, heart disease, vasospasm, arteriosclerosis, etc., such as bulimia nervosa, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, drug discontinuation Central disorders such as withdrawal symptoms, such as obesity, diabetes, hormonal abnormalities, metabolic disorders such as hypercholesterolemia and hyperlipidemia, and sexual and reproductive dysfunction such as digestive tract disorders such as digestive tract dysfunction It can be provided as a therapeutic agent for diseases, respiratory diseases, inflammation, glaucoma and the like, more preferably bulimia, obesity and diabetes. In clinical use of the compound of the present invention, it is also possible to add a pharmaceutically acceptable additive in accordance with its administration form and administer it after various preparations. As the additive in that case, various additives usually used in the pharmaceutical field can be used, for example, gelatin, lactose,
White sugar, titanium oxide, starch, crystalline cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminometasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, Sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, Examples thereof include cyclodextrin and hydroxypropyl cyclodextrin. Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections. These can be prepared according to the usual methods in the field of formulation.
The liquid preparation may be dissolved or suspended in water or another suitable medium before use. Further, particularly in the case of an injection, it may be dissolved or suspended in physiological saline or glucose solution, if necessary, and a buffer and a preservative may be added. These formulations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight, of the total drug. These formulations may also contain other therapeutically effective compounds. The compounds of the present invention may be used in combination with other agents useful in the treatment of metabolic disorders and / or eating disorders. The individual components of such combinations may be administered at different times during the treatment period or at the same time in divided or single dosage forms. Therefore,
The present invention should be construed to include all administrations at the same time or at different times, and the administrations of the present invention should be so interpreted. The scope of the combination of the compound of the present invention with other agents useful for the treatment of metabolic disorders and / or eating disorders includes, in principle, the combination with any pharmaceutical preparation useful for the treatment of metabolic disorders and / or eating disorders. Be interpreted as When the compound of the present invention is used, for example, in a clinical setting, the dose and the number of administrations vary depending on the sex of the patient, age, body weight, degree of symptoms, type and range of desired therapeutic effect, etc. In the case of administration, it is 0.01 to 100 per day for an adult.
mg / kg, preferably 0.03 to 3 mg / kg
In several divided doses, and in the case of parenteral administration, 0.001-
10 mg / kg, preferably 0.001-0.1 mg /
It is preferable to administer kg in 1 to several divided doses. An ordinary physician, veterinarian, or clinician can readily determine and control the effective amount of drug required to arrest, arrest or arrest the progress of the condition.

[0046]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The melting point is M unless otherwise specified.
The measurement was performed using a P-S3 model (manufactured by Yanagimoto Seisakusho Co., Ltd.), and the values are shown without correction.

[0047]

[Example] Example 1N- (4-benzoylphenyl) -3-oxospiro
[Isoindoline-1,4'-piperidine] -1'-cal
Production of ruboxamide (1) N-benzyl-N- (1-tert-butoxyca
Rubonyl-1,2,3,6-tetrahydropyridine-4
-Yl) -2-Iodobenzamide production N-tert-butoki dissolved in toluene (20 mL)
Cycarbonyl-4-piperidone (1.11 g) and benzene
A mixture of dillamine (597mg) at 100 ° C for 3 hours.
Stir then concentrate. Toluene (30m
L), o-iodobenzoyl chloride (1.13 g) and
And triethylamine (0.70 g) were added, and the mixture was added at 80 ° C for 2
Stir for hours. Pour the reaction mixture into water and extract with ethyl acetate.
I put it out. The ethyl acetate layer was dried over anhydrous sodium sulfate,
Concentrated. Silica gel column chromatography of the residue
Purified by (hexane / ethyl acetate = 4/1 to 1/2)
The title compound (2.44 g) was obtained. (2) 2-benzyl-1'-tert-butoxycarbo
Nyl-1 ', 6'-dihydrospiro [1H-isoindo
1,4 '(5'H) -pyridine] -3 (2H)-
Manufacturing on N-benzyl-N- (1-tert-butoxycarbonyl
Ru-1,2,3,6-tetrahydropyridin-4-i
) -2-iodobenzamide (2.4 g) with acetoni
Dissolve in tolyl, palladium acetate (80 mg), trif
Phenylphosphine (187 mg), anhydrous potassium carbonate
(987 mg) and tetraethylammonium chloride
(591 mg) was added, and the mixture was stirred at 80 ° C for 6 hr. reaction
The mixture was poured into water and extracted with ethyl acetate, ethyl acetate layer
Was dried over anhydrous sodium sulfate and then concentrated. The residue
Silica gel column chromatography (hexane / acetic acid
Ethyl = 4/1 to 1/2) to give the title compound
(1.64 g) was obtained.

(3) 2-benzyl-1'-tert-butoxycarbonylspiro [1H-isoindole-1,
Preparation of 4'-piperidin] -3 (2H) -one 2-benzyl-1'-t-butoxycarbonyl-1 ',
6'-dihydrospiro [1H-isoindole-1,
4 '(5'H) -Pyridine] -3 (2H) -one (1.
Trifluoroacetic acid (20 mL) was added to a chloroform (20 mL) solution of 0 g), and the mixture was stirred for 1 hour. The reaction mixture was concentrated, the residue was dissolved in methanol and 4M hydrogen chloride /
Ethyl acetate was added, and hydrogenation was carried out for 14 hours under hydrogen at 1 atmosphere using 20% palladium carbon as a catalyst. The catalyst was filtered off, the filtrate was concentrated, 1N aqueous sodium hydroxide solution (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/2) to give the title compound (200 mg). (4) Preparation of Spiro [1H-isoindole-1,4'-piperidin] -3 (2H) -one Hydrochloride Metallic sodium (23 mL) in liquid ammonia (10 mL).
5 mg), then 2-benzyl-1′-tert
-Butoxycarbonyl spiro [1H-isoindole-
1,4'-Piperidin] -3 (2H) -one (200 m
g) was added and stirred for 30 minutes. After adding methanol to the reaction solution and neutralizing it with a saturated ammonium chloride aqueous solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Dissolve the residue in methanol and add 4M hydrogen chloride /
Ethyl acetate was added, and the mixture was stirred at 50 ° C for 1 hr. The reaction solution was concentrated to give the title compound (591 mg). ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 1.70-1.90 (2H, m), 2.00-
2.20 (2H, m), 3.00-3.20 (2H,
m), 4.20-4.40 (2H, m), 7.40 (1
H, d, J = 7.5 Hz), 7.51 (1H, t, J =
7.5 Hz), 7.59 (1H, t, J = 7.5H
z), 7.84 (1H, d, J = 7.5 Hz).

(5) Preparation of phenyl N- (4-benzoylphenyl) carbamate 4-Aminobenzophenone (1.97 g) dissolved in pyridine (50 mL) was added to phenyl chlorocarbonate (1.
38 g) was added. After stirring for 1 hour at room temperature, the reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/2), and the title compound (3.1
g) was obtained. (6) N- (4-benzoylphenyl) -3-oxospiro [isoindoline-1,4'-piperidine] -1 '
-Preparation of carboxamide Spiro [1H-isoindole-1,4'-piperidin] -3 (2H) -one hydrochloride (48 mg), triethylamine (0.14 mL) and phenyl N- (4-benzoylphenyl) carbamate ( 58 mg) was stirred in chloroform at 80 ° C. for 2 hours. The reaction mixture was poured into water, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/2) and crystallized from ethyl ether-hexane to give the title compound (49 mg) as colorless crystals (melting point 253 ° C.). Example 1-
The phenyl N- (4-benzoylphenyl) carbamate used in (6) was replaced with a raw material corresponding to the desired compound, and otherwise the same as in Example 1- (6).
And 3 compounds were obtained.

Example 23-oxo-N- (5-phenyl-2-pyrazinyl) su
Pyro [isoindoline-1,4'-piperidine] -1 '
-Carboxamide Melting point 286-287 ° C

Example 3N- (7-methyl-2-quinolyl) -3-oxospiro
[Isoindoline-1,4'-piperidine] -1'-cal
Ruboxamide Melting point 194-196 ° C

Example 4N- (4-benzoylphenyl) -2-methyl-3-o
Xisospiro [isoindoline-1,4'-piperidine]
Production of -1'-carboxamide Spiro [1H-isoindole used in Example 1- (6)
Lu-1,4'-piperidin] -3 (2H) -one hydrochloride
2-methylspiro [1H-isoindole-1,4 '
-Piperidin] -3 (2H) -one hydrochloride,
The title compound was obtained in the same manner as in Example 1- (6). Melting point
154-156 ° C

Example 5N- (4-benzoylphenyl) -3,4-dihydro-
3-oxospiro [isoquinoline-1 (2H), 4'-
Preparation of piperidine] -1'-carboxamide Spiro [isoquinoline-1 (2H), 4'-piperidi
N] -3 (4H) -one hydrochloride (30 mg) and N-
Phenyl (4-benzoylphenyl) carbamate (3
7 mg) in dimethylsulfoxide (2 mL),
Add 10 N sodium hydroxide aqueous solution (12 μL) and
Stir for 30 minutes at warm temperature. Pour the reaction mixture into water and add vinegar.
Extracted with ethyl acidate (20 mL). The organic layer is water (20m
L), after washing with saturated saline (20 mL), anhydrous sulfuric acid
Dry over sodium and concentrate. The residue is washed with silica gel.
Rum chromatography (hexane / ethyl acetate = 4 /
1-1 / 2) and then chloroform-aceto
Recrystallized from benzene (1: 3) to give the title compound (81 mg)
Obtained as colorless crystals (melting point 241-243 ° C.). Spyro
[Isoquinoline-1 (2H), 4'-piperidine] -3
(4H) -one hydrochloride and the corresponding cal
Example 1- (6) was used except for using the phenyl bamate derivative.
Alternatively, the compounds of Examples 6 to 21 are obtained in the same manner as in Example 5.
It was

Example 63,4-dihydro-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [isoquinoline-1 (2H),
4'-piperidine] -1'-carboxamide Melting point 237-239 ° C

Example 73,4-dihydro-N- (7-methyl-2-quinolyl)
-3-Oxospiro [isoquinoline-1 (2H), 4 '
-Piperidine] -1'-carboxamide Melting point 216-218 ° C

Example 8N- (4-acetylphenyl) -3,4-dihydro-3
-Oxospiro [isoquinoline-1 (2H), 4'-pi
Peridine] -1'-carboxamide Melting point> 300 ° C

Example 93,4-dihydro-3-oxo-N- [1- (2-quino
Ryl) -4-imidazolyl] spiro [isoquinoline-1]
(2H), 4'-piperidine] -1'-carbo Xamide Melting point 264-266 ° C

Example 103,4-dihydro-3-oxo-N- (5-oxo-
5,6,7,8-Tetrahydro-2-naphthyl) spiro
[Isoquinoline-1 (2H), 4'-piperidine ]-
1'-carboxamide Melting point 220.5-222.2 ° C

Example 113,4-dihydro-N- [5- (2-methyl-1-pro
(Penyl) -2-pyrazinyl] -3-oxospiro [iso
Quinoline-1 (2H), 4'-piperidine]- 1'-
Ruboxamide Melting point 232.9-236.5 ° C

Example 123,4-dihydro-3-oxo-N- (3-phenyl-
5-isoxazolyl) spiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxa Mid Melting point 239-241 ° C

Example 13N- [1- (7-benzo [b] furanyl) -4-imid
Zolyl] -3,4-dihydro-3-oxospiro [iso
Quinoline-1 (2H), 4'-piperidine]- 1'-
Ruboxamide Melting point 192-194 ° C

Example 14N- [1- (3-difluoromethoxyphenyl) -4-
Imidazolyl] -3,4-dihydro-3-oxospiro
[Isoquinoline-1 (2H), 4'-piperidi ]-
1'-carboxamide Melting point 161-163 ° C

Example 153,4-dihydro-3-oxo-N- [4- (2-pyri
(Dilcarbonyl) phenyl] spiro [isoquinoline-1
(2H), 4'-piperidine] -1'-carbo Xamide Melting point 162-164 ° C

Example 16N- (3,4-dichlorophenyl) -3,4-dihydro
-3-Oxospiro [isoquinoline-1 (2H), 4 '
-Piperidine] -1'-carboxamide Melting point> 300 ° C

Example 17N- [1- (3-chlorophenyl) -4-imidazole
]]-3,4-Dihydro-3-oxospiro [isoquino]
Phosphorus-1 (2H), 4'-piperidine] -1'- Carbo
Xamide Melting point 255-258 ° C

Example 183,4-dihydro-3-oxo-N- (5-phenyl-
2-thiazolyl) spiro [isoquinoline-1 (2H),
4'-piperidine] -1'-carboxamide Melting point> 300 ° C

Example 193,4-dihydro-3-oxo-N- [5- (2-pyri
Dil) -2-pyrazinyl] spiro [isoquinoline-1
(2H), 4'-piperidine] -1'-carboxy Samide Melting point 223-225 ° C

Example 203,4-dihydro-N- (4-methyl-2-benzothia
Zolyl) -3-oxospiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxami Do Melting point 144-146 ° C

Example 21N- (5-chloro-2-benzoxazolyl) -3,4
-Dihydro-3-oxospiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxa Mid Melting point 256-258 ° C

Example 22N- (4-benzoylphenyl) -3-oxospiro
[Isobenzofuran-1 (3H), 4'-piperidine]
Production of -1'-carboxamide Spiro [isobenzofuran-1 (3H), 4'-piperi
Zin] -3-one hydrochloride (48 mg), N- (4-ben
Phenyl zoylphenyl) carbamate (58 mg)
And triethylamine (0.14 mL) with chloroform
(5 mL), and stirred at 80 ° C. for 2 hours. The reaction mixture
It was poured into water and extracted with chloroform (20 mL).
The organic layer was washed with saturated saline (20 mL) and then dried over anhydrous sulfur.
Dry over sodium acidate and concentrate. Silica gel residue
Column chromatography (hexane / ethyl acetate = 4
1 / 1-1 / 2) and then purified with ethyl ether
Recrystallized from xane to give the title compound (81 mg) as colorless crystals
(Melting point 161-163 ° C).

Example 233-oxo-N- (5-phenyl-2-pyrazinyl) su
Pyro [isobenzofuran-1 (3H), 4'-piperidi
] -1'-carboxamide production (1) N- (5-phenyl-2-pyrazinyl) carbami
Production of phenyl acid 2-Amino-5-phosphine dissolved in pyridine (200 mL)
Chlorocarbonic acid was added to phenylpyrazine (17.12g) at 0 ° C.
Phenyl (15.05 mL) was added. Stir for 2 hours at room temperature
The reaction mixture with water (200 mL) and ethyl ether.
When (200 mL) was added and stirred, crystals of the target compound
It precipitated and became a suspension. The precipitated crystals were collected by filtration and washed with ethyl ether.
(50 mL), and then dried under reduced pressure.
The product (24.57 g) was obtained as colorless crystals (melting point 192-198).
C, decomposition). (2) 3-oxo-N- (5-phenyl-2-pyrazini
Le) spiro [isobenzofuran-1 (3H), 4'-pi
Preparation of peridine] -1'-carboxamide (Crystalline A) Spiro [isobenzofuran-1 (3H), 4'-piperi
Gin] -3-one hydrochloride (6.24 g, 26.6 mmo
l), N- (5-phenyl-2-pyrazinyl) carbami
Phenyl acidate (7.59 g, 26.0 mmol) and
Chlorotriethylamine (18 mL, 180 mmol)
Stir in form (200 mL) at 80 ° C. for 3 hours. Anti
The reaction mixture was added with saturated sodium hydrogen carbonate solution (100 m
L), then washed with 10% aqueous citric acid solution (100 mL)
After cleaning, 1N sodium hydroxide solution (100m
L), and then washed with saturated saline (100 mL). Existence
The organic layer was dried over anhydrous sodium sulfate and then concentrated to remove the residue.
Silica gel column chromatography (hexane / vinegar
Purified with ethyl acetate = 1/2), colorless solid of the title compound
Got This colorless solid was converted to diethyl ether (30 mL)
The crystals were washed with to give crude crystals of the title compound (8.23 g).
The crude crystals were dissolved in hot ethyl acetate (300 mL) and evaporated.
When about 100mL of ethyl acetate was distilled off by distillation
It began to turn cloudy. Stop the distillation, allow to cool, and let this solution stand for 14:00.
Leave at room temperature for a while, and collect the resulting colorless prism-like crystals by filtration.
And washed with heptane (20 mL). The obtained crystals
Dry under vacuum at 50 ° C. for 6 hours to give the title compound (crystal form A).
(5.17 g) as colorless prism-like crystals (melting point 210-2
11 ° C.).

[0072]

[Table 2] The above powder X-ray diffraction analysis data is RINT1100.
(Manufactured by Rigaku Corporation). The analysis method is as follows. Light source (lamp): Cu Tube voltage: 40 kV Tube current: 30 mA Monochromator: Fully automatic monochromator Monochrome receiving slit: 0.60 mm Goniometer: Wide-angle goniometer Sampling angle: 0.02 degrees Scanning speed: 2.00 degrees / minute Divergence Slit: 1 degree Scattering slit: 1 degree Receiving slit: 0.15 mm Measurement temperature: room temperature (3) 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4 ' -Production of piperidine] -1'-carboxamide (crystal form A) (another method) The crude crystal (2 g) obtained in the above (2) was dissolved by heating in tetrahydrofuran (20 mL). After confirming that it was completely melted, it was allowed to cool to room temperature. Heptane (27 mL) was gradually added dropwise to the tetrahydrofuran solution, and the mixture was stirred at room temperature for 15 hours. The resulting colorless crystals were collected by filtration and washed with heptane (5 mL). The obtained crystals were dried under vacuum at 30 ° C. for 15 hours to give the title compound (crystal form A) (1.82).
g) was obtained.

(4) 3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide (crystal form B) The crude crystal (2 g) obtained in (2) above was dissolved in dimethylformamide (6 mL) with heating. After confirming complete dissolution, water (13 mL) was added dropwise at 80 ° C., cooled to room temperature, and stirred for 15 hours. The resulting colorless crystals were collected by filtration and washed with heptane (5 mL). The obtained crystals are dried under vacuum at room temperature for 15 hours to give the title compound (crystal form B).
(1.78 g) of colorless prism crystals (melting point 208 ° C .;
Bulchi Melting Point (M
(eluting Point) B-545.

[0074]

[Table 3] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 23 (2). (5) Preparation of 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide (Crystalline C) In the above (2). The obtained crude crystal (2 g) was heated and dissolved in tetrahydrofuran (20 mL). After confirming that it was completely melted, it was cooled to -30 ° C. Heptane (30 mL) was gradually added dropwise to this tetrahydrofuran solution,
The mixture was stirred at 30 ° C for 1 hour. The resulting colorless crystals were collected by filtration and washed with heptane (5 mL). The obtained crystals were dried under vacuum at room temperature for 15 hours to give the title compound (crystal form C) (monotetrahydrofuran hydrate) (1.90 g) as colorless fine granular crystals.

[0075]

[Table 4] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 23 (2). (6) Preparation of 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide (crystal form D) Spiro [isobenzofuran- 1 (3H), 4′-piperidin] -3-one hydrochloride (515 mg) and N- (5-
Phenyl-2-pyrazinyl) carbamate (5
83 mg) was dissolved in dimethyl sulfoxide (2.6 mL), dimethylbenzylamine (0.33 mL) was added dropwise, the temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, and an acetonitrile / water (1: 2) solution (7.8 mL) was added dropwise. At this time, seed crystals were seeded when 0.2 mL was dropped. After stirring at room temperature for 6 hours, the produced colorless crystals were collected by filtration and washed with acetonitrile / water (1: 1). The obtained crystals were dried under vacuum at room temperature for 15 hours to give the title compound (793 mg) as colorless crude crystals. Crude crystals (26 g) obtained by repeating this operation were suspended in water-saturated isopropyl acetate (143 mL), and seed crystals were seeded, followed by stirring at room temperature for 18 hours. The generated crystals were collected by filtration and washed with isopropyl acetate (20 mL).
The obtained crystals were dried under vacuum at 30 ° C. for 15 hours to give the title compound (crystal form D) (25.2 g) as colorless crystals (melting point 2
06 ° C .; measured with Melting Point B-545 manufactured by Buchi, without correction).

[0076]

[Table 5] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 23 (2). (7) Preparation of 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide (Crystalline B) (another method) The crude crystals (26 g) obtained in (6) were suspended in acetonitrile (260 mL), and the crystals obtained in (4) above were seeded as seed crystals, and then stirred at room temperature for 24 hours. The crystals formed were collected by filtration and acetonitrile (50 mL)
Washed with. The obtained crystals were dried under vacuum at 30 ° C. for 15 hours to give the title compound (crystal form B) (25.5 g). The compounds of Examples 24 to 39 were obtained in the same manner as in Example 22 except that the phenyl N- (4-benzoylphenyl) carbamate used in Example 22 was replaced with a raw material corresponding to the desired compound.

Example 24N- (7-methyl-2-quinolyl) -3-oxospiro
[Isobenzofuran-1 (3H), 4'-piperidine]
-1'-carboxamide Melting point 178-180 ° C

Example 253-oxo-N- (3-phenyl-5-isoxazoli
Le) Spiro [isobenzofuran-1 (3H), 4'-pi
Peridine] -1'-carboxamide Melting point 239-242 ° C

Example 263-oxo-N- (7-trifluoromethylpyrido
[3,2-b] Pyridin-2-yl) spiro [isoben
Zofuran-1 (3H), 4'-piperidine] -1 ' −
Ruboxamide Melting point 246-248 ° C

Example 273-oxo-N- (5-phenyl-2-pyrimidinyl)
Spiro [isobenzofuran-1 (3H), 4'-piperi
Gin] -1'-carboxamide Melting point 211-214 ° C

Example 283-oxo-N- [1- (3-quinolyl) -4-imidazole
Zolyl] spiro [isobenzofuran-1 (3H), 4 '
-Piperidine] -1'-carboxamide Melting point 251-254 ° C

Example 293-oxo-N- (5-phenyl-3-pyrazolyl) su
Pyro [isobenzofuran-1 (3H), 4'-piperidi
] -1'-Carboxamide Melting point 160-165 ° C

Example 30N- [5- (4-chlorophenyl) -3-pyrazolyl]
-3-oxospiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide Melting point 255-258 ° C

Example 313-oxo-N- [5- (3-quinolyl) -3-pyrazo
Ryl] spiro [isobenzofuran-1 (3H), 4'-
Piperidine] -1'-carboxamide Melting point 253-257 ° C

Example 32N- [5- (3-fluorophenyl) -2-pyrimidini
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxami Do Melting point 122-125 ° C

[Table 6] The above powder X-ray diffraction analysis data is RINT2100 Ulti
It was measured by ma + System (2 KW) (manufactured by Rigaku Corporation). The analysis method is as follows. Light source (lamp): Cu tube voltage: 40 kV Tube current: 30 mA Monochromator: Fully automatic monochromator Monochrome receiving slit: 0.15 mm Goniometer: Horizontal goniometer I-type sampling angle: 0.02 degrees Scanning speed: 2.00 degrees / Divergence / divergence slit: 1 degree Scattering slit: 1 degree Receiving slit: 0.15 mm Measurement temperature: Room temperature

Example 333-oxo-N- [5- (3-trifluoromethylphen
Nyl) -2-pyrimidinyl] spiro [isobenzofuran
-1 (3H), 4'-piperidine] -1'-carb Ruboxa
Mid Melting point 190-192 ° C

Example 34N- [5- (3-chlorophenyl) -2-pyrimidini
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Melting point 126-128 ° C

Example 35N- (7-difluoromethoxypyrido [3,2-b] pi
Lydin-2-yl) -3-oxospiro [isobenzof
Run-1 (3H), 4'-piperidine] -1 ' -Carbo
Xamide Melting point 193 ° C

Example 363-oxo-N- (5-phenyl-1,2,4-thiadi
Azol-3-yl) spiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxy Samide Melting point 239-241 ° C

Example 37N- {1- [3- (2-hydroxyethyl) phenyl]
-4-Imidazolyl} -3-oxospiro [isobenzo
Furan-1 (3H), 4'-piperidine] -1 '-Cal
Voxamide Melting point 99-100 ° C

Example 38N- [4- (1-ethyl-2-imidazolyl) phenyi
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Melting point 221-223 ° C

Example 39N- [1- (3-methoxyphenyl) -4-imidazole
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxami Do Melting point 208-210 ° C

Example 406-Fluoro-3-oxo-N- (5-phenyl-2-
Pyrazinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide Manufacturing 6-fluorospiro [isobenzofuran-1 (3H),
4'-Piperidin] -3-one hydrochloride (64 mg), N
-(5-Phenyl-2-pyrazinyl) carbamate
Nil (73 mg) and triethylamine (174 μL)
Was stirred in chloroform (5 mL) at 80 ° C for 2 hours.
It was The reaction mixture was poured into water and chloroform (20 m
L). Wash the organic layer with saturated saline (20 mL)
It was purified, dried over anhydrous sodium sulfate and then concentrated.
The residue is subjected to silica gel column chromatography (hexane
/ Ethyl acetate = 4/1 to 1/2)
The crystals were recrystallized from ether-hexane to give the title compound (101
to obtain colorless crystals (melting point: 222-224 ° C.)
It was

Example 416-Fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Made of
Construction N- (5-phenyl-2-pyrazini used in Example 40
) Phenyl carbamate to N- (5-phenyl-2-
Pyrimidinyl) phenyl carbamate replaced with others
The title compound was obtained in the same manner as in Example 40. Melting point 176-1
78 ° C

Example 425-fluoro-3-oxo-N- (5-phenyl-2-
Pyrazinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide Manufacturing 5-fluorospiro [isobenzofuran-1 (3H),
4'-Piperidin] -3-one hydrochloride (64 mg), N
-(5-Phenyl-2-pyrazinyl) carbamate
Nil (73 mg) and triethylamine (174 μL)
Was stirred in chloroform (5 mL) at 80 ° C for 2 hours.
It was The reaction mixture was poured into water and chloroform (20 m
L). Wash the organic layer with saturated saline (20 mL)
It was purified, dried over anhydrous sodium sulfate and then concentrated.
The residue is subjected to silica gel column chromatography (hexane
/ Ethyl acetate = 4/1 to 1/2)
The crystals were recrystallized from ether-hexane to give the title compound (100
mg) as colorless crystals (melting point 236-238 ° C.)
It was

Example 435-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Made of
Construction N- (5-phenyl-2-pyrazini used in Example 42
) Phenyl carbamate to N- (5-phenyl-2-
Pyrimidinyl) phenyl carbamate replaced with others
The title compound was obtained in the same manner as in Example 42. Melting point 255-257 ° C

Example 44N- (4-benzoylphenyl) -3,4-dihydro-
3-oxospiro [1H-2-benzopyran-1,4 '
-Piperidine] -1'-carboxamide Spiro [1H-2-benzopyran-1,4'-piperidi
] -3 (4H) -one hydrochloride (50.6 mg) and N-
Phenyl (4-benzoylphenyl) carbamate (6
3.4 mg) in dimethyl sulfoxide (1.0 mL)
Suspend and add 10M aqueous sodium hydroxide solution (30 μL)
Addition and vigorous stirring for 5 minutes. Dilute the reaction mixture with water and add vinegar.
It was extracted with ethyl acidate. The organic layer was washed with saturated saline and
The extract was dried over sodium sulfate and concentrated. Methano residue
Crystallized from isopropyl-diisopropyl ether to give the title compound.
Compound (68.0 mg) as colorless crystals (melting point 138-146.
° C). N- (4-benzo used in Example 44
Phenyl) carbamates, each desired
The same as Example 44 except for the raw materials corresponding to the compound of
The compounds of Examples 45 and 46 were obtained.

Example 453,4-dihydro-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [1H-2-benzopyran-
1,4'-piperidine] -1'-carboxamide Melting point 221 ° C

Example 46N- (5-benzoyl-2-pyrazinyl) -3,4-di
Hydro-3-oxospiro [1H-2-benzopyran-
1,4'-piperidine] -1'-carboxami Do Melting point 128-131 ° C

Example 47Trans-N- (4-benzoylphenyl) -3'-o
Xoxospiro [cyclohexane-1,1 '(3'H) -I
Sobenzofuran] -4-carboxamide production (1) Spiro [cyclohexane-1,1 '(3'H)-
Production of isobenzofuran] -3 ', 4-dione No 2-bromobenzoic acid (4.77 g) was added under a nitrogen atmosphere.
Water tetrahydrofuran (100 mL) solution at -78 ° C
Cool and keep the internal temperature below -55 ° C while n-butyl
Titanium (1.53M hexane solution, 31 mL) was added dropwise.
It was After stirring for 1 hour, 1,4-cyclohexanedione mono
Anhydrous tetrahydrof of ethylene ketal (5.18g)
While keeping the orchid (10 mL) solution at an internal temperature of -67 ° C or lower
Dropped. After raising the temperature to room temperature, add water to the reaction mixture.
(150 mL) and hexane (100 mL) were added,
I arranged it. The aqueous layer was acidified with concentrated hydrochloric acid and acetone (10 m
L) was added and the mixture was refluxed for 2 hours. After allowing to cool, add potassium carbonate
Neutralized and extracted with ethyl acetate. Saturated salt in the organic layer
It was washed with water and dried over anhydrous sodium sulfate. Solvent
The residue was crystallized from ethyl acetate-hexane and evaporated.
A compound (2.42 g) was obtained. (2) 4-methylenespiro [cyclohexane-1,1 '
Production of (3'H) -isobenzofuran] -3-one Methyltriphenylphosphonium bromide under nitrogen stream
(715 mg) anhydrous tetrahydrofuran (7.0 m
L) suspension was cooled to 0 ° C. and n-butyllithium (1.
53M hexane solution, 1.3 mL) was added. At the same temperature
After stirring for 20 minutes, cool the reaction mixture to -78 ° C and spiro.
[Cyclohexane-1,1 '(3'H) -isobenzof
Orchid] -3 ', 4-dione (216 mg) in anhydrous tetra
Hydrofuran (3 mL) solution was added. The reaction solution to 0 ℃
After raising the temperature and stirring for 20 minutes, add ammonium chloride water to the reaction solution.
The solution was added and the crude product was extracted with ethyl acetate. Organic
The layer was washed with saturated brine and dried over anhydrous sodium sulfate.
After that, concentrate and concentrate the residue on silica gel column chromatography.
-(Hexane / ethyl acetate = 4/1) for purification and title
A compound (196 mg) was obtained. (3) 4-hydroxymethyl spiro [cyclohexane-
1,1 '(3'H) -isobenzofuran] -3'-one
Manufacturing of 4-Methylenespiro [cyclohexane-1,1 '(3'
H) -isobenzofuran] -3-one (196 mg)
Cool the anhydrous tetrahydrofuran (5.0 mL) solution to 0 ° C
Borane-dimethyl sulfide complex (2M tetrahy
Drofuran solution, 690 μL) was added. 1. At the same temperature
After stirring for 5 hours, 2M aqueous sodium hydroxide solution (5.0 m
L) and 30% hydrogen peroxide solution (5.0 mL) were added,
Stir for another 20 minutes. Dilute the reaction mixture with water and then use ethyl acetate.
Extracted with sodium chloride, washed with saturated saline, and anhydrous sodium sulfate.
It was dried at. The solvent was distilled off, and the residue was put on a silica gel column.
Chromatography (hexane / ethyl acetate = 2/1)
The title compound (190 mg) was purified by
Obtained as a mixture.

(4) Preparation of trans-3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxylic acid 4-hydroxymethylspiro [cyclohexane-1,
1 '(3'H) -isobenzofuran] -3'-one (1
To 90 mg) were added chloroform (2.0 mL), acetonitrile (2.0 mL) and sodium phosphate buffer (2.0 mL) adjusted to pH 6.5, and the mixture was cooled to 0 ° C. Sodium periodate (612 mg) and ruthenium (III) chloride n-hydrate (10 mg) were added to this solution, and the mixture was stirred for 30 minutes. 1N hydrochloric acid (2.0 m
L) was added, the mixture was stirred for 30 minutes, water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1) to give the title compound (98.6 mg). (5) trans-N- (4-benzoylphenyl)-
3'-oxospiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxamide Preparation trans-3′-oxospiro [cyclohexane-1,
To a solution of 1 ′ (3′H) -isobenzofuran] -4-carboxylic acid (24.6 mg) in pyridine (500 μL) was added 4
-Aminobenzophenone (19.8 mg) and 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (57.5 mg) was added, and the mixture was stirred at 50 ° C for 2 hr. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with aqueous potassium hydrogen sulfate solution, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated and the residue was crystallized from ethyl acetate-hexane to give the title compound (31.2 mg) as colorless crystals (melting point 19
4 ° C.). The compounds of Examples 48 to 56 were obtained in the same manner as in Example 47- (5), except that 4-aminobenzophenone used in Example 47- (5) was replaced with a raw material corresponding to the desired compound. .

Example 48Trans-3'-oxo-N- (5-phenyl-2-pi
Razinyl) spiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxamide Melting point 223 ° C

Example 49Trans-3'-oxo-N- (1-phenyl-4-i
Midazolyl) spiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxami Do Melting point 264 ° C

Example 50Trans-3'-oxo-N- (5-phenyl-2-pi
Limidinyl) spiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxami Do Melting point 184 ° C

Example 51Trans-N- [1- (3,5-difluorophenyl)
-4-Imidazolyl] -3'-oxospiro [cyclohe
Xan-1,1 '(3'H) -isobenzofura ] -4
-Carboxamide Melting point 294 ° C

Example 52Trans-3'-oxo-N- (5-phenyl-3-pi
Razolyl) spiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxamide Melting point 238 ° C

Example 53Trans-N- [1- (2-fluorophenyl) -4-
Imidazolyl] -3'-oxospiro [cyclohexane
-1,1 '(3'H) -isobenzofuran]- 4-cal
Voxamide Melting point 258 ° C

Example 54Trans-N- (4-acetyl-3-trifluoromethyi
Ruphenyl) -3'-oxospiro [cyclohexane-
1,1 '(3'H) -isobenzofuran] -4 -Carbo
Xamide Melting point 274-275 ° C

Example 55Trans-3'-oxo-N- [1- (3-quinolyl)
-4-imidazolyl] spiro [cyclohexane-1,
1 '(3'H) -isobenzofuran] -4-cal Boxer
Mid Melting point> 300 ° C

Example 56Trans-N- [1- (3-cyanophenyl) -4-i
Midazolyl] -3'-oxospiro [cyclohexane-
1,1 '(3'H) -isobenzofuran] -4 -Carbo
Xamide Melting point 268-270 ° C

Example 57Trans-N- (4-benzoylphenyl) -3-oxy
Sospiro [4-azaisobenzofuran-1 (3H),
1'-Cyclohexane] -4'-carboxamide Manufacturing of (1) Dispyro [4-azaisobenzofuran-1 (3
H), 1'-cyclohexane-4 ', 2 "-1", 3 "
-Dioxolane] -3-one Under a nitrogen atmosphere, N-methyl-2-pyridinecarboxami
Anhydrous tetrahydrofuran (400m)
L) The solution was cooled to -78 ° C and n-butyllithium was added.
(1.54M hexane solution, 100 mL) was added dropwise.
After stirring for 1.5 hours at the same temperature, 1,4-cyclohexene
No Sandione Monoethylene Ketal (10.93g)
A solution of water in tetrahydrofuran (100 mL) was added dropwise.
After raising the temperature to room temperature, add water (300 m
L) and ethyl ether (100 mL) were added and distributed.
It was The aqueous layer was acidified with 2N hydrochloric acid and stirred for 30 minutes,
After that, it was neutralized with potassium carbonate. Allow to stand overnight and allow precipitated crystals to
The crystals were collected by filtration and dried to give the title compound (6.84 g). (2) Spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -3,4'-dione
Construction Dispiro [4-azaisobenzofuran-1 (3H),
1'-cyclohexane-4 ', 2 "-1", 3 "-dio
Xoxolan] -3-one (6.8 g) in 2N hydrochloric acid (20 m
L) and acetone (5 mL) were added, and the mixture was heated under reflux for 13 hours.
It was After allowing to cool, neutralize with potassium carbonate and use isopropyl ether.
Ether (5 mL) was added and the mixture was stirred for 3 hours. Precipitated crystals are collected by filtration
Wash with water and isopropyl ether, then dry.
The title compound (3.39 g) was obtained. (3) cis-4'-hydroxyspiro [4-azaisobe
Nzofuran-1 (3H), 1'-cyclohexane] -3
-On manufacturing Spiro [4-azaisobenzofuran-1 (3H), 1 '
-Cyclohexane] -3,4'-dione (5.7 g)
In tetrahydrofuran (50 mL) and water (10 mL)
Dissolved and cooled to 0 ° C. Sodium borohydride (9
93 mg) was added and stirred for 20 minutes. Acid with 10% sulfuric acid
After adjusting to pH, pH is adjusted with saturated aqueous sodium hydrogen carbonate solution.
7.4, chloroform-ethanol and chloroform
It was extracted with tetrahydrofuran. Anhydrous organic layer
The extract was dried over sodium acidate and concentrated, and the residue was washed with ethyl acetate-
Crystallization from isopropyl ether gave the title compound (2.0
2 g) was obtained.

(4) trans-3-oxospiro [4-
Preparation of azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carbonitrile cis-4'-hydroxyspiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane] -3-one (2.02 g) anhydrous tetrahydrofuran (60 mL)
Triethylamine (3.08 mL) was added to the solution, and the temperature was 0 ° C.
Cooled to. Methanesulfonyl chloride (1.3 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr. Dilute the reaction with water,
It was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from ethyl acetate-isopropyl ether to give mesylate (2.47).
g) was obtained. The obtained mesylate was dissolved in dimethylformamide (25 mL), tetraethylammonium cyanide (3.25 g) was added, and the mixture was stirred at 100 ° C for 3 hr. After allowing to cool, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
It was purified by 2/3) to obtain the title compound (1.0 g). (5) trans-3-oxospiro [4-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Production of carboxylic acid A 30% aqueous solution of trans-3-oxospiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carbonitrile (1.0 g) in sulfuric acid was heated under reflux for 11 hours. After allowing to cool, the reaction solution was diluted with water, potassium carbonate was added to adjust the pH to 6, and the precipitated crystals were collected by filtration, washed with water and air-dried to obtain the title compound (974 mg). (6) trans-N- (4-benzoylphenyl) -3
-Oxospiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide preparation Trans-3-oxospiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxylic acid (66 mg) in pyridine (1 mL) ) 4-Aminobenzophenone (52.6 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (153 mg) were added to the solution, and the mixture was stirred at 40 ° C for 2 hours. The reaction solution was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from ethyl acetate-hexane to give the title compound (94.4 mg) as colorless crystals (melting point 237 ° C.). The compounds of Examples 58 to 60 were obtained in the same manner as in Example 57- (6), except that 4-aminobenzophenone used in Example 57- (6) was replaced with a raw material corresponding to the desired compound. .

Example 58Trans-3-oxo-N- (5-phenyl-2-pyra
Dinyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxy Samide Melting point 203 ° C

Example 59Trans-3-oxo-N- (3-phenyl-5-iso
Oxazolyl) spiro [4-azaisobenzofuran-1
(3H), 1'-Cyclohexane] -4'-carb Ruboxa
Mid Melting point 217 ° C

Example 60Trans-3-oxo-N- (5-phenyl-2-pyri
Midinyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carbo Xamide Melting point 237 ° C

Example 61Trans-N- (4-benzoylphenyl) -3-oxy
Sospiro [5-azaisobenzofuran-1 (3H),
1'-Cyclohexane] -4'-carboxamide Manufacturing of (1) Disiro [5-azaisobenzofuran-1 (3
H), 1'-cyclohexane-4 ', 2 "-1", 3 "
-Dioxolane] -3-one 2,2,6,6-Tetramethylpiperidine (41.1m
L) is dissolved in anhydrous tetrahydrofuran (400 mL)
And cooled to −50 ° C., and then n-butyllithium (1.
50 M hexane solution, 217 mL) and nicotinic acid (1
0.0 g) were added sequentially. The reaction mixture is 1 at -50 ° C.
After stirring for 1 hour, 1,4-cyclohexanedionemonoe
Anhydrous tetrahydrofuran of thylene ketal (13.9g)
Solution (25 mL) and stirred at -50 ° C for 1 hour.
It was After warming the reaction mixture to room temperature, water (800 m
L), hexane-ether (1: 1, 500 m
L). Adjust pH to 3 by adding 6N hydrochloric acid to the aqueous layer
And stir at room temperature for 2 hours, then collect the resulting precipitate by filtration.
And washed with water. The solid obtained was chloroform (30
Dissolved in 0 mL) and saturated aqueous sodium hydrogen carbonate solution (1
It was washed with 50 mL), dried and concentrated. Acetic acid residue
Recrystallized from ethyl-hexane to give the title compound (4.29).
g) was obtained. (2) Spiro [5-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -3,4'-dione
Construction Dispiro [5-azaisobenzofuran-1 (3H),
1'-cyclohexane-4 ', 2 "-1", 3 "-dio
Xolan] -3-one (4.29 g) and p-toluene
Sulfonic acid monohydrate (3.74 g) was added to acetone (80 m
L) and water (8 mL), and heated under reflux for 3 hours.
After allowing to cool, acetone was distilled off, and chloroform (10
0 mL) was added, and saturated aqueous sodium hydrogen carbonate solution (50
After washing with mL × 2) and drying with anhydrous sodium sulfate,
The solvent was distilled off. The crystalline residue obtained was washed with ethyl acetate.
Recrystallized from xane to give the title compound (2.68 g)
It was (3) cis-4'-hydroxyspiro [5-azaisobe
Nzofuran-1 (3H), 1'-cyclohexane] -3
-On manufacturing Spiro [5-azaisobenzofuran-1 (3H), 1 '
-Cyclohexane] -3,4'-dione (167 mg)
Suspended in tetrahydrofuran-water (10: 1, 4 mL)
After cooling to 0 ° C, sodium borohydride (32m
g) was added and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture
Pour into water (5 mL) and stir at room temperature for 30 minutes, then
Extract with Loloform (20 mL x 3), and extract layer is anhydrous
The extract was dried over sodium sulfate and then concentrated. Ethyl acetate residue
Recrystallized from ru-hexane to give the title compound (77.7m
g) was obtained.

(4) trans-3-oxospiro [5-
Production of azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carbonitrile cis-4′-hydroxyspiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -3-one (1.31 g) and triethylamine (1.17 mL)
Is dissolved in anhydrous tetrahydrofuran (20 mL) and the temperature is 0 ° C.
Cooled to. Methanesulfonyl chloride (0.555 mL)
Was added and stirred at 0 ° C. for 1 hour. The reaction mixture was washed with water (5
(0 mL), extracted with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the desired crude product of mesylate (1.87 g). This was dissolved in anhydrous dimethylformamide (30 mL), triethylammonium cyanide (2.98 g) was added, and 10
The mixture was stirred at 0 ° C for 5 hours. The reaction mixture was mixed with water (100 m
L), extracted with ether (150 mL × 3) and ether-ethyl acetate (2: 1, 200 mL), the extracted layers were combined, dried over anhydrous sodium sulfate, and concentrated.
The oily residue obtained was subjected to silica gel column chromatography (hexane / ethyl acetate / methanol = 2/1/0).
After purification by 1/1 / 0-30 / 30/1), the obtained solid was recrystallized from ethyl acetate-hexane to obtain the title compound (631 mg). (5) trans-3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Preparation of carboxylic acid trans-3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carbonitrile (100 mg) in water (0.7 mL) and concentrated sulfuric acid (0.3 mL). ) Was added and refluxed for 11 hours. After cooling the reaction mixture to room temperature, the pH was adjusted to 4 with a 4N sodium hydroxide solution, the precipitated crystals were collected by filtration, washed successively with water, ethanol and diisopropyl ether, and then dried.
The title compound (78 mg) was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ , δpp
m): 1.63-1.87 (2H, m), 1.88-
2.20 (6H, m), 2.70 (1H, m), 7.7
6 (1H, dd, J = 5.2, 1.1 Hz), 8.86
(1H, d, J = 5.2 Hz), 9.06 (1H, d,
J = 1.1 Hz). (6) trans-N- (4-benzoylphenyl) -3
-Oxospiro [5-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide preparation trans-3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxylic acid (20 mg) and 4-amino. Benzophenone (1
6 mg) was dissolved in anhydrous pyridine (0.5 mL), and 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (20 mg) was added, and the mixture was stirred at 60 ° C for 2 hr. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL × 2). Combine the organic layers,
The extract was dried over anhydrous sodium sulfate and concentrated. The obtained oily residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (10 mg). Colorless crystals (melting point 256-257
° C).

Example 62Trans-N- (4-benzoylphenyl) -3-oxy
Sospiro [6-azaisobenzofuran-1 (3H),
1'-Cyclohexane] -4'-carboxamide Manufacturing of (1) Disspiro [6-azaisobenzofuran-1 (3
H), 1'-cyclohexane-4 ', 2 "-1", 3 "
-Dioxolane] -3-one 2,2,6,6-Tetramethylpiperidine (50 mL)
Was dissolved in anhydrous tetrahydrofuran (500 mL), and-
After cooling to 50 ° C, n-butyllithium (1.50M
Hexane solution, 270.7 mL) and isonicotinic acid
(12.5 g) were added sequentially. The reaction mixture to -50 ° C.
Stir for 10 minutes, raise the temperature to 25 ° C over 30 minutes,
The mixture was further stirred at 25 ° C for 10 minutes. The reaction mixture is -65 ° C.
After cooling to 1,4-cyclohexanedione monoethylene
Add ketal (19g) and stir at -65 ° C for 10 minutes
Then, raise the temperature to -15 ° C over 1 hour, and
After the temperature was raised to 0 ° C, the mixture was poured into water (300 mL).
The aqueous layer is separated, and the organic layer is further diluted with 2N aqueous sodium hydroxide.
Extracted with liquid. Combine the aqueous layers and add concentrated hydrochloric acid to adjust the pH to 3.
The mixture was adjusted and extracted with ethyl acetate (500 mL). Organic layer
Saturated aqueous sodium hydrogen carbonate solution (200 mL), then
Wash with saturated saline and dry over anhydrous magnesium sulfate
After that, it was concentrated. Silica gel column chromatograph of the residue
(Hexane / ethyl acetate = 1/0 to 4/1 to 3 /
After purification in 2), the residue is extracted from ethyl acetate-hexane.
Recrystallization was performed to obtain the title compound (7.20 g). (2) Spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -3,4'-dione
Construction Dispiro [6-azaisobenzofuran-1 (3H),
1'-cyclohexane-4 ', 2 "-1", 3 "-dio
Xolan] -3-one (7.20 g) and p-toluene
Sulfonic acid monohydrate (5.80 g) was added to acetone (150
mL) and water (15 mL) and heat for 5.5 hours.
Shed After allowing to cool, acetone was distilled off, and the residue was converted to ethyl acetate.
It was extracted with (100 mL × 3). Gather organic layers and add saturated food
Wash with brine (50 mL) and dry with anhydrous magnesium sulfate
After drying, the solvent was distilled off. The crystalline residue obtained is treated with acetic acid.
Recrystallize from chill-diisopropyl ether to give the title compound.
The product (1.96 g) was obtained. (3) Cis-4'-hydroxyspiro [6-azaisobe
Nzofuran-1 (3H), 1'-cyclohexane] -3
-On manufacturing Spiro [6-azaisobenzofuran-1 (3H), 1 '
-Cyclohexane] -3,4'-dione (1.0 g)
After dissolving in ethanol (100 mL) and cooling to 0 ° C.,
Sodium borohydride (174 mg) was added, and the mixture was heated to 0 ° C.
And stirred for 1 hour. Add 10% aqueous sulfuric acid to the reaction mixture.
PH 4 and then saturated aqueous sodium hydrogen carbonate solution
After basifying with chloroform, add chloroform (200 mL x 2)
Extracted. Extract layer dried over anhydrous magnesium sulfate
After that, it was concentrated. Recrystallize the residue from ethyl acetate-hexane
The title compound (954.5 mg) was obtained.

(4) trans-3-oxospiro [6-
Preparation of azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carbonitrile cis-4′-hydroxyspiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -3-one (954 mg) and triethylamine (0.91 mL)
Was dissolved in dimethylformamide (10 mL) and cooled to 0 ° C. Methanesulfonyl chloride (0.40 mL) was added, and the mixture was stirred at 0 ° C for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (50 mL × 2) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate-diisopropyl ether,
The desired mesylate (995 mg) was obtained. This was dissolved in anhydrous dimethylformamide (30 mL), triethylammonium cyanide (1.57 g) was added, and the temperature was 100 ° C.
The mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (2
Diluted with water (200 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL), and saturated saline (100 mL).
(mL), and the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (447 mg). (5) trans-3-oxospiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Preparation of carboxylic acid trans-3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carbonitrile (445 mg) in water (3.5 mL) and concentrated sulfuric acid (1.5 mL). ) Was added and refluxed for 6 hours. The reaction mixture was cooled to room temperature, adjusted to pH 8 with a 5N aqueous sodium hydroxide solution, and then adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (416 mg) as colorless crystals (melting point 222-223 ° C). ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 1.7-2.2 (6H, m), 2.65-2.7.
5 (1H, m), 7.83 (1H, dd, J = 1.2H
z, 4.9 Hz), 8.86 (1H, d, J = 4.9H)
z), 9.05 (1H, d, J = 1.2 Hz), 12.
3 (1H, brs). (6) trans-N- (4-benzoylphenyl) -3
-Oxospiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide preparation trans-3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxylic acid (50 mg) and 4-amino Benzophenone (5
1.6 mg) was dissolved in anhydrous pyridine (1 mL), and 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (48.7 mg) was added, and the mixture was stirred at 60 ° C for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), water (20 mL), 10% aqueous citric acid solution (20 m
L × 2), a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution were sequentially washed. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The oily residue obtained was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2).
~ 1/4), the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (62.7 mg).
Was obtained as colorless crystals (melting point 147-149 ° C.).

Example 63N- [5- (4-hydroxyphenyl) -2-pyrazini
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxami Made of
Construction (1) 2-amino-5- (4-hydroxyphenyl) pi
Manufacture of ladins 2-amino-5-bromopyrazine (366 mg)
4-hydroxypheny was added to the toxyethane solution (20 mL).
Ruboronic acid (320 mg), 1.5N aqueous sodium carbonate
Solution (2.5 mL) and tetrakis (triphenylphos)
Fin) Palladium (0) (54 mg) was added, and the temperature was 80 ° C.
And stirred for 3 hours. Add water (20 mL) to the reaction mixture.
And extracted with ethyl acetate (50 mL × 3). Extract
The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the obtained crystalline residue was converted to diethyl ether.
Wash with (10 mL) to give the title compound (305 mg).
It was (2) N- [5- (4-hydroxyphenyl) -2-pi
[Radinyl] phenyl carbamate production Phenyl chloroformate (199 μL) was added to 2-amino
-5- (4-hydroxyphenyl) pyrazine (283m
g) to a pyridine (20 mL) solution under ice cooling, and at 1:00
It was stirred for a while. The reaction solution was poured into water (30 mL) and diluted with acetic acid.
Extracted with chill (20 mL x 3). The extract is saturated saline
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated.
The crystalline residue obtained is taken up with diethyl ether (10 mL).
Washing gave the title compound (314 mg). (3) N- [5- (4-hydroxyphenyl) -2-pi
Razinyl] -3-oxospiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide
Manufacturing of Spiro [isobenzofuran-1 (3H), 4'-piperi
Zin] -3-one hydrochloride (96 mg), N- [5- (4
-Hydroxyphenyl) -2-pyrazinyl] carbamine
Phenyl acid (128 mg) and triethylamine (27
9 μL) in chloroform (5 mL) at 80 ° C. for 2 hours
It was stirred. Pour the reaction mixture into water and add chloroform.
It was extracted with (20 mL). The organic layer was saturated saline (20 m
L), washed with anhydrous sodium sulfate, and then concentrated
did. The residue is subjected to silica gel column chromatography (
Xane / ethyl acetate = 4/1 to 1/2)
After that, recrystallized from ethyl ether-hexane to give the title compound.
(114 mg) as colorless crystals (melting point 263-265 ° C.)
I got it.

Example 64N- [5- (3-hydroxyphenyl) -2-pyrazini
Ru] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxami Made of
Construction (1) 2-amino-5- (3-methoxyphenyl) pyra
Manufacture of gin 2-amino-5-bromopyrazine (642 mg)
To a solution of toxyethane (40 mL), add 3-methoxyphenyl
Ruboronic acid (560 mg), 1.5N aqueous sodium carbonate
Solution (4 mL) and tetrakis (triphenylphosphine
N) Palladium (0) (86 mg) was added, and the mixture was mixed at 80 ° C for 6
Stir for hours. Add water (20 mL) to the reaction mixture and add vinegar.
Extracted with ethyl acidate (50 mL x 3). Saturated extract
It was washed with brine and dried over anhydrous sodium sulfate. Solvent
The crystalline residue obtained by evaporation was distilled off with ethyl ether (10 m).
It wash | cleaned by L) and the title compound (760 mg) was obtained. (2) 2-amino-5- (3-hydroxyphenyl) pi
Manufacture of ladins 2-amino-5- (3-methoxyphenyl) pyrazine
(566 mg) was dissolved in methylene chloride (10 mL),
Boron tribromide (530 μL) was added under ice cooling. At room temperature
After reacting for 14 hours, 1N sodium hydroxide was added to the reaction solution.
Aqueous solution was added and extracted with ethyl acetate (30 mL x
2). The organic layer was washed with saturated brine, anhydrous sodium sulfate
After drying with, the solvent was distilled off and the title compound (94 mg) was yellowed.
Obtained as a colored solid. (3) N- [5- (3-hydroxyphenyl) -2-pi
[Radinyl] phenyl carbamate production Phenyl chloroformate (63 μL) was added to 2-amino-
5- (3-hydroxyphenyl) pyrazine (89 mg)
Was added to a pyridine (10 mL) solution under ice-cooling and stirred for 1 hour.
I stirred. The reaction solution was poured into water (30 mL), and ethyl acetate was added.
It was extracted with (20 mL × 3). Wash the extract with saturated saline.
It was washed and dried over anhydrous sodium sulfate. Evaporate the solvent,
The crystalline residue obtained is washed with ethyl ether (10 mL).
The title compound (51 mg) was obtained by purification. (4) N- [5- (3-hydroxyphenyl) -2-pi
Razinyl] -3-oxospiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide
Manufacturing of Spiro [isobenzofuran-1 (3H), 4'-piperi
Zin] -3-one hydrochloride (40 mg), N- [5- (3
-Hydroxyphenyl) -2-pyrazinyl] carbamine
Phenyl acid (51 mg) and triethylamine (119
μL) in chloroform (5 mL) at 80 ° C. for 2 hours.
I stirred. The reaction mixture was poured into water and chloroform (2
0 mL). The organic layer is saturated brine (20 mL)
Washed with water, dried over anhydrous sodium sulfate, and then concentrated.
It was The residue is subjected to silica gel column chromatography (hexane
After purification with sun / ethyl acetate = 4/1 to 1/2),
Recrystallization from ethyl ether-hexane gave the title compound (2
4 mg) as colorless crystals (melting point 257-259 ° C.)
It was

Example 654-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Made of
Construction 4-fluorospiro [isobenzofuran-1 (3H),
4'-piperidin] -3-one hydrochloride (150 mg),
N- (5-phenyl-2-pyrimidinyl) carbamic acid
Phenyl (170 mg) and triethylamine (0.2
4 mL) in chloroform (2 mL) at 60 ° C. for 3 hours
After stirring, it was concentrated. The residue is chromatographed on a silica gel column.
Tography (hexane / ethyl acetate / methanol = 1
/ 1 / 0-8 / 8 / 8-1 / 6/6/1),
Recrystallized from ethyl acetate-hexane to give the title compound (190
to obtain colorless crystals (melting point 247-249 ° C.)
It was

Example 667-Fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Made of
Construction 7-fluorospiro [isobenzofuran-1 (3H),
4'-piperidin] -3-one hydrochloride (150 mg),
N- (5-phenyl-2-pyrimidinyl) carbamic acid
Phenyl (170 mg) and triethylamine (0.2
4 mL) in chloroform (2 mL) at 60 ° C for 2 hours
It was stirred. The reaction mixture was diluted with ethyl acetate and diluted with 10%
Aqueous enoic acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated
After washing with brine and drying over anhydrous sodium sulfate,
Contracted. The residue was recrystallized from ethyl acetate to give the title compound (2
02 mg) as colorless crystals (melting point 244-246 ° C.)
Obtained.

Example 676-ethyl-3-oxo-N- (5-phenyl-2-pi
Razinyl) spiro [isobenzofuran-1 (3H),
Preparation of 4'-piperidine] -1'-carboxamide Construction (1) 2- (4-ethylphenyl) -4,4-dimethyl
-2-Oxazoline production No p-ethylbenzoic acid (3.80 g) was added under a nitrogen atmosphere.
Add triphenylphoh to a solution of water in acetonitrile (100 mL).
Sphine (20 g), 2-amino-2-methyl-1-p
Lopanol (2.74 mL) and triethylamine (2
8.2 mL) was added, and carbon tetrachloride was further cooled in an ice bath.
(5.36 mL) was added. Return the reaction solution to room temperature, 1
Stir for 8 hours. Add ethyl acetate and hexane to the reaction mixture.
After filtering the precipitate, the filtrate was concentrated and the silica gel column was
Chromatography (hexane / ethyl acetate = 9 / 1-
6/1) to give the title compound (1.15 g)
It was (2) 1'-benzyl-6-ethylspiro [isobenzo
Furan-1 (3H), 4'-piperidin] -3-one salt
Production of acid salt Under a nitrogen atmosphere, 2- (4-ethylphenyl) -4,4-
Anhydrous dimethyl-2-oxazoline (1.15 g)
Lahydrofuran (100 mL) solution cooled to -78 ° C
1.5M butyllithium hexane solution (4.53m
L) was added. After stirring for 1 hour, 1-benzyl-4-pipet
Redone (1.05 mL) was added dropwise. Raise temperature to room temperature
After raising the temperature, add 2N hydrochloric acid to the reaction solution to acidify it, and then for 2 hours.
Refluxed. After allowing to cool, use an aqueous solution of sodium hydroxide to
It was rendered acidic and extracted with ethyl ether. Saturated organic layer
It was washed with brine and dried over anhydrous sodium sulfate. Existence
After concentrating the organic layer, the crude product obtained
By chromatography (hexane / ethyl acetate = 3/2)
After purification, it was converted to the hydrochloride with hydrochloric acid and the title compound (409 m
g) was obtained. (3) 6-Ethylspiro [isobenzofuran-1 (3
H), 4'-Piperidin] -3-one hydrochloride salt 1'-benzyl-6-ethylspiro [isobenzofuran
-1 (3H), 4'-piperidin] -3-one (400
mg) in methanol (10 mL) and add 10% para.
Didium carbon was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours.
Palladium on carbon was removed by filtration, the filtrate was concentrated, and the residue was treated with methanol.
Crystallized from ethyl ether to give the title compound (22
2 mg) was obtained. (4) 6-Ethyl-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide
Construction 6-ethylspiro [isobenzofuran-1 (3H),
4'-piperidin] -3-one hydrochloride (53 mg) and
N- (5-phenyl-2-pyrazinyl) carbamic acid
Phenyl (58 mg) in dimethyl sulfoxide (1 mL)
Suspended in 10M aqueous sodium hydroxide solution (0.02m
L) was added. The reaction mixture was stirred vigorously for 5 minutes and then with water.
Partitioned with ethyl acetate. The organic layer is separated and saturated brine
Washed with water, dried over anhydrous sodium sulfate, and then concentrated
The residue was crystallized from ethyl acetate to give the title compound (46 m
g) was obtained as crystals (melting point 176-178 ° C).

Example 686-hydroxy-3-oxo-N- (5-phenyl-2
-Pyrazinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide Made of
Construction (1) 2- (4-methoxyphenyl) -4,4-dimethyl
Production of le-2-oxazoline 2-Amino-2-methyl-1-propanol (14.4
g) and triethylamine (23 mL) in dry THF
To the (200 mL) solution, under ice cooling, 4-methoxybenzene was added.
Zoyl chloride (25 g) dissolved in dry THF (20 mL)
The liquid was dropped. After reacting this solution at room temperature for 1 hour,
Add water (200 mL) and add to ethyl acetate (100 mL)
And extracted twice. After washing the organic layer with saturated saline,
It is dried over anhydrous sodium sulfate and the solvent is distilled off.
A white solid (29.5 g) was obtained. Thi chloride
Onyl (25 mL) was added, and the mixture was reacted at room temperature for 1 hr.
To the reaction solution, add 5N aqueous sodium hydroxide solution and
It was made acidic and extracted twice with ethyl acetate (100 mL).
The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
Dried The solvent was evaporated, and the title compound (22 g) was colorless.
Obtained as an oil. (2) 1'-benzyl-6-methoxyspiro [isoben
Zofran-1 (3H), 4'-piperidin] -3-one
Manufacturing of Under a nitrogen atmosphere, under ice bath, 2- (4-methoxyphenyl)
) -4,4-Dimethyl-2-oxazoline (7.9)
1.5M in a solution of g) in dry toluene (100 mL).
Butyllithium hexane solution (28 mL) was added dropwise.
Then, the mixture was stirred at the same temperature for 3 hours. Then 1-benzyl-4
-Piperidone (8 g) in dry toluene (20 mL) solution
Was added and reacted at room temperature for 14 hours, then saturated ammonium chloride was added.
Aqueous monium solution (50 mL) was added, and ethyl acetate (10 mL) was added.
It was extracted twice with 0 mL). Wash the organic layer with saturated saline
After that, it is dried over anhydrous sodium sulfate and the solvent is distilled off.
Thus, a white solid (8.3 g) was obtained. This compound
Dissolve in methanol (50 mL) and add concentrated sulfuric acid (4 mL)
The reaction was continued for 1 hour at room temperature. Add 1N sodium hydroxide to the reaction solution.
Add thorium solution to make it alkaline and add ethyl acetate.
It was extracted twice with (100 mL). The organic layer is saturated saline
Washed with water, dried over anhydrous sodium sulfate, and evaporated to remove the solvent.
The title compound (6.6g) was obtained as a yellow solid. (3) 6-hydroxyspiro [isobenzofuran-1
Preparation of (3H), 4'-piperidin] -3-one hydrochloride 1'-benzyl-6-methoxyspiro [isobenzofura
-1 (3H), 4'-Piperidin] -3-one (1.
8 g) was dissolved in methylene chloride (20 mL) and cooled under ice,
Boron tribromide (1.3 mL) was added. 14 hours at room temperature
After reacting, 1N sodium hydroxide aqueous solution was added, and vinegar was added.
It was extracted twice with ethyl acidate (30 mL). Saturated organic layer
After washing with brine, dry over anhydrous sodium sulfate and dissolve.
The medium was distilled off to obtain a yellow solid (1.2 g).
Dissolve this yellow solid in methanol (30 mL) and
Hydrogen chloride-ethyl acetate solution (5 mL), 20% hydroxide solution
Add radium-carbon (300 mg) and under hydrogen atmosphere 1
Stir for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated and filtered.
The title compound (891 mg) was obtained as a white solid. (4) 6-hydroxy-3-oxo-N- (5-phenyl
Lu-2-pyrazinyl) spiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide
Manufacturing of 6-hydroxyspiro [isobenzofuran-1 (3
H), 4'-piperidin] -3-one hydrochloride (51 m
g), N- (5-phenyl-2-pyrazinyl) carbami
Phenyl acid salt (58 mg) and triethylamine (11
9 μL) in chloroform (5 mL) at 80 ° C. for 2 hours
It was stirred. Pour the reaction mixture into water and add chloroform.
It was extracted with (20 mL). The organic layer was saturated saline (20 m
L), washed with anhydrous sodium sulfate, and then concentrated
did. The residue is subjected to silica gel column chromatography (
Xane / ethyl acetate = 4/1 to 1/2)
After that, recrystallized from ethyl ether-hexane to give the title compound.
(29 mg) as colorless crystals (melting point 206-208 ° C)
I got it. 4-Aminobenzophenone used in Example 61
For each of the raw materials corresponding to the desired compound,
The compounds of Examples 69 to 79 were obtained in the same manner as in Example 61.
It was

Example 69Trans-3-oxo-N- (5-phenyl-2-pyri
Midinyl) spiro [5-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carbo Xamide Melting point 215-217 ° C

Example 70Trans-N- [5- (3-fluorophenyl) -2-
Pyrimidinyl] -3-oxospiro [5-azaisoben
Zofuran-1 (3H), 1'-cyclohexane ] -4 '
-Carboxamide Melting point 205-207 ° C

Example 71Trans-N- [5- (2-fluorophenyl) -2-
Pyrimidinyl] -3-oxospiro [5-azaisoben
Zofuran-1 (3H), 1'-cyclohexane ] -4 '
-Carboxamide Melting point 226-228 ° C

[Table 7] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 32.

Example 72Trans-3-oxo-N- (4-phenyl-2-oxy
Sazolyl) spiro [5-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carbo Xamide Melting point 273-275 ° C

Example 73Trans-N- [5- (2-methylphenyl) -2-pi
Limidinyl] -3-oxospiro [5-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 213-215 ° C

Example 74Trans-N- [5- (3-methylphenyl) -2-pi
Limidinyl] -3-oxospiro [5-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 145-147 ° C

Example 75Trans-N- [5- (3-fluoromethoxyphenyl
) -2-Pyrimidinyl] -3-oxospiro [5-a
The isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide Melting point 157-159 ° C

Example 76Trans-N- [5- (3-fluoromethylphenyl)
-2-Pyrimidinyl] -3-oxospiro [5-azai
Sobenzofuran-1 (3H), 1'-cyclohe Xan]
-4'-carboxamide Melting point 153-155 ° C

Example 77Trans-N- [5- (3-fluoro-5-methoxyphenol
2-phenylimidinyl] -3-oxospiro [5
-Azaisobenzofuran-1 (3H), 1'- Cyclo
Xan] -4'-carboxamide Melting point 218-220 ° C

Example 78Trans-N- [5- (2-fluoro-5-methylphe
Nyl) -2-pyrimidinyl] -3-oxospiro [5-
Azaisobenzofuran-1 (3H), 1'-shi Black hex
Sun] -4'-carboxamide Melting point 151-153 ° C

Example 79Trans-N- [4- (3-fluoromethoxyphenyl)
) -2-Oxazolyl] -3-oxospiro [5-a
The isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide Melting point 214-217 ° C

Example 80Trans-N- [5- (3-hydroxymethylpheny
) -2-Pyrimidinyl] -3-oxospiro [5-a
The isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide production 2-chloro-1,3-dimethylimidazolium chloride
To a solution of (613 mg) in chloroform (10 mL),
Gin (0.489 mL), trans-3-oxospiro
[5-azaisobenzofuran-1 (3H), 1'-siku
Rohexane] -4'-carboxylic acid (300 mg) and 2
-Amino-5-bromopyrimidine (211 mg) was added.
And stirred at room temperature overnight. Reaction mixture with ethyl acetate
Dilute, 10% aqueous citric acid, saturated sodium bicarbonate
Washed with aqueous sodium chloride solution and saturated saline solution, anhydrous sodium sulfate
After being dried in, it was concentrated. The residue is purified by silica gel column chromatography.
Matography (hexane / ethyl acetate = 1/1 to 1 /
3 to 1/4 to 1/5) and then from ethyl acetate
Crystallization gave the desired amide (210 mg). This
The amide product is ethylene glycol dimethyl ether (3.5
mL), water (0.5 mL), 3-hydroxymeth
Tylphenylboronic acid (95 mg), 2M sodium carbonate
Aqueous solution (0.31 mL) and tetrakistriphenyl
Add phosphine palladium (30 mg) and heat for 2 hours
Refluxed. The reaction solution was diluted with water and extracted with ethyl acetate,
The extract was dried over anhydrous sodium sulfate and concentrated. Siri the residue
Kagel column chromatography (ethyl acetate / methano
= 1/0 to 30/1 to 20/1 to 15/1)
The title compound (151 mg) was prepared as pale yellow crystals (melting point: 20).
7-209 ° C).

Example 81Trans-N- [5- (3-hydroxyphenyl) -2
-Pyrimidinyl] -3-oxospiro [5-azaisobe
Nzofuran-1 (3H), 1'-cyclohexa ]-
Production of 4'-carboxamide 2-chloro-1,3-dimethylimidazolium chloride
Pyridinium was added to a solution of (622 mg) in chloroform (7 mL).
(0.50 mL), trans-3-oxospiro [5
-Azaisobenzofuran-1 (3H), 1'-cyclohe
Xan] -4'-carboxylic acid (303 mg) and 2-a
Mino-5- (3-benzyloxyphenyl) pyrimidine
(340 mg) was added, and the mixture was stirred at room temperature overnight. Reaction mixture
The mixture was diluted with ethyl acetate and washed with 10% aqueous citric acid solution.
Washed with an aqueous sodium hydrogencarbonate solution and saturated saline,
It was dried over anhydrous sodium sulfate and then concentrated. Remove the residue
Rica gel column chromatography (hexane / acetic acid
Chill = 1/1 to 1/2 to 1/4 to 1/5 to 1/6)
After purification, crystallized from ethyl acetate to obtain the desired amide
(210 mg) was obtained. This amide was converted to methanol (5
mL), dissolved in tetrahydrofuran (5 mL), 10
% Palladium carbon catalyst (120 mg) was added, and the atmosphere was hydrogen.
The mixture was stirred under air at room temperature overnight. The catalyst is filtered off and the filtrate is concentrated
did. The residue is subjected to silica gel column chromatography (
Purified with loroform / methanol = 50/1 to 30/1)
After manufacturing, the obtained solid was washed with ethanol. Change
The solid was recrystallized from ethyl acetate to give the title compound (95 m
g) as pale yellow crystals (melting point 260-262 ° C.)
It was The 4-aminobenzophenone used in Example 62 was
Change the raw material corresponding to the desired compound respectively, and carry out other
The compounds of Examples 82 to 89 were obtained in the same manner as in Example 62.

Example 82Trans-3-oxo-N- (5-phenyl-2-pyri
Midinyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carbo Xamide Melting point 189-191 ° C

Example 83Trans-N- [5- (3-fluoromethylphenyl)
-2-Pyrimidinyl] -3-oxospiro [6-azai
Sobenzofuran-1 (3H), 1'-cyclohe Xan]
-4'-carboxamide Melting point 199-200 ° C

Example 84Trans-N- [5- (3-fluoromethoxyphenyl
) -2-Pyrimidinyl] -3-oxospiro [6-a
The isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide Melting point 198-200 ° C

Example 85Trans-3-oxo-N- (6-phenyl-1,2,
4-triazin-3-yl) spiro [6-azaisoben
Zofuran-1 (3H), 1'-cyclohexane ] -4 '
-Carboxamide Melting point 272-275 ° C

Example 86Trans-N- [5- (2-difluoromethoxyphenyl
) -3-Pyrazolyl] -3-oxospiro [6-aza
Isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide Melting point 239-240 ° C

Example 87Trans-N- [5- (3-difluoromethoxyphenyi
) -3-Pyrazolyl] -3-oxospiro [6-aza
Isobenzofuran-1 (3H), 1'-cyclo Hexa
] -4'-carboxamide Melting point 183-185 ° C

Example 88Trans-N- [5- (3-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 182-184 ° C

Example 89Trans-N- [5- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 228-229 ° C

Example 90Trans-N- (4-benzoylphenyl) -3-oxy
Sospiro [7-azaisobenzofuran-1 (3H),
1'-Cyclohexane] -4'-carboxamide Manufacturing of (1) Production of 3-cyano-2-hydroxypyridine Malonaldehyde bisdimethyl acetal (16.4
0.5N hydrochloric acid (40 mL) was added to g), and the mixture was added at 50 ° C. for 2 hours.
After stirring for 0 minutes, the mixture was allowed to cool to room temperature. Triethylami
(16 mL) was added, followed by 2-cyanoacetamide
(9 g) was added, and the mixture was stirred at room temperature for 30 minutes and then at 60 ° C.
Heated for 90 minutes at 100 ° C. for 2 hours. After standing to cool, react
The mixture is concentrated and the residue is ethanol-ethyl ether.
The crystals were recrystallized to give the title compound (7.49 g). (2) Production of 2-bromo-3-cyanopyridine Tetrabutylammonium bromide (35.4 g) and
Diphosphorus pentoxide (15.58 g) was added to toluene (100 m
L) and stirred at 70 ° C. for 30 minutes, then 3-shi
Ano-2-hydroxypyridine (6.59 g) was added,
The mixture was heated under reflux for 4 hours. Reaction mixture in ice water (200 g)
Pour and extract with ethyl acetate (200mL × 2)
After drying with magnesium acid, it was concentrated. Oily residue obtained
The residue is subjected to silica gel column chromatography (hexane /
Obtained after purification with ethyl acetate = 4/1 to 3/1)
The solid was recrystallized from ethyl acetate-hexane to give the title compound.
The product (5.16 g) was obtained. (3) Spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -3,4'-dione
Construction 2-bromo-3-cyanopyridine (2.96 g), and
1,4-cyclohexanedione monoethylene ketal
(3.47 g) in anhydrous tetrahydrofuran (38 mL)
And was cooled to -78 ° C. n-butyl lithium
(1.50 M hexane solution, 12.64 mL) was added,
After stirring at −78 ° C. for 30 minutes, the temperature was raised to room temperature.
The reaction mixture was poured into water (40 mL) and ethyl acetate (10 mL) was added.
Extract with 0 mL x 3) and dry over anhydrous magnesium sulfate
After that, it was concentrated. The residue was reconstituted from ethyl ether-hexane.
Crystallize to give the corresponding imino ether (2.93 g)
It was This compound was added to acetone (5 mL) and 2N hydrochloric acid (3
It was dissolved in 0 mL) and heated under reflux for 2 hours. After cooling down, 2N
Add sodium hydroxide solution to adjust the pH to 4, and add ethyl acetate.
Extraction (100 mL x 3) with anhydrous magnesium sulfate
After drying, it was concentrated. The residue was reconstituted from ether-hexane.
Crystallization gave the title compound (1.07 g)

(4) cis-4'-hydroxyspiro [7
-Preparation of azaisobenzofuran-1 (3H), 1'-cyclohexane] -3-one Spiro [7-azaisobenzofuran-1 (3H), 1 '
-Cyclohexane] -3,4'-dione (1.6 g) was suspended in tetrahydrofuran (37 mL), cooled to 0 ° C, and then lithium tri-tert-butoxyaluminum hydride (1.0 M tetrahydrofuran solution, 9.58).
mL) was added, and the mixture was stirred at 0 ° C. for 90 minutes. To the reaction mixture was added 1N hydrochloric acid to adjust the pH to 2, and ethyl acetate (100
(mL × 4) extraction, dried over anhydrous magnesium sulfate,
Concentration gave the title compound (1.58g). (5) trans-3-oxospiro [7-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Preparation of carbonitrile cis-4'-hydroxyspiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -3-one (1.58 g) and triethylamine (1.81 mL)
Was dissolved in chloroform (28 mL) and cooled to 0 ° C. Methanesulfonyl chloride (0.67 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (50 mL), and chloroform (10 mL) was added.
It was extracted with 0 mL × 3), dried over anhydrous magnesium sulfate, and concentrated. The oily residue obtained was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/1 to
1/2), and then the resulting solid was washed with ethyl acetate-
Recrystallization from hexane gave the desired mesylate (2.03
g) was obtained. This compound was dissolved in anhydrous dimethylformamide (30 mL), triethylammonium cyanide (3.2 g) was added, and the mixture was stirred at 100 ° C. for 3 hr.
After allowing to cool, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous magnesium sulfate, and concentrated. The obtained oily residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
3/1 to 2/1), the obtained solid was recrystallized from ethyl ether-hexane to give the title compound (51
5 mg) was obtained. (6) trans-3-oxospiro [7-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Preparation of carboxylic acid trans-3-oxospiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carbonitrile (515 mg) in water (6.6 mL) and concentrated sulfuric acid (2.2 mL). ) Was added and the mixture was heated under reflux for 13 hours. The reaction mixture was cooled to 0 ° C., pH was adjusted to 4 with 4N sodium hydroxide solution, the precipitated crystals were collected by filtration, washed with water, ethanol and diisopropyl ether successively, and dried to give the title compound (500 mg). Obtained. ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 1.73-1.80 (2H, m), 1.81-
1.94 (2H, m), 1.99-2.08 (2H,
m), 2.14-2.22 (2H, m), 2.64-
2.68 (1H, m), 7.63 (1H, dd, J =
7.8, 4.8 Hz), 8.28 (1H, dd, J =
7.8, 1.5 Hz), 8.89 (1H, dd, J =
4.8, 1.5 Hz). (7) trans-N- (4-benzoylphenyl) -3
-Oxospiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide preparation trans-3-oxospiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxylic acid (26 mg) and 4-amino Benzophenone (2
0 mg) was dissolved in anhydrous pyridine (1 mL), and 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (29 mg) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The obtained oily residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 2/1), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (30 mg). Colorless crystals (melting point 214-216
° C). The 4-aminobenzophenone used in Example 90 (7) was replaced with the corresponding starting material for the desired compound, and otherwise the same as in Example 90 (7).
1-95 compounds were obtained.

Example 91Trans-N- [1- (3,5-difluorophenyl)
-4-Imidazolyl] -3-oxospiro [7-azai
Sobenzofuran-1 (3H), 1'-cyclohe Xan]
-4'-carboxamide Melting point 269-271 ° C

[Table 8] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 32.

Example 92Trans-3-oxo-N- [2-phenyl-4-pyri
Zil] spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxa Mid Melting point 221-223 ° C

Example 93Trans-3-oxo-N- (1-phenyl-4-pyra
Zolyl) spiro [7-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carboxamide Melting point 240-242 ° C

Example 94Trans-3-oxo-N- (1-phenyl-3-pyro
Ryl) spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxa Mid Melting point 214-217 ° C

Example 95Trans-N- [1- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [7-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 210-212 ° C Substantially the same as the method described in Example 57- (6).
Method, but used in Example 57- (6)
Amines in place of the defined 4-aminobenzophenone
To prepare the compounds of the Examples of Examples 96-98.
It was

Example 96Trans-3-oxo-N- (1-phenyl-3-pyra
Zolyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxy Samide Melting point 200-202 ° C

Example 97Trans-3-oxo-N- (1-phenyl-4-pyra
Zolyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxy Samide Melting point 223-225 ° C

[Table 9] The powder X-ray diffraction analysis data was measured under the same conditions as in Example 32.

Example 98Trans-N- [1- (3-fluorophenyl) -4-
Pyrazolyl] -3-oxospiro [4-azaisobenzo]
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 176-178 ° C Substantially the same as the method described in Example 62- (6).
Method, but used in Example 62- (6)
Amines in place of the defined 4-aminobenzophenone
To prepare the compounds of the Examples of Examples 99-106.
did.

Example 99Trans-3-oxo-N- (1-phenyl-3-pyra
Zolyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxy Samide Melting point 249-250 ° C

Example 100Trans-N- [1- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 254-257 ° C

Example 101Trans-N- [1- (2-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzo
Furan-1 (3H), 1'-cyclohexane] -4'-
Carboxamide Melting point 239-241 ° C

Example 102Trans-3-oxo-N- (5-phenyl-1,2,
4-thiadiazol-3-yl) spiro [6-azaiso
Benzofuran-1 (3H), 1′-cyclohex Sun]-
4'-carboxamide Melting point 221-223 ° C

Example 103Trans-3-oxo-N- (5-phenyl-3-iso
Oxazolyl) spiro [6-azaisobenzofuran-1
(3H), 1'-Cyclohexane] -4'-carb Ruboxa
Mid Melting point 259-261 ° C

Example 104Trans-3-oxo-N- (6-phenyl-3-pyri
Dil) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxa Mid Melting point 249-251 ° C

Example 105Trans-3-oxo-N- (2-phenyl-3-thia
Zolyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxy Samide Melting point 278-280 ° C

Example 106Trans-3-oxo-N- (2-phenyl-1,2,
3-triazol-4-yl) spiro [6-azaisobe
Nzofuran-1 (3H), 1'-cyclohexa ]-
4'-carboxamide Melting point 232-233 ° C

Formulation Example 1 20.0 g of the compound of Example 1, 417 g of lactose, a crystal cell
80 g of loin and 80 g of partially pregelatinized starch
After mixing using a mold mixer, magnesium stearate
3.0 g of aluminum was added and mixed. Tablet the mixed powder according to the usual method.
Diameter 3000 mm, one tablet weighing 150 mg 3000
I got a lock.Content per tablet (150 mg) 5.0 mg of the compound of Example 1 Lactose 104.25mg Crystalline cellulose 20.0mg Partially pregelatinized starch 20.0 mg Magnesium stearate 0.75 mg

Formulation Example 2 Hydroxypropyl cellulose 2910 10.8 g and
And polyethylene glycol 6000 2.1 g purified water
After dissolving in 172.5 g, 2.1 g of titanium dioxide was added to
And the coating solution was prepared. Example of separately prepared formulation
1 tablet 2500 tablets using a high coater mini
Spray coating the coating solution to a weight of 155 mg
A film-coated tablet was obtained.Content per tablet (155mg) Formulation Example 1 tablet 150 mg Hydroxypropyl cellulose 2910 3.6 mg Polyethylene glycol 6000 0.7mg Titanium dioxide 0.7mg

[0167]

INDUSTRIAL APPLICABILITY Since the compound of the present invention has an NPY antagonistic action, various diseases associated with NPY, that is, cardiovascular diseases such as hypertension, kidney disease, heart disease, vascular spasm, arteriosclerosis, etc. , Central disorders such as bulimia, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, for example obesity, diabetes, hormonal abnormalities, hypercholesterolemia, It is useful as a therapeutic agent for metabolic diseases such as hyperlipidemia, sexual and reproductive dysfunction, gastrointestinal diseases such as gastrointestinal motility disorders, respiratory diseases, inflammation and glaucoma.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/444 A61K 31/444 31/4709 31/4709 31/4747 31/4747 31/497 31/497 31/506 31/506 31/53 31/53 A61P 1/00 A61P 1/00 3/04 3/04 3/06 3/06 3/10 3/10 5/00 5/00 9/10 9/10 101 101 9/12 9 / 12 11/00 11/00 13/12 13/12 15/00 15/00 25/08 25/08 25/22 25/22 25/24 25/24 25/28 25/28 25/30 25/30 25/32 25/32 27/06 27/06 29/00 29/00 43/00 111 43/00 111 C07D 307/94 C07D 307/94 405/12 405/12 491/048 491/048 491/107 491 / 107 519/00 301 519/00 301 (72) Inventor Yasuyuki Ishii, 3 Okubo, Tsukuba City, Ibaraki Prefecture, Banyu Pharmaceutical Co., Ltd., Tsukuba Research Institute (72) Toshiyuki Takahashi, 3 Okubo, Tsukuba City, Ibaraki Manyu Pharmaceutical Co., Ltd. Company Tsukuba Research Institute (72) Inventor Yuji Hashita Ibaraki 3 Okubo, Tsukuba, Japan Prefectural Banyu Pharmaceutical Co., Ltd., Tsukuba Research Institute (72) Inventor Toshihiro Sakamoto 3 Okubo, Tsukuba, Ibaraki Prefectural Banyu Pharmaceutical Co., Ltd., Tsukuba Research Institute (72) Inventor Takahiro Ito Kamiroku, Aichi Prefecture 3-9-1 Manju Pharmaceutical Co., Ltd. Okazaki Plant (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 471/10 C07D 491/048 C07D 491/107 C07D 519/00 C07D 307/94 C07D 405/12 A61K 31/343 A61K 31/4155 A61K 31/4178 A61K 31/438 A61K 31/444 A61K 31/4709 A61K 31/4747 A61K 31/497 A61K 31/506 A61K 31/53

Claims (33)

(57) [Claims] 1. A compound represented by the general formula (I): [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Means an aryl group or a heteroaryl group; n is 0
Or 1 means; Q means a single bond or a carbonyl group; T, U, V and W are each independently selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group. A methine group which may have a substituent or a nitrogen atom, of which at least 2
Represents a methine group; X represents a methine group or a nitrogen atom; Y represents an imino group optionally substituted with a lower alkyl group or an oxygen atom], a salt thereof or a carboxyl group. Ester in the group . 2. The compound according to claim ^{1, wherein} the aryl group of Ar ¹ is a phenyl group. 3. A heteroaryl group for Ar ¹ is a pyrrolyl group,
Imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, isoxazolyl group, 1,2,3-triazolyl group, 1,2,4-thiadiazolyl group, pyridyl group,
Pyrazinyl group, pyrimidinyl group, 1,2,4-triazinyl group, benzoxazolyl group, benzothiazolyl group,
The compound according to claim 1, which is a quinolyl group or a pyrido [3,2-b] pyridyl group. 4. T, U, V and W are independent of each other.
The compound according to claim 1, which is a methine group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group. 5. T, U, V and W are independently of each other.
The compound according to claim 4, which is a methine group which may be substituted with a halogen atom. 6. The compound according to claim 1, wherein any one of T, U, V and W is a nitrogen atom. 7. The compound according to claim 1, wherein Y is an unsubstituted imino group or an oxygen atom. 8. The compound according to claim 1, wherein Y is an oxygen atom. 9. A compound represented by the general formula (Ia): [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, The compound according to claim 1, which represents an aryl group or a heteroaryl group; Q represents a single bond or a carbonyl group; and R ¹ represents a hydrogen atom or a halogen atom]. 10. The compound according to claim 9, wherein the aryl group of Ar ¹ is a phenyl group. 11. A heteroaryl group for Ar ¹ is an imidazolyl group, a pyrazolyl group, an isoxazolyl group, 1,2,4.
-Thiadiazolyl group, pyrazinyl group, pyrimidinyl group,
The compound according to claim 9, which is a quinolyl group or a pyrido [3,2-b] pyridyl group. 12. A compound represented by the general formula (Ib): [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Q means a single bond or a carbonyl group; T, U, V and W are each an aryl group or a heteroaryl group;
Each independently represents a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, at least two of which are the methine group; A compound represented by the formula [1]. 13. The compound according to claim 12, wherein the aryl group of Ar ¹ is a phenyl group. 14. The heteroaryl group of Ar ¹ is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-thiadiazolyl group, a pyridyl group. The compound according to claim 12, which is a pyrazinyl group, a pyrimidinyl group or a 1,2,4-triazinyl group. 15. The compound according to claim 12, wherein any one of T, U, V and W is a nitrogen atom. 16. The compound according to claim 12, wherein V is a nitrogen atom, and T, U and W are unsubstituted methine groups. 17. N- (4-benzoylphenyl) -3-
Oxospiro [isoindoline-1,4'-piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isoindoline-1,4'-piperidine] -1 '
-Carboxamide, N- (7-methyl-2-quinolyl) -3-oxospiro [isoindoline-1,4'-piperidine] -1'-carboxamide, N- (4-benzoylphenyl) -2-methyl-3- Oxospiro [isoindoline-1,4'-piperidine]
-1'-carboxamide, N- (4-benzoylphenyl) -3,4-dihydro-
3-oxospiro [isoquinoline-1 (2H), 4'-
Piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [isoquinoline-1 (2H),
4'-piperidine] -1'-carboxamide, 3,4-dihydro-N- (7-methyl-2-quinolyl)
-3-Oxospiro [isoquinoline-1 (2H), 4 '
-Piperidine] -1'-carboxamide, N- (4-acetylphenyl) -3,4-dihydro-3
-Oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- [1- (2-quinolyl) -4-imidazolyl] spiro [isoquinoline- 1
(2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-oxo-
5,6,7,8-Tetrahydro-2-naphthyl) spiro [isoquinoline-1 (2H), 4'-piperidine]-
1'-carboxamide, 3,4-dihydro-N- [5- (2-methyl-1-propenyl) -2-pyrazinyl] -3-oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1 ' -Carboxamide, 3,4-dihydro-3-oxo-N- (3-phenyl-
5-isoxazolyl) spiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxamide, N- [1- (7-benzo [b] furanyl) -4-imidazolyl] -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H). , 4'-piperidine] -1'-carboxamide, N- [1- (3-difluoromethoxyphenyl) -4-
Imidazolyl] -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'-piperidine]-
1′-carboxamide, 3,4-dihydro-3-oxo-N- [4- (2-pyridylcarbonyl) phenyl] spiro [isoquinoline-1
(2H), 4′-piperidine] -1′-carboxamide, N- (3,4-dichlorophenyl) -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4 ′
-Piperidine] -1'-carboxamide, N- [1- (3-chlorophenyl) -4-imidazolyl] -3,4-dihydro-3-oxospiro [isoquinoline-1 (2H), 4'-piperidine] -1 ' -Carboxamide, 3,4-dihydro-3-oxo-N- (5-phenyl-
2-thiazolyl) spiro [isoquinoline-1 (2H),
4'-piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- [5- (2-pyridyl) -2-pyrazinyl] spiro [isoquinoline-1
(2H), 4'-piperidine] -1'-carboxamide, 3,4-dihydro-N- (4-methyl-2-benzothiazolyl) -3-oxospiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxamide, N- (5-chloro-2-benzoxazolyl) -3,4
-Dihydro-3-oxospiro [isoquinoline-1 (2
H), 4'-piperidine] -1'-carboxamide, N- (4-benzoylphenyl) -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine]
-1'-carboxamide, 3-oxo-N- (5-phenyl-2-pyrazinyl)-
Spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- (7-methyl-2-quinolyl) -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine]
-1'-carboxamide, 3-oxo-N- (3-phenyl-5-isoxazolyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- (7 -Trifluoromethylpyrido [3,2-b] pyridin-2-yl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl -2-pyrimidinyl)
Spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- [1- (3-quinolyl) -4-imidazolyl] spiro [isobenzofuran-1 (3H), 4 '
-Piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl-3-pyrazolyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- [5- (4-Chlorophenyl) -3-pyrazolyl]
-3-oxospiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide, 3-oxo-N- [5- (3-quinolyl) -3-pyrazolyl] spiro [isobenzofuran-1 (3H), 4'-
Piperidine] -1'-carboxamide, N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 3-oxo-N- [5- (3-trifluoromethylphenyl) -2-pyrimidinyl] spiro [isobenzofuran-1 (3H), 4'-piperidine ] -1'-Carboxamide, N- [5- (3-chlorophenyl) -2-pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, N- (7-difluoromethoxypyrido [3,2-b] pyridin-2-yl) -3-oxospiro [isobenzofuran-1 (3H), 4. '-Piperidine] -1'-carboxamide, 3-oxo-N- (5-phenyl-1,2,4-thiadiazol-3-yl) spiro [isobenzofuran-1
(3H), 4'-piperidine] -1'-carboxamide, N- {1- [3- (2-hydroxyethyl) phenyl]
-4-Imidazolyl} -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide, N- [4- (1-ethyl-2-imidazolyl) phenyl] -3-oxospiro [ Isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, N- [1- (3-methoxyphenyl) -4-imidazolyl] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 6-fluoro-3-oxo-N- (5-phenyl-2-
Pyrazinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide, 6-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 5-fluoro-3-oxo-N- (5-phenyl-2-
Pyrazinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide, 5-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, N- (4-benzoylphenyl) -3,4-dihydro-
3-oxospiro [1H-2-benzopyran-1,4 '
-Piperidine] -1'-carboxamide, 3,4-dihydro-3-oxo-N- (5-phenyl-
2-pyrazinyl) spiro [1H-2-benzopyran-
1,4'-piperidine] -1'-carboxamide, N- (5-benzoyl-2-pyrazinyl) -3,4-dihydro-3-oxospiro [1H-2-benzopyran-
1,4'-piperidine] -1'-carboxamide, trans-N- (4-benzoylphenyl) -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxamide, trans -3'-oxo-N- (5-phenyl-2-pyrazinyl) spiro [cyclohexane-1,1 '(3'
H) -isobenzofuran] -4-carboxamide, trans-3'-oxo-N- (1-phenyl-4-imidazolyl) spiro [cyclohexane-1,1 '(3'
H) -isobenzofuran] -4-carboxamide, trans-3'-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [cyclohexane-1,1 '(3'
H) -Isobenzofuran] -4-carboxamide, trans-N- [1- (3,5-difluorophenyl)
-4-Imidazolyl] -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4
-Carboxamide, trans-3'-oxo-N- (5-phenyl-3-pyrazolyl) spiro [cyclohexane-1,1 '(3'
H) -isobenzofuran] -4-carboxamide, trans-N- [1- (2-fluorophenyl) -4-
Imidazolyl] -3'-oxospiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxamide, trans-N- (4-acetyl-3-trifluoromethylphenyl) -3'-oxospiro [ Cyclohexane-
1,1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-3′-oxo-N- [1- (3-quinolyl)
-4-imidazolyl] spiro [cyclohexane-1,
1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-N- [1- (3-cyanophenyl) -4-imidazolyl] -3′-oxospiro [cyclohexane-
1,1 ′ (3′H) -isobenzofuran] -4-carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [4-azaisobenzofuran-1 (3H),
1'-cyclohexane] -4'-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (3-phenyl-5-isoxazolyl) spiro [4-azaisobenzofuran-1
(3H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [5-azaisobenzofuran-1 (3H),
1′-cyclohexane] -4′-carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [6-azaisobenzofuran-1 (3H),
1'-cyclohexane] -4'-carboxamide, N- [5- (4-hydroxyphenyl) -2-pyrazinyl] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, N- [5- (3-hydroxyphenyl) -2-pyrazinyl] -3-oxospiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 4-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 7-fluoro-3-oxo-N- (5-phenyl-2-
Pyrimidinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, 6-ethyl-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [isobenzofuran-1 (3H),
4'-piperidine] -1'-carboxamide, 6-hydroxy-3-oxo-N- (5-phenyl-2
-Pyrazinyl) spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [5-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [5- (3-fluorophenyl) -2-
Pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Carboxamide, trans-N- [5- (2-fluorophenyl) -2-
Pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Carboxamide, trans-3-oxo-N- (4-phenyl-2-oxazolyl) spiro [5-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [5- (2-methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1 '. -Cyclohexane] -4'-
Carboxamide, trans-N- [5- (3-methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-
Carboxamide, trans-N- [5- (3-fluoromethoxyphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans- N- [5- (3-fluoromethylphenyl)
-2-Pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane]
-4'-carboxamide, trans-N- [5- (3-fluoro-5-methoxyphenyl) -2-pyrimidinyl] -3-oxospiro [5
-Azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N- [5- (2-fluoro-5-methylphenyl) -2-pyrimidinyl] -3-oxospiro [5-
Azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [4- (3-fluoromethoxyphenyl) -2-oxazolyl] -3-oxospiro [5-azaisobenzofuran- 1 (3H), 1′-cyclohexane] -4′-carboxamide, trans-N- [5- (3-hydroxymethylphenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H) , 1'-Cyclohexane] -4'-carboxamide, trans-N- [5- (3-hydroxyphenyl) -2
-Pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane]-
4'-carboxamide, trans-3-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carboxamide, trans-N- [5- (3-fluoromethylphenyl)
-2-Pyrimidinyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane]
-4'-carboxamide, trans-N- [5- (3-fluoromethoxyphenyl) -2-pyrimidinyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'- Carboxamide, trans-3-oxo-N- (6-phenyl-1,2,
4-triazin-3-yl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4 ′
-Carboxamide, trans-N- [5- (2-difluoromethoxyphenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans -N- [5- (3-difluoromethoxyphenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, trans-N- [ 5- (3-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- [5- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- (4-benzoylphenyl) -3-oxospiro [7-azaisobenzofuran-1 (3H),
1'-cyclohexane] -4'-carboxamide, trans-N- [1- (3,5-difluorophenyl)
-4-Imidazolyl] -3-oxospiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane]
-4'-carboxamide, trans-3-oxo-N- [2-phenyl-4-pyridyl] spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (1-phenyl-4-pyrazolyl) spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (1-phenyl-3-pyrrolyl) spiro [7-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [1- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [7-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-3-oxo-N- (1-phenyl-3-pyrazolyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (1-phenyl-4-pyrazolyl) spiro [4-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [1- (3-fluorophenyl) -4-
Pyrazolyl] -3-oxospiro [4-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-3-oxo-N- (1-phenyl-3-pyrazolyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-N- [1- (4-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-N- [1- (2-fluorophenyl) -3-
Pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-
Carboxamide, trans-3-oxo-N- (5-phenyl-1,2,
4-thiadiazol-3-yl) spiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane]-
4'-carboxamide, trans-3-oxo-N- (5-phenyl-3-isoxazolyl) spiro [6-azaisobenzofuran-1
(3H), 1′-Cyclohexane] -4′-carboxamide, trans-3-oxo-N- (6-phenyl-3-pyridyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-Cyclohexane] -4'-carboxamide, trans-3-oxo-N- (2-phenyl-3-thiazolyl) spiro [6-azaisobenzofuran-1 (3
H), 1'-cyclohexane] -4'-carboxamide or trans-3-oxo-N- (2-phenyl-1,2,2
3-triazol-4-yl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane]-
The compound according to claim 1, which is 4'-carboxamide. 18. 3-Oxo-N- (5-phenyl-2-
Pyrazinyl) -spiro [isobenzofuran-1 (3
H), 4'-piperidine] -1'-carboxamide. 19. Oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridin-2-yl) spiro [isobenzofuran-1 (3H), 4′-piperidine]
The compound according to claim 1, which is -1'-carboxamide. 20. N- [5- (3-fluorophenyl)-
The compound according to claim 1, which is 2-pyrimidinyl] -3-oxospiro [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide. 21. Trans-3'-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [cyclohexane-
The compound according to claim 1, which is 1,1 '(3'H) -isobenzofuran] -4-carboxamide. 22. Trans-3′-oxo-N- [1-
(3-quinolyl) -4-imidazolyl] spiro [cyclohexane-1,1 '(3'H) -isobenzofuran]-
The compound according to claim 1, which is 4-carboxamide. 23. Trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide. The described compound. 24. Trans-N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5
-Azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide. 25. Trans-N- [5- (2-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5
-Azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide. 26. Trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3-oxospiro [7-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′- A carboxamide.
The described compound. 27. A trans-3-oxo-N- (1-phenyl-4-pyrazolyl) spiro [4-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide. The described compound. 28. Trans-3-oxo-N- (1-phenyl-3-pyrazolyl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide. The described compound. 29. Trans-3-oxo-N- (2-phenyl-1,2,3-triazol-4-yl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4. The compound according to claim 1, which is'-carboxamide. 30. The general formula (II): [ ^Wherein Ar ^1p is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group,
Substituted by a lower alkenyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group and a group represented by -Q ^p -Ar ^2p and an optionally protected oxo group. Optionally an lower alkylene group, a hydroxy lower alkyl group, and an aryl group which may have a substituent selected from the group consisting of a carboxyl group, or a heteroaryl group; Ar ^2p is a halogen atom, a cyano group , A lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, a di lower alkylamino group,
A lower alkanoyl group and an aryl group, and an optionally protected aryl group or heteroaryl group, which may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group and a lower alkylamino group. Ar ³ represents a phenyl group which may be substituted with a halogen atom or a nitro group; Q ^p represents a single bond or an optionally protected carbonyl group] and a compound represented by the general formula: (III) embedded image [Wherein n represents 0 or 1; t, u, v and w are
Each independently a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and a hydroxyl group which may be protected; At least 2
Represents the methine group; Y represents an imino group which may be substituted with a lower alkyl group or an oxygen atom] and is reacted with a compound represented by the general formula (IV-1): [Wherein Ar ^1p , n, t, u, v, w, and Y have the above-mentioned meanings], and a protecting group is removed, if necessary, in the general formula (I -1) [Chemical formula 7] [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Q means a single bond or a carbonyl group; T, U, V and W are each an aryl group or a heteroaryl group;
Each independently represents a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, at least two of which are the methine group; Group, and n and Y have the above-mentioned meanings], a process for producing a compound thereof, a salt thereof, or an ester at a carboxyl group . 31. A compound represented by the general formula (V): [ ^Wherein Ar ^1p is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group,
Substituted by a lower alkenyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group and a group represented by -Q ^p -Ar ^2p and an optionally protected oxo group. Optionally an lower alkylene group, a hydroxy lower alkyl group, and an aryl group which may have a substituent selected from the group consisting of a carboxyl group, or a heteroaryl group; Ar ^2p is a halogen atom, a cyano group , A lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, a di lower alkylamino group,
A lower alkanoyl group and an aryl group, and an optionally protected aryl group or heteroaryl group, which may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group and a lower alkylamino group. Q ^p represents a single bond or an optionally protected carbonyl group] and a compound represented by the general formula (VI): [Wherein n represents 0 or 1; t, u, v and w are
Each independently a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and a hydroxyl group which may be protected; At least 2
Represents the methine group; Y represents an imino group which may be substituted with a lower alkyl group or an oxygen atom], and is reacted with a carboxylic acid or a reactive derivative thereof,
General formula (IV-2): [Wherein Ar ^1p , n, t, u, v, w, and Y have the above-mentioned meanings], and a protecting group is removed, if necessary, in the general formula (I -2) [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Q means a single bond or a carbonyl group; T, U, V and W are each an aryl group or a heteroaryl group;
Each independently represents a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, at least two of which are the methine group; Group, and n and Y have the above-mentioned meanings], a process for producing a compound thereof, a salt thereof, or an ester at a carboxyl group . 32. A compound represented by the general formula (I): [Wherein Ar ¹ is a halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, lower alkoxy group, halo lower alkoxy group, lower alkylthio group, carboxyl A group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylene group optionally substituted with an oxo group, and a group selected from the group represented by -Q-Ar ² may have a substituent. , An aryl group or a heteroaryl group; Ar ² is a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group,
It may have a substituent selected from the group consisting of a hydroxy lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkylamino group, a dilower alkylamino group, a lower alkanoyl group and an aryl group, Means an aryl group or a heteroaryl group; n is 0
Or 1 means; Q means a single bond or a carbonyl group; T, U, V and W are each independently selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group. A methine group which may have a substituent or a nitrogen atom, of which at least 2
Represents the methine group; X represents a methine group or a nitrogen atom; Y represents an imino group optionally substituted with a lower alkyl group or an oxygen atom], a salt thereof or a carboxyl group. A therapeutic agent for bulimia, obesity or diabetes containing an ester in the base as an active ingredient. 33. A compound represented by the general formula (VI-1): [In the formula, t, u, v and w each independently have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group and an optionally protected hydroxyl group. A methine group or a nitrogen atom, at least two of which mean the methine group].