JP2021119130A - Drug comprising fused lactam derivative - Google Patents

Abstract

To provide a drug for treating neuropsychiatric disease which has both antagonist activity on a serotonin 5-HT2A receptor and agonist activity on a serotonin 5-HT1A receptor.SOLUTION: The drug for treating neuropsychiatric disease contains, as an active ingredient, a compound represented by the formula (1) in the figure or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

The present invention comprises _{a fused lactam derivative having antagonistic activity on serotonin 5-HT 2A} receptor and agonist activity on serotonin 5-HT _1A receptor or a pharmaceutically acceptable salt thereof for treating neuropsychiatric disorders. Regarding.

Serotonin (5-hydroxytryptamine) (hereinafter, sometimes referred to as "5-HT"), which is known as one of the major neurotransmitters in the central nervous system, has various brains including emotional response and cognitive function. It is known to be involved in function.

_{5-HT 1A} receptor, which is one of the subtypes of 5-HT receptor, is a Gi / o protein-conjugated receptor and is expressed in the cerebral cortex, hippocampus, raphe nuclei, amygdala and the like. Examples of the compound having an agonist activity on the 5- _{HT1A receptor include tandospirone and buspirone.} Tandospirone is used as a therapeutic agent for depression, fear, psychosomatic disorder (autonomic imbalance, essential hypertension, digestive ulcer) in neurosis, as well as depression, anxiety, impatience, and sleep disorders. In addition, buspirone is used as a therapeutic agent for generalized anxiety disorder (Non-Patent Document 1).

_{5-HT 2A} receptors are Gq / 11 protein coupled receptors, the cerebral cortex, hippocampus, is highly expressed in such raphe nucleus. Examples of drugs having antagonistic activity against 5-HT _2A receptor, an antidepressant mianserin or mirtazapine, and the like. Also have atypical antipsychotics antagonist activity against both 5-HT _2A receptor, schizophrenia, bipolar disorder, have been used as major depression, treatment such as Autism spectrum disorders ( Non-Patent Document 2 and Non-Patent Document 3).

As mentioned above, _{agonists for 5-HT 1A} receptors and antagonists for 5-HT _2A receptors have each been shown to be useful in neuropsychiatric disorders alone, but for selective 5-HT _1A receptors. simultaneously antagonist activity against agonist activity and 5-HT _2A receptor, and reported examples of agents that strongly indicate no.

D. P. Taylor, Neuropeptides. 19 Suppl: 15-9, 1991 Jul P. Seeman, Can. J. Psychiatry. 4: 27-38, 2002 C. J. Schmidt, Life Science. 56 (25): 2209-2222, 1995

An object of the present invention is to provide a drug which has both an antagonist activity for _{a serotonin 5-HT 2A receptor and an agonist activity for a serotonin 5-HT 1A} receptor and is useful for the treatment of neuropsychiatric disorders.

As a result of diligent research to achieve the above problems, the present inventors may refer to the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, referred to as "the compound of the present invention"). It has been found that (there is) has both an antagonist activity for the _{serotonin 5-HT 2A receptor and an agonist activity for the serotonin 5-HT 1A} receptor, and has completed the present invention.

[式中、
Ｖは、ＣＲ^ＡＲ^Ｂを表し；
ｎは、１または２を表し；
Ｚは、窒素原子、炭素原子または−ＣＲ^J−を表し；
ｔは、１、２または３を表し；
破線を含む結合（ａ）は、単結合または二重結合を表し；
Ｒ^ＡおよびＲ^Ｂは、それぞれ独立して、また、Ｒ^ＡまたはＲ^Ｂが複数ある場合はそれぞれ独立して、水素原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシまたはＣ_３−１０シクロアルキル（該アルキル、該アルコキシおよび該シクロアルキルは、それぞれ独立して、同一または異なる１〜３個のハロゲンで置換されていてもよい）を表し；
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃおよびＲ^１ｄは、それぞれ独立して、水素原子、ハロゲンまたは同一もしくは異なる１〜３個のハロゲンで置換されていてもよいＣ_１−６アルキルを表し；
環Ｑ¹は、下記式（２）：

｛式中、
環Ｑ^３は、置換されていてもよい５または６員の芳香族複素環を表し；
Ｗは、ＣＲ^ＣＲ^Ｄを表し；
ｍは、０または１を表し；
Ｘは、−ＣＲ^Ｅ−または−ＣＲ^ＦＲ^Ｇ−を表し；
Ｙは、窒素原子または−ＣＲ^Ｈ−を表し；
破線を含む結合（ｂ）は、単結合または二重結合を表す｝で表される基を表し；
環Ｑ^２は、下記式（３ａ）または（３ｂ）：

｛式中、
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃおよびＲ^２ｄは、それぞれ独立して、水素原子、ハロゲン、シアノ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ（該アルキルおよび該アルコキシは、それぞれ独立して、同一または異なる１〜３個のハロゲンで置換されていてもよい）または同一もしくは異なる１〜２個のＣ_１−６アルキルで置換されていてもよいアミノを表す｝で表される基を表し；
Ｒ^Ｃ、Ｒ^Ｄ、Ｒ^Ｅ、Ｒ^Ｆ、Ｒ^Ｇ、Ｒ^ＨおよびＲ^Ｊは、それぞれ独立して、水素原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシまたはＣ_３−１０シクロアルキル（該アルキル、該アルコキシおよび該シクロアルキルは、それぞれ独立して、同一または異なる１〜３個のハロゲンで置換されていてもよい）を表し、ここにおいて、Ｒ^ＦおよびＲ^ＧがＣ_１−６アルキルである場合、これらが結合している炭素原子と一緒になって３〜６員の飽和炭素環を形成していてもよい；
ここにおいて、
（Ｉ）環Ｑ^３が置換されていてもよい５員の芳香族複素環であるとき、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、およびＲ^２ｄは、ともに水素原子であり；
（ＩＩ）環Ｑ^３が置換されていてもよい６員の芳香族複素環であるとき、ｍは０であり；
（ＩＩＩ）破線を含む結合（ａ）が二重結合であるとき、Ｚは炭素原子であり；
（ＩＶ）破線を含む結合（ｂ）が単結合であるとき、Ｘは−ＣＲ^ＦＲ^Ｇ−であり；
（Ｖ）破線を含む結合（ｂ）が二重結合であるとき、Ｘは−ＣＲ^Ｅ−である]で表される化合物またはその製薬学的に許容される塩を含有する医薬。 That is, the present invention is as follows.
[Item 1] Equation (1):

[During the ceremony,
V represents ^CR A ^{R B;}
n represents 1 or 2;
Z represents a nitrogen atom, a carbon atom or -CR ^J- ;
t represents 1, 2 or 3;
The bond (a) containing the dashed line represents a single bond or a double bond;
R ^A and ^{R B} are each independently, also independent from each other when ^{the R A} or ^{R B} is more, a hydrogen _{atom, C 1-6 alkyl, C 1-6} alkoxy or _{C 3-10} cycloalkyl (The alkyl, the alkoxy and the cycloalkyl may be independently substituted with the same or different 1 to 3 halogens);
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen or a C _1-6 alkyl which may be substituted with the same or different 1 to 3 halogens;
Ring Q ¹ is expressed by the following equation (2):

{In the formula,
Ring Q ³ are an aromatic heterocycle optionally substituted 5 or 6-membered;
W represents ^CR C ^{R D;}
m represents 0 or 1;
X is, -CR ^E - or ^-CR F ^{R G} - represents;
Y represents a nitrogen atom or -CR ^H- ;
The bond (b) containing the broken line represents the group represented by}, which represents a single bond or a double bond;
Ring ^{Q 2} is the following formula (3a) or (3b):

{In the formula,
R ^2a , R ^2b , R ^2c and R ^2d are independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are independent and the same, respectively). Represents an amino represented by (or may be substituted with 1 to 3 different halogens) or may be substituted with the same or different 1 to 2 C _{1-6 alkyl}.}
^{R C, R D, R E} , R F, R G, R H and ^{R J} are each independently a hydrogen _{atom, C 1-6 alkyl, C 1-6} alkoxy or _{C 3-10} cycloalkyl (said Alkyl, the alkoxy and the cycloalkyl may be independently substituted with the same or different 1-3 halogens), where ^RF and ^RG are C _1-6 alkyl. In some cases, they may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbon ring;
put it here,
When (I) the ring ^{Q 3} is an aromatic heterocyclic ring may 5 membered ^{substituted, R 2a, R 2b, R} 2c and ^{R 2d,} is an both hydrogen atoms;
(II) when ring Q ³ is an aromatic heterocyclic 6-membered optionally substituted, m is 0;
(III) When the bond (a) containing the broken line is a double bond, Z is a carbon atom;
When (IV) bond containing a broken line (b) is a single bond, X is ^-CR F ^{R G} - a and;
(V) when coupling including dashed (b) is a double bond, X is -CR E ^- a is] a compound or a pharmaceutically acceptable medicament containing a salt represented.

The [claim 2] ring ^{Q 3,} a hydrogen atom, a halogen, _{cyano, C 1-6 alkyl, C 3-10} cycloalkyl (which alkyl and the cycloalkyl are each independently the same or different 1-3 (May be substituted with halogen), and C _1-6 alkoxy (the alkoxy may be substituted with the same or different 1-3 halogens or 4-8 member saturated heterocyclic groups). Item 2. The medicament according to Item 1, which is a 5- or 6-membered aromatic heterocycle which may be substituted with 1 to 3 identical or different substituents selected from the group.

［式中、Ｑ^１、Ｑ²、Ｖ、Ｚ、ｎ、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄおよび破線を含む結合（ａ）は、前記と同義である］である、項１または項２に記載の医薬。 [Item 3] Equation (1) is the equation (1a):

[In the equation, the ^{bond (a) including Q 1} , Q ² , V, Z, n, R ^1a , R ^1b , R ^1c , R ^1d and the dashed line is synonymous with the above], item 1 or item. 2. The drug according to 2.

[Item 4] The medicament according to any one of Items 1 to 3, wherein ^{R 1a} , R ^1b , R ^1c and R ^{1d are all hydrogen atoms.}

[Claim 5] R ^A and R ^B are both hydrogen atoms, medicament according to any one of claim 4 to claim 1.

[Item 6] The medicament according to any one of Items 1 to 5, wherein n is 2.

[Item 7] The medicament according to any one of Items 1 to 6, wherein the bond (a) including the broken line is a single bond.

［式中、Ｑ^１、Ｑ^２およびＺが、前記と同義である］で表される、項１または項２に記載の医薬。 [Item 8] Equation (1) is the following equation (1b):

^Wherein, Q 1, ^{Q 2} and Z has the same meanings as defined above] is represented by the medicament according to claim 1 or claim 2.

[Item 9] The medicament according to any one of Items 1 to 8, wherein Z is a nitrogen atom.

[Item 10] The medicament according to any one of Items 1 to 8, wherein Z is −CH−.

[Item 11] The medicament according to any one of Items 1 to 10, wherein Y is a nitrogen atom.

[Item 12] The medicament according to any one of Items 1 to 11, wherein the bond (b) including the broken line is a single bond and X is −CH _{2 −.}

[式中、
Ｒ^３ａおよびＲ^３ｂは、それぞれ独立して、水素原子、ハロゲン、シアノ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ（該アルキルおよび該アルコキシは、それぞれ独立して、同一または異なる１〜３個のハロゲンで置換されていてもよい）、または同一もしくは異なる１〜２個のＣ_１−６アルキルで置換されていてもよいアミノを表す］である、項１から項１２のいずれか一項に記載の医薬。 [Claim 13] ring Q ¹ is represented by the following formula (4a), (4b), (4c), (4d), (4e) or (4f):

[During the ceremony,
R ^3a and R ^3b are independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are independently the same or different 1-3). _{Represents an amino that may be substituted with one or two C 1-6} alkyls that are the same or different], according to any one of Items 1 to 12. The listed drug.

[式中、
Ｒ^４ａは、Ｃ_１−６アルキルまたはＣ_１−６アルコキシを表し、
Ｒ^４ｂは、水素原子またはＣ_１−６アルキルを表し、
Ｒ^４ｃおよびＲ^４ｄは、それぞれ独立して、水素原子またはＣ_１−６アルキルを表し、ここにおいて、Ｒ^４ｃまたはＲ^４ｄのいずれかが水素原子のとき、もう一方はＣ_１−６アルキルを表し、また、Ｒ^４ｃおよびＲ^４ｄはこれらが結合する炭素原子と一緒になって３〜６員の飽和炭素環を形成していてもよい］である、項１から項１２のいずれか一項に記載の医薬。 [Claim 14] ring Q ¹ is represented by the following formula (5a), (5b), (5c), (5d), (5e), (5f) or (5 g):

[During the ceremony,
R ^4a represents C _1-6 alkyl or C _1-6 alkoxy.
R ^4b represents a hydrogen atom or C _1-6 alkyl.
R ^4c and R ^4d independently represent a hydrogen atom or C _1-6 alkyl, where ^{when either R 4c} or R ^4d is a hydrogen atom, the other represents a _{C 1-6 alkyl.} In addition, R ^4c and R ^4d may form a 3- to 6-membered saturated carbon ring together with the carbon atom to which they are bonded], according to any one of Items 1 to 12. The listed drug.

[Claim 15] ring ^{Q 2} is formula (3a), medicament according to any one of claim 14 to claim 1.

[Claim 16] ring ^{Q 2} is formula (3b), A medicament according to any one of claim 14 to claim 1.

[Item 17] The medicament according to any one of Items 1 to 16, wherein ^{R 2a} , R ^2b , R ^2c and R ^{2d are all hydrogen atoms.}

[Item 18] The medicament according to Item 1, wherein the compound represented by the formula (1) is represented by any of the following formulas.

Item 19. The medicament according to any one of Items 1 to 18, for use in the treatment of a psychiatric disorder or a central nervous system disease.

[Item 20] Mental illness or central nervous system illness is an organic psychiatric disorder including symptomatic; mental and behavioral disorders due to the use of psychoactive substances; schizophrenia, schizophrenia-type disorders and delusional disorders; mood [emotion] ] Disorders; Neuropathic Disorders, Stress-Related Disorders and Physical Expression Disorders; Non-Organic Sleep Disorders; Not Due to Sexual Dysfunction, Organic Disorders or Diseases; Diffuse Developmental Disorders; Usually Onset in Childhood and Adolescence 19. The medicament according to Item 19, wherein the behavioral and emotional disorders that occur; extrapyramidal tract disorders and abnormal movements; other degenerative diseases of the nervous system; or sleep disorders.

[Item 21] Mental illness or central nervous system disease is schizophrenia, positive symptom of schizophrenia, negative symptom of schizophrenia, bipolar disorder with psychiatric characteristics, depressive disorder with psychiatric characteristics, Psychiatric symptoms associated with dementia, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, psychiatric symptoms associated with Parkinson's disease dementia, psychiatric symptoms associated with Parkinson's disease, or irritation, excitement or attack associated with Alzheimer's disease Item 9. The medicament according to Item 19, which is sex.

[Item 22] Psychiatric disorders or central nervous system disorders include schizophrenia, psychiatric symptoms associated with dementia, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, or irritation, excitement or agitation associated with Alzheimer's disease. Item 19. The medicament according to Item 19, which is aggressive.

[Item 23] For treating a psychiatric disorder or a central nervous system disease, which comprises administering a therapeutically effective amount of the drug according to any one of Items 1 to 18 to a patient in need of treatment. Method.

[Item 24] The use of the medicament according to any one of Items 1 to 18, for producing a therapeutic agent for a psychiatric disorder or a central nervous system disease.

[Item 25] The drug according to any one of Items 1 to 18, antidepressants, antidepressants, schizophrenia therapeutic agents, dopamine replacement agents, dopamine receptor agonists, Parkinson's disease therapeutic agents, antiepileptic drugs. At least one drug selected from the group consisting of drugs, anticonvulsants, analgesics, hormone preparations, migraine treatments, adrenaline β receptor antagonists, dementia treatments, mood disorder treatments, antiemetics and sleep-inducing agents. A combination of drugs for use in the treatment of psychiatric or central nervous system disorders.

[Item 26] Antidepressants, anxiolytics, schizophrenia drugs, dopamine replacement drugs, dopamine receptor agonists, Parkinson's disease drugs, antiepileptic drugs, anticonvulsants, analgesics, hormone preparations, headache treatment drugs To treat psychiatric or central nervous system disorders in combination with at least one drug selected from the group consisting of adrenergic β-receptor antagonists, dementia therapeutic agents, mood disorders therapeutic agents, antiemetics and sleep-inducing agents. The medicament according to any one of Items 1 to 18.

The present invention compounds have an agonistic activity against antagonist activity and _{5-HT 1A} receptors for _{5-HT 2A} receptor. Further, in a preferred embodiment, it may be referred to as _{a dopamine D 2} receptor (hereinafter, _{referred to as "D 2} receptor") which is excellent in metabolic stability, has a long elimination half-life (T1 / 2) in humans, and is another GPCR. There is high selectivity with the inhibitory effect on the hERG channel. Therefore, the preferred compound of the present invention is useful as a therapeutic agent for neuropsychiatric disorders, which has a long duration in the human body and is highly safe.

It is a figure which shows the result of the MK-801-induced hyperkinesia suppression test (Test Example 7) of the compound of Example 37. It is a figure which shows the result of the MK-801-induced hyperkinesia suppression test (Test Example 7) of the compound of Example 103. It is a figure which shows the measurement chart of the powder XRD of the compound of Example 37.

Hereinafter, the present invention will be described in more detail. In the present specification, the number of carbons in the definition of "substituent" may be expressed as _{, for example, "C 1-6".} Specifically, the _{notation "C 1-6} alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms.

Examples of the "halogen" include fluorine, chlorine, bromine and iodine.

"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. As the C _1-6 alkyl, preferably "C _1-4 alkyl" is mentioned, and more preferably "C _1-3 alkyl" is mentioned. Specific examples of "C _1-3 alkyl" include, for example, methyl, ethyl, propyl, 1-methylethyl and the like. Specific examples of "C _1-4 alkyl" include, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methyl, in addition to those listed as specific examples of _{"C 1-3 alkyl".} Examples include propyl. Specific examples of "C _1-6 alkyl" include, for example, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1 in addition to those mentioned as specific examples of _{"C 1-4 alkyl".} -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like can be mentioned.

The “C _3-10 cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. The "C _3-10 cycloalkyl" is preferably "C _3-7 cycloalkyl". Specific examples of "C _3-7 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Specific examples of "C _3-10 cycloalkyl" include, for example, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like in addition to those mentioned as specific examples of _{"C 3-7 cycloalkyl".}

"C _1-6 alkoxy" means "C _1-6 alkyloxy", and the "C _1-6 alkyl" moiety is synonymous with the _{"C 1-6 alkyl".} As the "C _1-6 alkoxy", preferably "C _1-4 alkoxy" is mentioned, and more preferably "C _1-3 alkoxy" is mentioned. Specific examples of "C _1-3 Alkoxy" include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy and the like. Specific examples of "C _1-4 alkoxy" include, for example, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methyl, in addition to those listed as specific examples of _{"C 1-3 alkyl".} Propoxy and the like can be mentioned. Specific examples of "C _1-6 alkoxy" include, for example, pentyroxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1 in addition to those listed as specific examples of _{"C 1-4 alkyl".} -Methylbutoxy, 2-methylbutoxy, 4-methylpentyroxy, 3-methylpentyroxy, 2-methylpentyroxy, 1-methylpentyroxy, hexyloxy and the like can be mentioned.

The "4- to 8-membered saturated heterocyclic group" is 4 to 8 atoms including 1 to 2 atoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom. It means a saturated ring composed of the atoms of the above, and includes those having a partially unsaturated bond and those having a crosslinked structure. The "4- to 8-membered saturated heterocyclic group" is preferably a "4- to 6-membered monocyclic saturated heterocyclic group", and more preferably a "5- or 6-membered monocyclic saturated heterocyclic group". "Cyclic" can be mentioned. Specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group" include, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl. , Thiazoridinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like. Examples of the "4- to 6-membered monocyclic saturated heterocyclic group" include those listed as specific examples of the above-mentioned "5- or 6-membered monocyclic saturated heterocycle", such as oxetanyl and azetidinyl. Can be mentioned. Examples of the "4- to 8-membered saturated heterocycle" include those mentioned as specific examples of the "4- to 6-membered monocyclic saturated heterocycle", as well as azepinyl and oxepanyl.

The “3 to 6-membered saturated carbocyclic ring” means a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. The "3- to 6-membered saturated carbocycle" is preferably a "5- or 6-membered monocyclic saturated carbocycle". Specific examples of the "5- or 6-membered monocyclic saturated carbocycle" include cyclopentane and cyclohexane. Specific examples of the "3- to 6-membered saturated carbocycle" include, for example, cyclopropane, cyclobutane, and the like, in addition to those mentioned as specific examples of the "5- or 6-membered monocyclic saturated carbocycle". Be done.

A "5- or 6-membered aromatic heterocycle" is a 5- or 6-membered monocyclic ring containing 1-3 atoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. It means an aromatic heterocycle. Preferred include pyrrole, imidazole, pyrazole, oxazole, isoxazole, pyridine and pyrimidine. More preferably, pyrrole, pyrazole and pyridine are mentioned. Specific examples of the "5- or 6-membered aromatic heterocycle" include, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine. And so on.

As a "optionally substituted 5- or 6-membered aromatic heterocycle", preferably
(A) Halogen,
(B) Hydroxy,
(C) Cyano,
(D) halogen and _{C 1-6} is selected from the group consisting of alkoxy, same or different one to three optionally substituted with a substituent _{C 1-6} alkyl,
_{(E) C 1-6} alkoxy which may be substituted with 1 to 3 halogens which are the same or different, and (f) Amino which may be substituted with _{1 to 2 C 1-6} alkyl which are the same or different. ,
Included are 5- or 6-membered aromatic heterocycles selected from the group consisting of, which may be substituted with the same or different 1-5 substituents.
More preferably, halogen and C _1-6 is selected from the group consisting of alkoxy, same or different one to three optionally substituted with a substituent C _1-6 alkyl; the same or different 1-3 _{Halogen-substituted C 1-6} alkoxy; as well as 5- or 6-membered aromatic heterocycles selected from the group consisting of halogens, which may be substituted with the same or different 1-5 substituents. Can be mentioned. More preferably, it may be substituted with C _1-6 alkyl, which may be substituted with 1 to 4 fluorines, or C _1-6 alkoxy, which may be substituted with 1 to 4 fluorines, 5 or A 6-membered aromatic heterocycle can be mentioned. Particularly preferred are 5- or 6-membered aromatic heterocycles which may be substituted with _{C 1-6} alkyl or C _{1-6 alkoxy.}

Among the compound of the present invention represented by the formula (1), n, t, Z, bond containing a broken line ^{(a), R A, R} B, R 1a, R 1b, R 1c, R 1d, Q 3, m , X, Y, bond containing a broken line ^(b), preferred ^{Q 2, R 2a, R 2b} , R 2c, R 2d, R C, R D, R E, R F, R G, R H and ^{R J} The following are the following, but the technical scope of the present invention is not limited to the range of the compounds listed below.

It is preferably 2 as n.

One embodiment of Z is a nitrogen atom. Moreover, as another aspect of Z, -CH- can be mentioned.

The t is preferably 2.

The bond (a) including the broken line is preferably a single bond. ..

Preferably the R ^A and ^{R B,} include hydrogen atom or _{C 1-6} alkyl. More preferably, a hydrogen atom or a C _1-3 alkyl can be mentioned. More preferably, a hydrogen atom, methyl or ethyl can be mentioned. Most preferably, it is a hydrogen atom.

Preferred examples of R ^1a , R ^1b , R ^1c and R ^1d include a hydrogen atom or C _{1-6 alkyl.} More preferably, a hydrogen atom or a C _1-3 alkyl can be mentioned. More preferably, a hydrogen atom, methyl or ethyl can be mentioned. Most preferably, it is a hydrogen atom.

As one aspect of Q ^3, and aromatic heterocyclic 5-membered optionally substituted. Another one embodiment of the Q ^3, include nitrogen-containing aromatic heterocyclic 5-membered optionally substituted. Another one embodiment of Q ^3, the same or 1-3 halogen or _{C 1-6} optionally substituted alkoxy _{C 1-6} alkyl heterogeneous; with 1-3 halogens same or different _{C 1-6} alkoxy which may be substituted; and a 5-membered nitrogen-containing aromatic heterocycle which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of halogens. Be done. Another one embodiment of the Q ^3, C _1-6 alkyl and C _1-6 is selected from the group consisting of alkoxy, same or different one to two free 5-membered to be substituted with a substituent Examples include nitrogen aromatic heterocycles.
As one aspect of Q ^3, and aromatic heterocyclic rings may also be 6 membered substituted. Another one embodiment of the Q ^3, include nitrogen-containing aromatic heterocyclic ring may also be 6 membered substituted. Another one embodiment of Q ^3, the same or 1-3 halogen or _{C 1-6} optionally substituted alkoxy _{C 1-6} alkyl heterogeneous; with 1-3 halogens same or different 6-membered nitrogen-containing aromatic heterocycles, optionally substituted with 1-5 substituents of the same or different, selected from the group consisting of optionally substituted C _{1-6 alkoxy; and halogens.} Be done. Another one embodiment of the Q ^3, C _1-6 alkyl and C _1-6 is selected from the group consisting of alkoxy, same or different one to two free or 6-membered optionally substituted with a substituent Examples include nitrogen aromatic heterocycles.

0 is mentioned as one aspect of m. Moreover, 1 is mentioned as another aspect of m.

Y is preferably a nitrogen atom.

The bond (b) including the broken line is preferably a single bond.

As one aspect of Q ^2, like the formula (3a) is. As another one aspect of ^{Q 2,} like the formula (3b) it is.

Preferred examples of R ^2a , R ^2b , R ^2c and R ^2d include a hydrogen atom or C _{1-6 alkyl.} More preferably, a hydrogen atom or a C _1-3 alkyl can be mentioned. More preferably, a hydrogen atom, methyl or ethyl can be mentioned. Most preferably, it is a hydrogen atom.

^{R C, R D, R E} , R F, preferably as R G, ^{R H} and ^{R J,} include hydrogen atom or _{C 1-6} alkyl. More preferably, a hydrogen atom or a C _1-3 alkyl can be mentioned. More preferably, a hydrogen atom, methyl or ethyl can be mentioned. Most preferably, it is a hydrogen atom.

One embodiment of the compound of the present invention represented by the formula (1) includes the following (A).
(A)
Equation (1) is Equation (1b).
Z is -CH-
Ring ^{Q 2} is a formula (3a),
R ^2a , R ^2b , R ^2c and R ^2d are all hydrogen atoms,
Ring ^{Q 1} is a formula (4c) or formula (4f),
R ^3a and R ^3b are independently hydrogen atoms, C _1-6 alkyl or C _1-6 alkoxy, respectively.
A compound or a pharmaceutically acceptable salt thereof.

Another aspect of the compound of the present invention represented by the formula (1) is the following (B).
(B)
Equation (1) is Equation (1b).
Z is a nitrogen atom,
Ring ^{Q 2} is a formula (3a),
R ^2a , R ^2b , R ^2c and R ^2d are all hydrogen atoms,
Ring ^{Q 1} is a formula (4a),
R ^3a and R ^3b are independently hydrogen atoms, C _1-6 alkyl or C _1-6 alkoxy, respectively.
A compound or a pharmaceutically acceptable salt thereof.

Another aspect of the compound of the present invention represented by the formula (1) is the following (C).
(C)
Equation (1) is Equation (1b).
Z is a nitrogen atom,
Ring ^{Q 2} is a formula (3b),
R ^2a , R ^2b , R ^2c and R ^2d are all hydrogen atoms,
Ring ^{Q 1} is a formula (4a) or formula (4c),
R ^3a and R ^3b are independently hydrogen atoms, C _1-6 alkyl or C _1-6 alkoxy, respectively.
A compound or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (1) may exist as a tautomer. Therefore, the compound of the present invention also includes tautomers of the compound represented by the formula (1).

The compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compound of the present invention includes not only the racemic compound of the compound represented by the formula (1) but also the optically active compound of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, it may cause steric isomerism. Therefore, the compounds of the present invention also include stereoisomers of these compounds and mixtures thereof.

Also included in either one or deuterium converter which converts the two or more ^{1 H 2} to ^H (D) compounds represented by the formula (1) of the compound represented by formula (1) ..

Since the compound represented by the formula (1) and the pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates or ethanol solvates. Solvates such as are also included in the compounds of the present invention. Furthermore, the compounds of the present invention also include those in crystalline form in all aspects.
As a pharmaceutically acceptable salt, when the compound represented by the formula (1) has an acidic group, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline soil such as a calcium salt or a magnesium salt. Kind of metal salt; Inorganic metal salt such as zinc salt; Organic base salt such as triethylamine, triethanolamine, trihydroxymethylaminomethane, amino acid and the like.
When the compound represented by the formula (1) has a basic group, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionate. , Succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate and other organics Examples include acid salts.

Hereinafter, the method for producing the compound of the present invention will be described with reference to examples, but the present invention is not limited thereto.

Production Method The compound of the present invention is synthesized by a method that combines the production method shown below and a known synthesis method.
The compounds in the reaction formula include the case where each compound forms a salt, and examples of the salt include those similar to the salt of the compound represented by the formula (1). It should be noted that these reactions are merely examples, and the compound of the present invention can be produced by other methods as appropriate based on the knowledge of a person who is proficient in organic synthesis.

In each of the production methods described below, even if the use of a protecting group is not specifically specified, if a functional group that requires protection exists, the functional group is protected as necessary. The desired product may be obtained by deprotecting after completion of the reaction or after performing a series of reactions.

As the protecting group, the usual protecting group described in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) is used. Can be used. More specifically, examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like. Further, examples of the protection of hydroxy include trialkylsilyl, acetyl, benzyl and the like.
The introduction and elimination of protecting groups is a commonly used method in synthetic organic chemistry (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999). ) Or a similar method.

〔式中、Ｖ、ｎ、Ｚ、ｔ、破線を含む結合（ａ）、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、環Ｑ^１および環Ｑ^２は、項１と同義であり、ＬＧ^１は、脱離基（例えば、ヨウ素、臭素、塩素、置換スルホニル（例えば、メタンスルホニル、ｐ-トルエンスルホニルなど）など）を表す。〕 Manufacturing method 1
The compound represented by the formula (1) is produced, for example, by the method shown below.

[In the equation, V, n, Z, t, the bond (a) including the broken line, R ^1a , R ^1b , R ^1c , R ^1d , ring Q ¹ and ring Q ² are synonymous with item 1, and LG ¹ Represents a leaving group (eg, iodine, bromine, chlorine, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.)). ]

Compound (5) should be commercially available or produced according to a known method, for example, the method described in the European Journal of Medicinal Chemistry 2002, 37 (9), 721-730, etc. Can be done.

Compound (6) can be produced by using a commercially available compound or by using a known method, for example, the method described in the European Journal of Medicinal Chemistry 2012, 55, 58-66 and the like.

Compound (1) is produced by reacting compound (5) with compound (6) in the presence of a suitable base in a suitable inert solvent. The reaction may be carried out in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the base used, the raw material and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxyde, potassium tert-butoxide, etc. Be done.
Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate and the like.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.

〔式中、Ｖ、ｎ、Ｚ、ｔ、破線を含む結合（ａ）、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、環Ｑ^１および環Ｑ^２は、項１と同義であり、Ｒ^４は、置換されていてもよいＣ_１−６アルキルを表す。〕 Manufacturing method 2
Among the compounds represented by the formula (1), the compound represented by the formula (1c) is produced, for example, by the method shown below.

[In the equation, V, n, Z, t, the bond (a) including the broken line, R ^1a , R ^1b , R ^1c , R ^1d , ring Q ¹ and ring Q ² are synonymous with item 1, and R ⁴ Represents a _{C 1-6} alkyl which may be substituted. ]

Compound (7) can be produced by using a commercially available compound, or by using a known method, for example, the method described in Journal of Medicinal Chemistry 1985, 28 (6), 761-769, etc. can.

Compound (1c) is reductively aminated in a suitable inert solvent using compound (7) and an aldehyde represented by the formula (8a) or a hemiacetal represented by the formula (8b) and a suitable reducing agent. Manufactured by reacting. The reaction may be carried out in the presence of a suitable base or acid, if desired. The reaction temperature usually ranges from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the reducing agent used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the reducing agent include complex hydrogen compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, and sodium cyanoborohydride; borane complexes (borane-dimethylsulfide complex or borane-tetrahydrofuran). Complexes, etc.) and the like.
Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the acid include organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid.
Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as water, chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane. System solvents; alcohol-based solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide and N-methyl-2-pyrrolidinone; and mixed solvents thereof and the like.

〔式中、Ｖ、ｎ、Ｚ、ｔ、破線を含む結合（ａ）、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、および環Ｑ^２は、項１と同義であり、ＬＧ^１およびＬＧ^２は、脱離基（例えば、ヨウ素、臭素、塩素、置換スルホニル（例えば、メタンスルホニル、ｐ−トルエンスルホニルなど）など）を表す。〕 Manufacturing method 3
The compound represented by the formula (5) is produced, for example, by the method shown below.

[In the equation, V, n, Z, t, the bond (a) including the broken line, R ^1a , R ^1b , R ^1c , R ^1d , and ring Q ² are synonymous with item 1, and LG ¹ and LG ² Represents a leaving group (eg, iodine, bromine, chlorine, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.)). ]

Use commercially available compound (9), or prepare compound (9) according to a known method, for example, the method described in Organic Process Research & Development 2005, 9 (6), 774-781, etc. Can be done.

Compound (10) is commercially available, or is produced according to a known method, for example, the method described in Journal of the Chemical Society, Perkin Transactions 1 2001, 10, 1204-1211, etc. be able to.

Compound (5) is produced by reacting compound (7) with an alkylating agent represented by the formula (9) in a suitable inert solvent. The reaction may be carried out in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxyde, potassium tert-butoxide, etc. Be done.
Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate and the like.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.

Compound (5) is produced by converting the hydroxyl group of compound (11) into a halogen or a substituted sulfonyloxy such as p-toluenesulfonyloxy or methanesulfonyloxy in a suitable inert solvent by a conventional method.
Specifically, for example, ^{the compound (5) in which LG 1} is a halogen is produced by reacting the compound (11) with carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine in a suitable inert solvent. Manufactured.
Further ^{, the compound (5) in which LG 1} is substituted sulfonyloxy is prepared by reacting the compound (11) with, for example, p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of an appropriate base in an inert solvent. Manufactured. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbon solvents such as chloroform and dichloromethane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; acetonitrile, dimethyl formamide, and the like. Aprotic polar solvents such as N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixed solvents thereof and the like can be mentioned.
Specific examples of the base include organic bases such as triethylamine and pyridine; and inorganic bases such as potassium carbonate and sodium hydroxide.

The ^{compound (5) in which LG 1} is a halogen can also be obtained by reacting the compound (5) in which LG ¹ is a substituted sulfonyloxy in a suitable inert solvent, for example, with lithium bromide or lithium chloride. Manufactured.

Compound (11) is produced by reacting compound (7) with an alkylating agent represented by the formula (10) in a suitable inert solvent. The reaction may be carried out in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxyde, potassium tert-butoxide, etc. Be done.
Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate and the like.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.

〔式中、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃおよびＲ^２ｄは、項１と同義であり、Ａはヨウ素、臭素、塩素などのハロゲンを表す。〕 Manufacturing method 4
Among the compounds represented by the formula (7), the compound represented by the formula (7a) is produced, for example, by the method shown below.

[In the formula, R ^2a , R ^2b , R ^2c and R ^2d are synonymous with Item 1, and A represents a halogen such as iodine, bromine and chlorine. ]

The compound (13) can be produced by using a commercially available compound or by using a known method, for example, the method described in Chemical Communications 2016, 52 (5), 958-961 and the like.

Compound (7a) is produced by treating compound (16) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Ether-based solvents; lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof and the like.
Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

Compound (16) is produced by treating compound (15) with a suitable base in a suitable inert solvent. The treatment temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the base used, the raw material and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxyde, potassium tert-butoxide, etc. Be done.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.

Compound (15) is produced by reacting compound (14) with hydroxylamine or a salt thereof in a suitable inert solvent, if necessary, in the presence of a suitable base. The treatment temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide; sodium acetate And so on.
Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower grades such as methanol, ethanol and 2-propanol. Alcohols; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone; water, and mixed solvents thereof and the like.

Compound (14) is produced by reacting compound (12) with a lithioxide generated by treating compound (13) with an organolithium such as n-butyllithium in a suitable inert solvent. The treatment temperature is usually in the range from about −78 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixed solvents thereof.

Compound (12) contains 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid with N, O-dimethylhydroxyamine or hydrochloride thereof in a suitable inert solvent in the presence of a suitable condensing agent. Manufactured by reacting. The reaction may be carried out in the presence of a suitable base, if necessary. The reaction temperature usually ranges from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.
Compound (12) is derived from N, O-dimethylhydroxyamine or a salt thereof from a 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in a suitable inert solvent in the presence of a suitable base. It is also produced by reacting with an acid halide or an acid anhydride. The reaction temperature usually ranges from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, and the raw material solvent, but is usually 10 minutes to 48 hours.

Specific examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopyrucarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), and benzotriazole-1-yl-. Tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphonyldiamide (DPPA), N, N-carbonyldimidazole (CDI), benzotriazole-1-yl-N, N, N', N '-Tetramethyluronium hexafluorophosphate (HBTU) and the like can be mentioned. If necessary, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. The reaction can be carried out by adding the additive of.
Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof and the like can be mentioned.

〔式中、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃおよびＲ^２ｄは、項１と同義である。〕 Manufacturing method 5
Among the compounds represented by the formula (7), the compound represented by the formula (7b) is produced, for example, by the method shown below.

[In the formula, R ^2a , R ^2b , R ^2c and R ^2d are synonymous with Item 1. ]

Compound (17) can be produced by using a commercially available compound or by using a known method, for example, the method described in European Journal of Organic Chemistry 2018, 40, 5520-5523 and the like.

Compound (7b) is produced by treating compound (18) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxy. Ether-based solvents such as ethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof. Be done.
Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

Compound (18) is prepared by converting compound (17) into a halogenated phosphoryl such as phosphoryl chloride, a sulfonylating agent such as methanesulfonyl chloride, or a bromotri (pyrrolidin-1-yl) phosphonium hexafluorophos in a suitable inert solvent. It is produced by reacting with a reagent such as Fate (V) to activate it, and then reacting with tert-butylpiperazin-1-carboxylate in the presence of an appropriate base. The reaction temperature usually ranges from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples include ether-based solvents; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

〔式中、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃおよびＲ^２ｄは、項１と同義である。〕 Manufacturing method 6
Among the compounds represented by the formula (7), the compound represented by the formula (7c) is produced, for example, by the method shown below.

[In the formula, R ^2a , R ^2b , R ^2c and R ^2d are synonymous with Item 1. ]

Compound (7c) is produced by treating compound (20) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxy. Ether-based solvents such as ethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof. Be done.
Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

Compound (20) is produced by treating compound (19) with sulfyl chloride and then reacting with ammonia in a suitable inert solvent. The reaction temperature usually ranges from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples thereof include ether solvents; lower alcohols such as methanol, ethanol and 2-propanol; and mixed solvents thereof.

Compound (19) is produced by reacting compound (14) with sodium sulfide in a suitable inert solvent and then treating with benzyl halide such as benzyl bromide in the presence of a suitable base. Compound (19) is also produced by reacting compound (14) with benzyl mercaptan in a suitable inert solvent in the presence of a suitable base. The reaction temperature usually ranges from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples include ether-based solvents; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

〔式中、Ｖ、ｎおよび環Ｑ^１は、項１と同義であり、Ｒ^４は、置換されていてもよいＣ_１−６アルキルを表し、ＬＧ^１は、脱離基（例えば、ヨウ素、臭素、塩素、置換スルホニル（例えば、メタンスルホニル、ｐ−トルエンスルホニルなど）など）を表す。〕 Manufacturing method 7
The compound represented by the formula (8a) or the formula (8b) is produced, for example, by the method shown below.

[In the formula, V, n and ring Q ¹ are synonymous with item 1, R ⁴ represents a optionally substituted C _1-6 alkyl, and LG ¹ is a leaving group (eg, iodine, Represents bromine, chlorine, substituted sulfonyls (eg, methanesulfonyls, p-toluenesulfonyls, etc.). ]

Compound (21) can be produced by using a commercially available compound, or by using a known method, for example, the method described in Organic & Biomolecular Chemistry 2018, 16 (41), 7753-7759, etc. can.

Compound (8a) or compound (8b) is produced by reacting compound (22) with a catalytic amount of osmium tetroxide in the presence of an oxidizing agent such as sodium periodate in a suitable inert solvent. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; acetonitrile, acetone, dimethylformamide and N-methyl. -2-Aprotonic polar solvents such as pyrrolidinone; water, and mixed solvents thereof and the like.

Compound (22) is produced by reacting compound (6) with an alkylating agent represented by the formula (21) in a suitable inert solvent in the presence of a suitable base. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples include ether-based solvents; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

〔式中、Ｗ、ｍおよび環Ｑ^３は、項１と同義であり、Ｒ^４は、置換されていてもよいＣ_１−６アルキルを表し、ＬＧは、脱離基（例えば、ヨウ素、臭素、塩素、置換スルホニル（例えば、トリフルオロメタンスルホニル、ｐ-トルエンスルホニルなど）など）を表し、ＢＧは、ボロン酸（−Ｂ（ＯＨ）_２）、ボロン酸エステル（例えば、ピナコールボロン酸エステルなど）、トリフルオロボレートを表す。〕 Manufacturing method 8
Among the compounds represented by the formula (2), the compound (2a) is produced, for example, by the method shown below.

Wherein, W, m and ring ^{Q 3} are the same meaning as in claim 1, ^{R 4} represents a _{C 1-6} alkyl which may be substituted, LG is a leaving group (e.g., iodine, bromine , Chlorine, substituted sulfonyl (eg, trifluoromethanesulfonyl, p-toluenesulfonyl, etc.), etc., where BG is boronic acid (-B (OH) ₂ ), boronic acid ester (eg, pinacol boronic acid ester, etc.), Represents trifluoroboronic acid. ]

Compound (23) can be produced by using a commercially available compound, or by using a known method, for example, the method described in Journal of Medicinal Chemistry 2011, 54 (2), 635-654, etc. can.

Compounds (24a) and (24b) may be commercially available or prepared according to known methods, such as those described in Tetrahedron Letters 2004, 45 (11), 2467-2471, etc. be able to.

Compound (2a) is produced by treating compound (25a) with a suitable acid in a suitable inert solvent and then intramolecularly cyclizing the compound (25a) in the presence of a suitable base, if necessary. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Ether-based solvents; lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof and the like.
Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.
Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

Compound (2a) is subjected to intramolecular cyclization of compound (25b) in a suitable inert solvent under normal pressure or pressurized hydrogen atmosphere, and then in the presence of a suitable base, if necessary. Also manufactured by. Specific examples of the catalyst used in this hydrogenolysis reaction include palladium-based catalysts such as palladium-carbon and palladium-carbon hydroxide. The reaction temperature is usually in the range from 0 ° C. to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the catalyst used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include, for example, an ester solvent such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane and the like. Ether-based solvents; alcohol-based solvents such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.
Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxydo, potassium tert-butoxide, etc. Be done.

Compound (25a) is produced by subjecting compound (23) and compound (24a) to a coupling reaction in the presence of a suitable transition metal catalyst in a suitable inert solvent. The reaction can be carried out in the presence of a suitable ligand, a suitable base, a suitable additive and the like, if necessary. The reaction temperature usually ranges from −10 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the transition metal catalyst used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the transition metal catalyst include palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), and bis (triphenyl). Phosphine) Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), or [1,1'-bis (diphenylphosphino) ferrocene ] Dichloropalladium (II) and the like can be mentioned.
Specific examples of the ligand include, for example, triphenylphosphine, tri-O-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1'-bis. Examples thereof include (diphenylphosphine) ferrocene, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl and the like.
Specific examples of the base include organic bases such as triethylamine and diisopropylethylamine; and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
Specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.
Specific examples of the inert solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane. Examples include ether solvents such as, alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone, and mixed solvents thereof.

Compound (25b) is produced by subjecting compound (23) and compound (24b) to a coupling reaction in the presence of a suitable transition metal catalyst in a suitable inert solvent. The reaction can be carried out in the presence of a suitable ligand, a suitable base, a suitable additive and the like, if necessary. The reaction temperature usually ranges from −10 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the transition metal catalyst used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the transition metal catalyst include palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), and bis (triphenyl). Phosphine) Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), or [1,1'-bis (diphenylphosphino) ferrocene ] Dichloropalladium (II) and the like can be mentioned.
Specific examples of the ligand include, for example, triphenylphosphine, tri-O-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1'-bis. Examples thereof include (diphenylphosphine) ferrocene, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl and the like.
Specific examples of the base include organic bases such as triethylamine and diisopropylethylamine; and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
Specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.
Specific examples of the inert solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane. Examples include ether solvents such as, alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone, and mixed solvents thereof.

〔式中、Ｗおよびｍは、項１と同義であり、Ｒ^３ａおよびＲ^３ｂは、項１３と同義である。〕 Manufacturing method 9
Among the compounds represented by the formula (2), the compound represented by the formula (2b) is produced, for example, by the method shown below.

[In the formula, W and m are synonymous with Item 1, and R ^3a and R ^3b are synonymous with Item 13. ]

Compound (26) can be produced by using a commercially available compound or by using a known method, for example, the method described in Organic Letters 2009, 11 (10), 2133-2136 and the like.

Compound (2b) is reacted with compound (26) in a suitable inert solvent with alkylhydrazine such as hydrazine or methylhydrazine, if necessary, in the presence of a suitable acid, and then dimethylformamide dimethylacetamide or Dimethylacetamide Manufactured by reacting with an amide acetal such as dimethylformamide. Alternatively, the compound (2b) is also produced by reacting the compound (26) with an amide acetal such as dimethylformamide dimethylacetal or dimethylacetamide dimethylacetal and then reacting with an alkylhydrazine such as hydrazine or methylhydrazine. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol and 2-. Lower alcohols such as propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide; and mixed solvents thereof and the like can be mentioned.
Specific examples of the acid include organic acids such as acetic acid.

〔式中、Ｖ、Ｗ、ｍ、ｎ、Ｚ、ｔ、破線を含む結合（ａ）、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄおよび環Ｑ^２は、項１と同義であり、ＬＧ^１は、脱離基（例えば、ヨウ素、臭素、塩素、置換スルホニル（例えば、メタンスルホニル、ｐ-トルエンスルホニルなど）など）を表し、Ｒ^５ａおよびＲ^５ｂは、置換されていてもよいＣ_１−６アルキルを表し、これらが一緒になって５〜７員の環状アセタールを形成していてもよい。〕 Manufacturing method 10
Among the compounds represented by the formula (1), the compound represented by the formula (1d) is produced, for example, by the method shown below.

[In the equation, V, W, m, n, Z, t, the bond (a) including a broken line, R ^1a , R ^1b , R ^1c , R ^1d and ring Q ² are synonymous with item 1 and LG ¹ Represents a leaving group (eg, iodine, bromine, chlorine, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.), etc.), and R ^5a and R ^5b may be substituted C _1-6. It represents an alkyl, which may be combined to form a 5- to 7-membered cyclic acetal. ]

Compound (1d) is produced by reacting compound (29) with 2,2-dimethoxy-N-methylethane-1-amine in the presence of compound (29), a suitable dehydrating agent and a suitable acid in a suitable inert solvent. Will be done. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol and 2-. Lower alcohols such as propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide; and mixed solvents thereof and the like can be mentioned.
Specific examples of the dehydrating agent include magnesium sulfate, sodium sulfate and the like.
Specific examples of the acid include organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

Compound (29) is produced by treating compound (28) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Ether-based solvents; lower alcohols such as methanol, ethanol, 2-propanol; aprotonic polar solvents such as acetone, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof. ..
Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

Compound (28) is produced by reacting compound (5) with compound (27) in the presence of a suitable base in a suitable inert solvent. The reaction may be carried out in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus. Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, etc .; metal alkoxides such as sodium methoxyde, potassium tert-butoxide, etc. Be done.
Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate and the like.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.

Compound (27) is produced by reacting compound (26) with a suitable alcohol in the presence of a suitable acid in a suitable inert solvent. If necessary, the reaction may be carried out under azeotropic dehydration conditions using a Dean-Stark apparatus. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw material, and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotonic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof and the like.
Specific examples of the acid include organic acids such as methanesulfonic acid and p-toluenesulfonic acid.
Specific examples of the alcohol include lower alcohols such as methanol, ethanol and ethane-1,2-diol.

By appropriately combining the above production methods, the compound of the present invention having a desired substituent at a desired position can be obtained. Isolation and purification of intermediates and products in the above production method may be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various types of chromatography. can. Further, the intermediate can be subjected to the next reaction without any particular purification.

Depending on the reaction conditions and the like, the raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride, but can be used as it is or in a free form. If the starting compound or intermediate is obtained in the form of a salt and you want to use or obtain the starting compound or intermediate in free form, dissolve or suspend them in a suitable solvent and base, for example, an aqueous sodium hydrogen carbonate solution. It can be converted to a free form by neutralizing with.

Among the compounds represented by the formula (1) or pharmaceutically acceptable salts thereof are tautomers such as keto-enol, positional isomers, geometric isomers or optical isomers. All possible isomers, including these, and mixtures in any proportion of the isomers are also included in the invention.
Further, the optical isomer can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method. An optically active substance can also be used as a starting material.

When it is desired to obtain the salt of the compound represented by the formula (1), if the salt of the compound represented by the formula (1) can be obtained, it may be purified as it is, and the compound represented by the formula (1) can be obtained. When obtained in the free form, the compound represented by the formula (1) may be dissolved or suspended in an appropriate solvent, and an acid or base may be added to form a salt.

Since the compound of the present invention has both an agonist activity for _{5-HT 1A receptor and an antagonist activity for 5-HT 2A} receptor and has a mechanism of action different from that of existing therapeutic agents for psychiatric disorders, it is a drug in various psychiatric disorders. It can provide new treatment options. That is, the compound of the present invention is effective for the treatment of mental illness. The compound of the present invention is also effective for central nervous system diseases.

Examples of psychiatric disorders or central nervous system disorders that are expected to be effective include F00-F09: organic psychiatric disorders including symptomatic illnesses and F10-F19: psychiatric effects in the International Classification of Diseases 10th Edition (ICD-10). Psychiatric and behavioral disorders due to substance use, F20-F29: schizophrenia, schizophrenia-type disorders and delusional disorders, F30-F39: mood [emotion] disorders, F40-F48: neurotic disorders, stress-related disorders and Physical expression disorders, F51: non-organic sleep disorders, F52: sexual dysfunction, organic disorders or non-diseased, F84: diffuse developmental disorders, F90-F98: behaviors that normally occur in childhood and adolescence And emotional disorders, G20-G26: extrapyramidal tract disorders and abnormal movements, G30-G32: other degenerative disorders of the nervous system, G47: sleep disorders and the like.

F00-F09: Specific examples of organic psychiatric disorders including symptomatic disorders include, for example, dementia vascular dementia of Alzheimer's disease, Levy body dementia, dementia of Parkinson's disease, and psychiatric disorders associated with brain damage. These include disorders, brain dysfunction and other mental disorders due to physical illness.
F10-F19: Specific examples of mental and behavioral disorders due to the use of psychoactive substances include delirium tremens, psychotic disorders, amnestic syndrome, etc. due to the use of various substances.
F20-F29: Specific examples of schizophrenia, schizophrenia-type disorder, and delusional disorder include delusional schizophrenia, simple schizophrenia, and delusional disorder.
F30-F39: Specific examples of mood [emotional] disorders include manic episodes, bipolar affective disorders, and depression episodes.
F40-F48: Specific examples of neurotic disorders, stress-related disorders and somatic symptom disorders include, for example, phobic anxiety disorders, obsessive-compulsive disorders, and somatic symptom disorders.
F51: Specific examples of non-organic sleep disorders include non-organic insomnia, sleepwalking, nightmares and the like.
F52: Specific examples of those not due to sexual dysfunction, organic disorder or disease include, for example, lack of libido, loss of libido, and unspecified sexual dysfunction.
F84: Specific examples of pervasive developmental disorders include, for example, autism, mental retardation and hyperactivity disorders associated with stereotyped movements.
F90-F98: Hyperactivity Disorder Specific examples of behavioral and emotional disorders that usually occur in childhood and adolescence include hyperactivity disorder, conduct disorder, and mixed behavior and emotional disorders.
G20-G26: Specific examples of extrapyramidal tract disorders and abnormal movements include, for example, Parkinson's disease, secondary Parkinson's syndrome, dyskinesia, spinocerebellar degeneration and the like.
G30-G32: Specific examples of other degenerative diseases of the nervous system include, for example, Alzheimer's disease, frontotemporal lobar dementia, frontotemporal lobar dementia, Lewy body dementias, senile cerebral dementia, progressive Examples include supranuclear palsy.
G47: Specific examples of sleep disorders include, for example, sleep induction and maintenance disorders [insomnia], sleep / wake schedule disorders, narcolepsy, and cataplexy.
The compound of the present invention is used for treating or preventing recurrence of various symptoms associated with these diseases (psychiatric symptoms, restlessness, aggression, irritability and irritability, sleep disorders, depressive symptoms, anxiety symptoms, cognitive dysfunction, etc.). Is also useful.

Psychiatric disorders or central nervous system disorders that are expected to be effective are preferably psychiatric disorders, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic characteristics, and psychotic disorders. For characteristic depressive disorders, psychiatric symptoms associated with dementia, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, psychiatric symptoms associated with Parkinson's disease dementia, psychiatric symptoms associated with Parkinson's disease, or Alzheimer's disease Frustration, agitation or aggression associated with, more preferably schizophrenia, psychiatric symptoms associated with dementia, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, or irritability associated with Alzheimer's disease, Excitement or aggression.

The compound of the present invention _{showed a strong binding affinity for 5-HT 1A} receptor and 5-HT _2A receptor (Test Example 1), and showed _{agonist activity for 5-HT 1A} receptor, 5-HT _2A. Has antagonistic activity on the receptor. In a preferred embodiment of the compound of the present invention, the binding affinity for _{5-HT 1A} receptor and 5-HT _2A receptor is 100 times or more stronger than the binding affinity for _{D 2 receptor.} Therefore, in the blood concentration side effects we do not express such extrapyramidal symptoms and hyperprolactinemia probably due to D ₂ receptor antagonist activity, 5-HT _1A receptor agonistic activity and 5-HT _2A receptor antagonist activity It is possible to exert a pharmacological action based on. That is, the expression concentration of the pharmacological action and the expression concentration of the side effect are different.

In a preferred embodiment of the compound of the present invention, the hERG channel inhibition concentration, which is an index of the expression of arrhythmia due to QT prolongation, and the expression concentration of pharmacological action based on _{5-HT 1A} receptor agonist activity and 5-HT _{2A receptor antagonist activity.} Since there is a divergence from (Test Example 5), it can be expected that the effect on the cardiovascular system will be small. That is, the expression concentration of the pharmacological action and the expression concentration of the side effect are different.

The elimination half-life of a drug (hereinafter, also referred to as "T1 / 2") is a factor that determines the number of doses to sustain its effect. If T1 / 2 is short, it is necessary to administer multiple doses a day, leading to missed doses and leftovers, which hinders proper drug treatment. In addition, as the number of doses increases, there is a concern that the tolerability may decrease due to an increase in the incidence of side effects or a restriction on high-dose administration. From the above viewpoint, it can be expected that achieving a long T1 / 2 will create a long-acting drug with less concern and reduce the burden on the patient taking the drug.
In a preferred embodiment of the compound of the present invention, the predicted human elimination half-life (hereinafter, may be referred to as “predicted human T1 / 2”) is as long as 8 hours or more (Test Example 4). That is, in a preferred embodiment of the compound of the present invention, it is expected that the drug efficacy lasts for a long time in the human body, thereby improving the medication adherence of the drug-treated patient and exhibiting high tolerability at the time of administration.

The compounds of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenteral can be administered in the form of topical agents, injections, transdermal agents, nasal agents and the like. Oral or rectal administrations include, for example, capsules, tablets, pills, powders, cashiers, suppositories, liquids and the like. Examples of the injection include a sterile solution or suspension. Examples of topically administered agents include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.

The above dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives and the like. Be done.
Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragant, methyl cellulose, sodium carboxymethyl cellulosic, low melting point wax, cacao butter. And so on. Capsules can be formulated by placing the compounds of the invention together with a pharmaceutically acceptable carrier. The compounds of the invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. The cashier can be produced in the same manner.

Examples of the liquid preparation for injection include solutions, suspensions, emulsions and the like. For example, an aqueous solution, a water-propylene glycol solution and the like can be mentioned. The liquid may also be prepared in the form of a solution of polyethylene glycol and / and propylene glycol, which may contain water. A liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a flavor, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. A liquid preparation suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Thickeners include, for example, pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or known suspending agents.

The dose varies depending on the individual compound and the patient's disease, age, body weight, sex, symptoms, route of administration, etc., but usually, for an adult (body weight 50 kg), 0.1 to 1000 mg of the compound of the present invention is used. / Day, preferably 1 to 300 mg / day, is administered once daily or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.

The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

Specific examples of concomitant drugs include antidepressants, anxiolytics, schizophrenia drugs, dopamine replacement drugs, dopamine receptor agonists, Parkinson's disease drugs, antiepileptic drugs, anticonvulsants, analgesics, hormones. Examples thereof include preparations, therapeutic agents for migraine, adrenaline β-receptor antagonists, therapeutic agents for dementia, therapeutic agents for mood disorders, antidepressants, and sleep-inducing agents. Concomitant medications preferably include anxiolytics such as selective serotonin reuptake inhibitors.

The administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. Further, it may be a mixture of the compound of the present invention and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to this. The compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature. The compounds were identified using a proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), LC-MS, or the like.

LC-MS was measured under the following conditions. The retention time (RT) represents the time when the mass spectrum peak appears in the LC-MS measurement.
Condition A
Analyzer: Shimadzu LCMS-2020
Column: Phenomenex Kinetex 1.7 μm C18 (50 mm x 2.10 mm)
Elution solvent: Solution A: MeOH, solution B: 0.05% TFA / H ₂ O
Gradient condition:
0.0 min; A / B = 30:70
0.0-1.90 min; A / B = 99: 1
1.91-3.00 min; A / B = 30:70
Flow velocity: 0.5 mL / min
Wavelength: 220 nm
Column temperature: 40 ° C

The powder X-ray diffraction measurement (powder XRD) was performed under the following conditions.
Equipment: Empyrian (manufactured by Spectris)
X-ray: CuKα / 45 kV / 40 mA
Divergence slit: 1/4 °
Solar slit: 0.04 rad
Anti-scattering slit: 5.5 mm
Step size: 0.013 °
Scanning range: 4-30 ° (2θ)
Accumulation time: 100 seconds / step measurement temperature: 23 ° C (296K)

Differential scanning calorimetry (DSC) was performed under the following conditions.
Equipment: TA Instrument Q1000
Measurement temperature range: 10-250 ° C
Heating rate: 10 ° C / min Container: Aluminum hermetic pan (Pinhole)
Atmospheric gas flow rate: Dry nitrogen approx. 50 mL / min

The following abbreviations may be used herein.
Me: Methyl DMF: N, N-dimethylformamide THF: tetrahydrofuran tert-: Terriary CDCl ₃ : Deuterated chloroform DMSO-d ₆ : Deuterated dimethyl sulfoxide

The proton nuclear magnetic resonance spectrum was measured using an FT-NMR measuring device (300 MHz or 400 MHz) manufactured by JEOL Ltd. The chemical shift value is described as a δ value (ppm). As symbols used in NMR, s is a single line, d is a double line, dd is a double double line, dt is a double triple line, t is a triple line, q is a quadruple line, and m is multiplex. Line, br is wide, brs is wide single line, and J means coupling constant.

６，７−ジヒドロ−１，７−ナフチリジン−８（５Ｈ）−オン（２４０ ｍｇ）のトルエン溶液（５．０ ｍＬ）に、室温で参考例１の化合物（４５２ ｍｇ）、水酸化カリウム（１３６ ｍｇ）、テトラブチルアンモニウムブロミド（１７２ ｍｇ）を加えた。１.５時間の還流加熱撹拌後、室温にて反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（３７７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.71 (6H, m), 3.03 (2H, t, J = 6.6 Hz), 3.55 (4H, t, J = 6.6 Hz), 3.68 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.3 Hz), 7.19 (1H, m), 7.31 (1H, dd, J = 7.7, 4.8 Hz), 7.41-7.50 (2H, m), 7.52-7.56 (1H, m), 7.66 (1H, d, J = 8.0 Hz), 8.67 (1H, dd, J = 4.6, 1.7 Hz). Example 1
7- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -6,7-dihydro-1,7-naphthylidine-8 (5H) -one

In a toluene solution (5.0 mL) of 6,7-dihydro-1,7-naphthalene-8 (5H) -one (240 mg), the compound of Reference Example 1 (452 mg) and potassium hydroxide (136 mg) were added at room temperature. mg) and tetrabutylammonium bromide (172 mg) were added. After reflux heating and stirring for 1.5 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (377 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.71 (6H, m), 3.03 (2H, t, J = 6.6 Hz), 3.55 (4H, t, J = 6.6 Hz), 3.68 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.3 Hz), 7.19 (1H, m), 7.31 (1H, dd, J = 7.7, 4.8 Hz), 7.41-7.50 (2H, m), 7.52- 7.56 (1H, m), 7.66 (1H, d, J = 8.0 Hz), 8.67 (1H, dd, J = 4.6, 1.7 Hz).

参考例１０の化合物（９９．０ ｍｇ）のトルエン溶液（３．７ ｍＬ）に、室温で参考例２の化合物（１６４ ｍｇ）、水酸化カリウム（４６．８ ｍｇ）、テトラブチルアンモニウムブロミド（５９．１ ｍｇ）を加えた。１５時間の還流加熱撹拌後、室温にて反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、さらに、２−プロパノールで再結晶することにより、表題化合物（１６０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.93 (2H, t, J = 6.4 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 6.49 (1H, s), 7.31-7.36 (1H, m), 7.42-7.47 (1H, m), 7.77-7.80 (1H, m), 7.86-7.89 (1H, m), 8.80 (1H, s). Example 2
2- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -6-methoxy-3,4-dihydro-2,7-naphthylidine-1 (2H) − On

In a toluene solution (3.7 mL) of the compound of Reference Example 10 (99.0 mg), the compound of Reference Example 2 (164 mg), potassium hydroxide (46.8 mg), and tetrabutylammonium bromide (59) at room temperature. .1 mg) was added. After reflux heating and stirring for 15 hours, water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and recrystallized from 2-propanol to give the title compound (160 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.93 (2H, t, J = 6.4 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 6.49 (1H, s), 7.31 -7.36 (1H, m), 7.42-7.47 (1H, m), 7.77-7.80 (1H, m), 7.86-7.89 (1H, m), 8.80 (1H, s).

参考例１９の化合物（６８４ ｍｇ）のトルエン溶液（８．４ ｍＬ）に、室温で参考例１の化合物（１．１８ ｇ）、水酸化カリウム（３５５ ｍｇ）、テトラブチルアンモニウムブロミド（４４９ ｍｇ）を加えた。２時間の還流加熱撹拌後、室温にて反応混合物に飽和食塩水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（１．２０ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.56 (3H, s), 2.65-2.85 (6H, m), 2.96 (2H, t, J = 6.7 Hz), 3.60-3.66 (4H, m), 3.65 (2H, t, J = 6.7 Hz), 3.70-3.85 (2H, m), 6.97 (1H, s), 7.21 (1H, dd, J = 7.3, 7.3 Hz), 7.42-7.49 (2H, m), 7.65 (1H, d, J = 7.9 Hz), 9.05 (1H, s). Example 3
2- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -6-methyl-3,4-dihydro-2,7-naphthylidine-1 (2H) − On

In a toluene solution (8.4 mL) of the compound of Reference Example 19 (684 mg), the compound of Reference Example 1 (1.18 g), potassium hydroxide (355 mg), and tetrabutylammonium bromide (449 mg) at room temperature. Was added. After reflux heating and stirring for 2 hours, saturated brine was added to the reaction mixture at room temperature, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.20 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.56 (3H, s), 2.65-2.85 (6H, m), 2.96 (2H, t, J = 6.7 Hz), 3.60-3.66 (4H, m), 3.65 (2H, t, J = 6.7 Hz), 3.70-3.85 (2H, m), 6.97 (1H, s), 7.21 (1H, dd, J = 7.3, 7.3 Hz), 7.42-7.49 (2H, m) , 7.65 (1H, d, J = 7.9 Hz), 9.05 (1H, s).

Examples 4-21
According to the method described in Example 3, the compounds of Examples 4 to 21 were obtained from the corresponding compounds of the reference example.

３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（１．４４ ｇ）のジクロロメタン溶液（２０ ｍＬ）に参考例２２の化合物（１．５８ ｇ）と水素化トリアセトキシホウ素ナトリウム（１．９６ ｇ）を加え、室温で２時間攪拌した。その後、反応混合物へ飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（２．３０ ｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.96-2.16 (4H, m), 2.27 (2H, td, J = 11.4, 2.9 Hz), 2.72 (2H, t, J = 6.3 Hz), 3.00-3.17 (5H, m), 3.72 (2H, t, J = 6.6 Hz), 3.79 (2H, t, J = 6.3 Hz), 7.28-7.37 (2H, m), 7.49-7.60 (3H, m), 7.69-7.74 (1H, m), 8.70 (1H, dd, J = 4.7, 1.6 Hz). Example 22
7- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -6,7-dihydro-1,7-naphthylidine-8 (5H) -one

Compound (1.58 g) of Reference Example 22 and sodium borohydride (1.96) in a dichloromethane solution (20 mL) of 3- (piperidine-4-yl) benzo [d] isoxazole (1.44 g). g) was added, and the mixture was stirred at room temperature for 2 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.30 g).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.96-2.16 (4H, m), 2.27 (2H, td, J = 11.4, 2.9 Hz), 2.72 (2H, t, J = 6.3 Hz), 3.00- 3.17 (5H, m), 3.72 (2H, t, J = 6.6 Hz), 3.79 (2H, t, J = 6.3 Hz), 7.28-7.37 (2H, m), 7.49-7.60 (3H, m), 7.69 -7.74 (1H, m), 8.70 (1H, dd, J = 4.7, 1.6 Hz).

Examples 23-31
According to the method described in Example 22, the compounds of Examples 23 to 31 were obtained from the corresponding compounds of the reference example.

参考例１の化合物（４０．０ ｍｇ）、３−メチル−６，７−ジヒドロ［１，２］オキサゾロ［４，５−ｃ］ピリジン−４（５Ｈ）−オン（２２．９ ｍｇ）、炭酸セシウム（９８．０ ｍｇ）、ヨウ化カリウム（１２．０ ｍｇ）とアセトニトリル（２．０ ｍＬ）の混合物をマイクロウェーブ照射下、１５０℃で２時間撹拌した。その後、反応混合物をろ過後、ろ液を減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製した後、さらに分取薄層クロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１０．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.50 (3H, s), 2.66 (2H, t, J = 6.6 Hz), 2.73 (4H, t, J = 5.0 Hz), 3.09 (2H, t, J = 7.1 Hz), 3.56 (4H, t, J = 4.8 Hz), 3.66 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 7.1 Hz), 7.20-7.25 (1H, m), 7.43-7.51 (2H, m), 7.68 (1H, d, J = 7.8 Hz). Example 32
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -3-methyl-6,7-dihydro [1,2] oxazolo [4,5- c] Pyridine-4 (5H) -on

Reference Example 1 compound (40.0 mg), 3-methyl-6,7-dihydro [1,2] oxazolo [4,5-c] pyridine-4 (5H) -one (22.9 mg), carbonate A mixture of cesium (98.0 mg), potassium iodide (12.0 mg) and acetonitrile (2.0 mL) was stirred at 150 ° C. for 2 hours under microwave irradiation. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by amino silica gel column chromatography (hexane / ethyl acetate), and then further separated and purified by preparative thin layer chromatography (chloroform / methanol) to give the title compound (10.0 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.50 (3H, s), 2.66 (2H, t, J = 6.6 Hz), 2.73 (4H, t, J = 5.0 Hz), 3.09 (2H, t, J = 7.1 Hz), 3.56 (4H, t, J = 4.8 Hz), 3.66 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 7.1 Hz), 7.20-7.25 (1H, m) , 7.43-7.51 (2H, m), 7.68 (1H, d, J = 7.8 Hz).

Examples 33-34
According to the method described in Example 32, the compounds of Examples 33 to 34 were obtained from the corresponding compounds of the reference example.

５５％水素化ナトリウム（３４．４ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド懸濁液（１．０ ｍＬ）に氷冷下、参考例２６の化合物（１００ ｍｇ）を加えた。室温で３０分間攪拌後、参考例３の化合物（２０９ ｍｇ）とヨウ化カリウム（５４．６ ｍｇ）を加え、室温で１８時間攪拌した。その後、反応混合物に水を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製後、さらに、アミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（１６０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.97-2.11 (4H, m), 2.19-2.28 (2H, m), 2.52 (3H, s), 2.61 (2H, t, J = 6.4 Hz), 2.88 (2H, t, J = 7.1 Hz), 3.03-3.13 (3H, m), 3.62 (2H, t, J = 6.4 Hz), 3.72 (2H, t, J = 7.1 Hz), 7.24-7.29 (1H, m), 7.48-7.56 (2H, m), 7.70 (1H, d, J = 7.8 Hz). Example 35
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7-dihydro [1,3] oxazolo [5,4- c] Pyridine-4 (5H) -on

The compound of Reference Example 26 (100 mg) was added to an N, N-dimethylformamide suspension (1.0 mL) of 55% sodium hydride (34.4 mg) under ice-cooling. After stirring at room temperature for 30 minutes, the compound of Reference Example 3 (209 mg) and potassium iodide (54.6 mg) were added, and the mixture was stirred at room temperature for 18 hours. Then, water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) and then separated and purified by amino silica gel column chromatography (hexane / ethyl acetate) to give the title compound (160 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.97-2.11 (4H, m), 2.19-2.28 (2H, m), 2.52 (3H, s), 2.61 (2H, t, J = 6.4 Hz), 2.88 (2H, t, J = 7.1 Hz), 3.03-3.13 (3H, m), 3.62 (2H, t, J = 6.4 Hz), 3.72 (2H, t, J = 7.1 Hz), 7.24-7.29 (1H) , m), 7.48-7.56 (2H, m), 7.70 (1H, d, J = 7.8 Hz).

５５％水素化ナトリウム（６１．９ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド懸濁液（８．０ ｍＬ）に氷冷下、参考例１３の化合物（１５６ ｍｇ）を加えた。室温で３０分間攪拌後、参考例２の化合物（３４９ ｍｇ）とヨウ化カリウム（８６．０ ｍｇ）を加え、５０℃で１６時間攪拌した。その後、反応混合物に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（２０５ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.77 (2H, t, J = 6.6 Hz), 2.85-2.87 (4H, br m), 2.95 (2H, t, J = 6.4 Hz), 3.59-3.60 (4H, m), 3.66-3.73 (4H, m), 3.89 (3H, s), 7.36 (1H, ddd, J = 8.3, 8.3, 0.8 Hz), 7.47 (1H, ddd, J = 8.3, 8.3, 0.8 Hz), 7.75 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz). Example 36
5- {2- [4- (1,2-benzoisothiazole-3-yl) piperazin-1-yl] ethyl} -2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo [4, 3-c] Pyridine-4-one

The compound of Reference Example 13 (156 mg) was added to an N, N-dimethylformamide suspension (8.0 mL) of 55% sodium hydride (61.9 mg) under ice-cooling. After stirring at room temperature for 30 minutes, the compound of Reference Example 2 (349 mg) and potassium iodide (86.0 mg) were added, and the mixture was stirred at 50 ° C. for 16 hours. Then, water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (205 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.77 (2H, t, J = 6.6 Hz), 2.85-2.87 (4H, br m), 2.95 (2H, t, J = 6.4 Hz), 3.59-3.60 (4H, m), 3.66-3.73 (4H, m), 3.89 (3H, s), 7.36 (1H, ddd, J = 8.3, 8.3, 0.8 Hz), 7.47 (1H, ddd, J = 8.3, 8.3, 0.8 Hz), 7.75 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz).

５５％水素化ナトリウム（２３．２ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド懸濁液（１．６ ｍＬ）に氷冷下、参考例３８の化合物（８０．０ ｍｇ）を加えた。室温で３０分間攪拌後、参考例３の化合物（１４１ ｍｇ）とヨウ化カリウム（４０．２ ｍｇ）を加え、５０℃で１５時間攪拌した。その後、反応混合物に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、さらに、アミノシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で分離精製し、表題化合物（８７．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.04-2.10 (4H, m), 2.22-2.29 (2H, m), 2.53 (3H, s), 2.64 (2H, t, J = 6.9 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.04-3.16 (3H, m), 3.61-3.67 (4H, m), 3.75 (3H, s), 7.26-7.29 (1H, m), 7.50-7.57 (2H, m), 7.73 (1H, d, J = 7.8 Hz).
粉末ＸＲＤ（°, 2θ±0.2）
7.47 10.26, 11.51, 12.05, 13.22, 13.83, 14.50, 15.01, 16.42, 17.42, 17.67, 18.15, 18.39, 18.98, 19.51, 19.80, 20.46, 21.12, 21.37, 21.71, 22.63, 22.95, 23.25, 23.94, 24.46, 24.69, 25.23, 25.76, 26.66, 27.12, 27.32, 27.91, 28.52, 29.15（これらのうち、特徴的な１０個のピークは10.26, 12.05, 13.22, 17.42, 17.67, 18.98, 22.63, 23.25, 25.76, 28.52、更に特徴的な４個のピークは13.22, 17.42, 18.98, 23.25であった。）
ＤＳＣ
Enthalpy (normalized): 82.52 J／g
Onset x: 125.06℃ Example 37
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo [ 4,3-c] Pyridine-4-one

The compound of Reference Example 38 (80.0 mg) was added to an N, N-dimethylformamide suspension (1.6 mL) of 55% sodium hydride (23.2 mg) under ice-cooling. After stirring at room temperature for 30 minutes, the compound of Reference Example 3 (141 mg) and potassium iodide (40.2 mg) were added, and the mixture was stirred at 50 ° C. for 15 hours. Then, water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by amino silica gel column chromatography (ethyl acetate / methanol) to give the title compound (87.0 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.10 (4H, m), 2.22-2.29 (2H, m), 2.53 (3H, s), 2.64 (2H, t, J = 6.9 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.04-3.16 (3H, m), 3.61-3.67 (4H, m), 3.75 (3H, s), 7.26-7.29 (1H, m), 7.50-7.57 ( 2H, m), 7.73 (1H, d, J = 7.8 Hz).
Powder XRD (°, 2θ ± 0.2)
7.47 10.26, 11.51, 12.05, 13.22, 13.83, 14.50, 15.01, 16.42, 17.42, 17.67, 18.15, 18.39, 18.98, 19.51, 19.80, 20.46, 21.12, 21.37, 21.71, 22.63, 22.95, 23.25, 23.94, 24.46, 24.69 , 25.23, 25.76, 26.66, 27.12, 27.32, 27.91, 28.52, 29.15 (Of these, the 10 characteristic peaks are 10.26, 12.05, 13.22, 17.42, 17.67, 18.98, 22.63, 23.25, 25.76, 28.52, and more. The four characteristic peaks were 13.22, 17.42, 18.98, 23.25.)
DSC
Enthalpy (normalized): 82.52 J / g
Onset x: 125.06 ℃

Examples 38-87
According to the method described in Example 37, the compounds of Examples 38 to 87 were obtained from the corresponding compounds of the reference example.

参考例３の化合物（８５２ ｍｇ）、参考例４２の化合物（５００ ｍｇ）、５５％水素化ナトリウム（１３４ ｍｇ）とＮ，Ｎ−ジメチルホルムアミド（１５ ｍＬ）の混合物を６０℃で３．５時間攪拌した。その後、反応混合物に水（５．０ ｍＬ）を加え、クロロホルム／メタノール（９０／１０）で抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残留したＮ，Ｎ−ジメチルホルムアミドをトルエンにより共沸除去した後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で分離精製し、さらに、エタノール（１２ ｍＬ）で再結晶することにより、表題化合物（７１０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.98-2.15 (4H, m), 2.23-2.31 (2H, m), 2.69 (2H, t, J = 6.4 Hz), 2.78 (3H, s), 3.05-3.17 (5H, m), 3.70-3.79 (4H, m), 7.27-7.31 (1H, m), 7.50-7.59 (2H, m), 7.70 (1H, d, J = 7.8 Hz), 9.15 (1H, s). Example 88
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2-methyl-7,8-dihydropyrido [4,3-d] pyrimidine-5 ( 6H) -On

A mixture of the compound of Reference Example 3 (852 mg), the compound of Reference Example 42 (500 mg), 55% sodium hydride (134 mg) and N, N-dimethylformamide (15 mL) at 60 ° C. for 3.5 hours. Stirred. Then, water (5.0 mL) was added to the reaction mixture, the mixture was extracted with chloroform / methanol (90/10), dried over anhydrous sodium sulfate, filtered and concentrated. The residual N, N-dimethylformamide was azeotropically removed with toluene, the residue was separated and purified by silica gel column chromatography (ethyl acetate), and further recrystallized from ethanol (12 mL) to give the title compound (710). mg) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.98-2.15 (4H, m), 2.23-2.31 (2H, m), 2.69 (2H, t, J = 6.4 Hz), 2.78 (3H, s), 3.05-3.17 (5H, m), 3.70-3.79 (4H, m), 7.27-7.31 (1H, m), 7.50-7.59 (2H, m), 7.70 (1H, d, J = 7.8 Hz), 9.15 ( 1H, s).

Examples 89-92
According to the method described in Example 88, the compounds of Examples 89 to 92 were obtained from the corresponding compounds of the reference example.

参考例４３の化合物（１００ ｍｇ）のジメチルスルホキシド溶液（１．０ ｍＬ）に水酸化カリウム（３８．０ ｍｇ）と参考例２の化合物（１５９ ｍｇ）を順に加え、室温で２時間攪拌した。その後、反応混合物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、さらに、アミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（９２．７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.38 (3H, t, J = 7.7 Hz), 2.69-2.80 (6H, m), 3.01 (2H, q, J = 7.0 Hz), 3.14 (2H, t, J = 6.7 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.72-3.79 (4H, m), 7.33-7.38 (1H, m), 7.44-7.49 (1H, m), 7.81 (1H, dd, J = 8.2, 0.9 Hz), 7.90 (1H, dd, J = 8.0, 0.7 Hz), 9.17 (1H, s). Example 93
6- {2- [4- (1,2-benzoisothiazole-3-yl) piperazin-1-yl] ethyl} -2-ethyl-7,8-dihydropyrido [4,3-d] pyrimidine-5 ( 6H) -On

Potassium hydroxide (38.0 mg) and the compound of Reference Example 2 (159 mg) were sequentially added to a dimethyl sulfoxide solution (1.0 mL) of the compound of Reference Example 43 (100 mg), and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by amino silica gel column chromatography (hexane / ethyl acetate) to give the title compound (92.7 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.38 (3H, t, J = 7.7 Hz), 2.69-2.80 (6H, m), 3.01 (2H, q, J = 7.0 Hz), 3.14 (2H, 2H, t, J = 6.7 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.72-3.79 (4H, m), 7.33-7.38 (1H, m), 7.44-7.49 (1H, m), 7.81 (1H) , dd, J = 8.2, 0.9 Hz), 7.90 (1H, dd, J = 8.0, 0.7 Hz), 9.17 (1H, s).

Examples 94-95
According to the method described in Example 93, the compounds of Examples 94 to 95 were obtained from the corresponding compounds of the reference example.

参考例４５の化合物（１００ ｍｇ）のジクロロメタン懸濁液（２．１ ｍＬ）にＮ，Ｎ−ジイソプロピルエチルアミン（０．１１０ ｍＬ）を加え、室温で５分間攪拌した。その後、参考例４６の化合物（３８．３ ｍｇ）と酢酸（０．０２４１ ｍＬ）を加えた後、水素化トリアセトキシホウ素ナトリウム（８９．０ ｍｇ）を加え、室温で２４時間攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（４．６０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.01-2.15 (4H, m), 2.23-2.33 (2H, m), 2.66 (2H, t, J = 6.9 Hz), 2.83 (2H, t, J = 6.6 Hz), 3.05-3.16 (3H, m), 3.64-3.71 (4H, m), 4.18 (3H, s), 7.27-7.32 (2H, m), 7.51-7.59 (2H, m), 7.71 (1H, d, J = 7.8 Hz). Example 96
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo [3, 4-c] Pyridine-7-on

N, N-diisopropylethylamine (0.110 mL) was added to a dichloromethane suspension (2.1 mL) of the compound (100 mg) of Reference Example 45, and the mixture was stirred at room temperature for 5 minutes. Then, the compound of Reference Example 46 (38.3 mg) and acetic acid (0.0241 mL) were added, sodium borohydride triacetoxyboron (89.0 mg) was added, and the mixture was stirred at room temperature for 24 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (4.60 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.15 (4H, m), 2.23-2.33 (2H, m), 2.66 (2H, t, J = 6.9 Hz), 2.83 (2H, t, J) = 6.6 Hz), 3.05-3.16 (3H, m), 3.64-3.71 (4H, m), 4.18 (3H, s), 7.27-7.32 (2H, m), 7.51-7.59 (2H, m), 7.71 ( 1H, d, J = 7.8 Hz).

参考例４７の化合物（０．１０２ ｇ）、トリエチルアミン（０．１４５ ｍＬ）、Ｎ,Ｎ−ジメチルホルムアミドジメチルアセタール（０．０７００ ｍＬ）とジクロロメタン（５．０ ｍＬ）の混合物を室温で６０時間撹拌した。その後、Ｎ,Ｎ−ジメチルホルムアミドジメチルアセタール（０．１００ ｍＬ）を加え、３時間加熱還流後、さらに、Ｎ,Ｎ−ジメチルホルムアミドジメチルアセタール（０．２５０ ｍＬ）を加え、２．５時間加熱還流した。反応混合物にトルエン（３０ ｍＬ）を加え、減圧濃縮した。濃縮残渣のエタノール溶液（１０ ｍＬ）にヒドラジン一水和物（１４．３ ｍｇ）を加えた。２４時間加熱還流後、反応混合物を減圧濃縮し、得られた残渣を分取薄層クロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１３．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.01-2.20 (6H, m), 2.22-2.34 (2H, m), 2.66 (2H, t, J = 6.6 Hz), 2.99 (2H, t, J = 6.9 Hz), 3.05-3.20 (3H, m), 3.52 (2H, t, J = 4.8 Hz), 3.73 (2H, t, J = 6.6 Hz), 7.26-7.31 (1H, m), 7.50-7.58 (2H, m), 7.70-7.73 (1H, m), 8.07 (1H, s). Example 97
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -5,6,7,8-tetrahydropyrazolo [4,3-c] azepine- 4 (1H) -on

A mixture of the compound of Reference Example 47 (0.102 g), triethylamine (0.145 mL), N, N-dimethylformamide dimethylacetal (0.0700 mL) and dichloromethane (5.0 mL) is stirred at room temperature for 60 hours. did. Then, N, N-dimethylformamide dimethylacetal (0.100 mL) was added, and after heating under reflux for 3 hours, N, N-dimethylformamide dimethylacetal (0.250 mL) was further added, and the mixture was heated under reflux for 2.5 hours. did. Toluene (30 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hydrazine monohydrate (14.3 mg) was added to an ethanol solution (10 mL) of the concentrated residue. After heating under reflux for 24 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative thin layer chromatography (chloroform / methanol) to give the title compound (13.0 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.20 (6H, m), 2.22-2.34 (2H, m), 2.66 (2H, t, J = 6.6 Hz), 2.99 (2H, t, J) = 6.9 Hz), 3.05-3.20 (3H, m), 3.52 (2H, t, J = 4.8 Hz), 3.73 (2H, t, J = 6.6 Hz), 7.26-7.31 (1H, m), 7.50-7.58 (2H, m), 7.70-7.73 (1H, m), 8.07 (1H, s).

参考例５０の化合物（９．００ ｍｇ）のトリフルオロ酢酸溶液（１．０ ｍＬ）を２時間加熱還流した。その後、反応混合物を濃縮し、テトラヒドロフラン（１．０ ｍＬ）とトリエチルアミン（０．５０ ｍＬ）を加えた。７８時間加熱還流後、反応混合物を濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、さらに、分取薄層カラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（２．３０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.03-2.16 (4H, m), 2.20-2.34 (2H, m), 2.62-2.73 (2H, m), 2.87 (2H, t, J = 6.8 Hz), 3.03-3.19 (3H, m), 3.67-3.75 (4H, m), 7.27-7.31 (1H, m), 7.46 (1H, s), 7.51-7.58 (2H, m), 7.71 (1H, d, J = 8.0 Hz). Example 98
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1,4,5,6-tetrahydro-7H-pyrazolo [3,4-c] Pyridine-7-on

A trifluoroacetic acid solution (1.0 mL) of the compound of Reference Example 50 (9.00 mg) was heated to reflux for 2 hours. The reaction mixture was then concentrated and tetrahydrofuran (1.0 mL) and triethylamine (0.50 mL) were added. After heating and refluxing for 78 hours, the reaction mixture was concentrated, purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by preparative thin layer column chromatography (chloroform / methanol), and the title compound (2.30) was purified. mg) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.16 (4H, m), 2.20-2.34 (2H, m), 2.62-2.73 (2H, m), 2.87 (2H, t, J = 6.8 Hz) ), 3.03-3.19 (3H, m), 3.67-3.75 (4H, m), 7.27-7.31 (1H, m), 7.46 (1H, s), 7.51-7.58 (2H, m), 7.71 (1H, d) , J = 8.0 Hz).

参考例４８の化合物（１０３ ｍｇ）に、室温で４８％臭化水素酸（１．５０ ｍＬ）を加えた。室温にて２時間撹拌後、反応混合物に４ ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、反応混合物をｐＨ７に調整後、クロロホルム／メタノール（４／１）で抽出した。有機層を無水硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮した。得られた濃縮残渣（８４．７ ｍｇ）の塩化メチレン溶液（１．２ ｍＬ）に、室温でピリジン（０．０４０１ ｍＬ）、塩化マグネシウム（２３．６ ｍｇ）、無水酢酸（０．０２５７ ｍＬ）を加えた。室温で２時間撹拌後、反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルム／メタノール（４／１）で抽出した。有機層を無水硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮した。得られた濃縮残渣（８１．７ ｍｇ）のエタノール溶液（０．７１ ｍＬ）に、室温でヒドラジン（１０．７ ｍｇ）の水溶液（０．３５５ ｍｌ）を加えた。室温で４８時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）にて精製し、表題化合物（１．１ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.01-2.14 (4H, m), 2.22-2.32 (2H, m), 2.55 (3H, s), 2.61-2.69 (2H, m), 2.92 (2H, t, J = 6.9 Hz), 3.05-3.18 (2H, m), 3.66 (2H, t, J = 6.9 Hz), 7.26-7.31 (1H, m), 7.48-7.57 (2H, m), 7.71 (1H, d, J = 7.8 Hz). Example 99
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo [4, 3-c] Pyridine-4-one

To the compound of Reference Example 48 (103 mg), 48% hydrobromic acid (1.50 mL) was added at room temperature. After stirring at room temperature for 2 hours, a 4 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, the reaction mixture was adjusted to pH 7, and then extracted with chloroform / methanol (4/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Pyridine (0.0401 mL), magnesium chloride (23.6 mg), anhydrous acetic acid (0.0257 mL) in a methylene chloride solution (1.2 mL) of the obtained concentrated residue (84.7 mg) at room temperature. Was added. After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (4/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. An aqueous solution of hydrazine (10.7 mg) (0.355 ml) was added to an ethanol solution (0.71 mL) of the obtained concentrated residue (81.7 mg) at room temperature. After stirring at room temperature for 48 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (1.1 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.14 (4H, m), 2.22-2.32 (2H, m), 2.55 (3H, s), 2.61-2.69 (2H, m), 2.92 (2H) , t, J = 6.9 Hz), 3.05-3.18 (2H, m), 3.66 (2H, t, J = 6.9 Hz), 7.26-7.31 (1H, m), 7.48-7.57 (2H, m), 7.71 ( 1H, d, J = 7.8 Hz).

参考例５１の化合物（４０１ ｍｇ）、２０％水酸化パラジウム−炭素（１．２５ ｇ）とメタノール（４．５ ｍＬ）の混合物を水素雰囲気化（１気圧）、６０℃で１．５時間撹拌した。その後、反応混合物をろ過後、ろ液を減圧濃縮した。得られた残渣（２８３ ｍｇ）、トリエチルアミン（９１５ ｍｇ）とエタノール（４．５ ｍＬ）の混合物を８０℃で７２時間撹拌した。濃縮後、反応混合物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製した。得られた精製物（１０．５ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（０．３７ ｍＬ）に、氷冷下５５％水素化ナトリウム（２．９８ ｍｇ）を加えた。氷冷下、３０分撹拌後、参考例２の化合物（１１．０ ｍｇ）とヨウ化カリウム（３．１０ ｍｇ）を加え、室温で１２時間撹拌した。その後、反応混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製した。得られた精製物をジクロロメタン（０．３７ ｍＬ）に溶解し、トリフルオロ酢酸（０．３７ ｍＬ）を加えた。混合物を室温で１時間撹拌後、反応混合物を濃縮した。その後、反応混合物を逆相液体クロマトグラフィー（水／アセトニトリル）で分離精製し、表題化合物（０．８７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.11-2.18 (2H, m), 2.63-2.84 (6H, m), 2.95 (2H, t, J = 6.6 Hz), 3.40-3.62 (6H, m), 3.73 (2H, t, J = 6.4 Hz), 7.36 (1H, dd, J = 7.1, 7.1 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.64 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz). Example 100
5- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -5,6,7,8-tetrahydroimidazole [4,5-c] azepine-4 (3H) -On

A mixture of the compound of Reference Example 51 (401 mg), 20% palladium hydroxide-carbon (1.25 g) and methanol (4.5 mL) is hydrogen-conditioned (1 atm) and stirred at 60 ° C. for 1.5 hours. did. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue (283 mg), a mixture of triethylamine (915 mg) and ethanol (4.5 mL) was stirred at 80 ° C. for 72 hours. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (chloroform / methanol). To a solution of the obtained purified product (10.5 mg) in N, N-dimethylformamide (0.37 mL) was added 55% sodium hydride (2.98 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, the compound of Reference Example 2 (11.0 mg) and potassium iodide (3.10 mg) were added, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). The resulting purified product was dissolved in dichloromethane (0.37 mL) and trifluoroacetic acid (0.37 mL) was added. The mixture was stirred at room temperature for 1 hour and the reaction mixture was concentrated. The reaction mixture was then separated and purified by reverse phase liquid chromatography (water / acetonitrile) to give the title compound (0.87 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.11-2.18 (2H, m), 2.63-2.84 (6H, m), 2.95 (2H, t, J = 6.6 Hz), 3.40-3.62 (6H, m) ), 3.73 (2H, t, J = 6.4 Hz), 7.36 (1H, dd, J = 7.1, 7.1 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.64 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz).

参考例５１の化合物（６９７ ｍｇ）、２０％水酸化パラジウム−炭素（３３１０ ｍｇ）とメタノール（７．９ ｍＬ）の混合物を水素雰囲気下（１気圧）、６０℃で１．５時間撹拌した。その後、反応混合物をろ過し、減圧濃縮した。得られた残渣（４９２ ｍｇ）、トリエチルアミン（２．１８ ｍＬ）とエタノール（７．９ ｍＬ）の混合物を７２時間加熱還流した。反応混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製した。得られた精製物（５．９ ｍｇ）をジクロロメタン（０．４２ ｍＬ）に溶解し、トリフルオロ酢酸（０．４２ ｍＬ）を添加した。この混合物を室温で３時間撹拌した。反応混合物を濃縮後、残渣をＮ，Ｎ−ジメチルホルムアミド（０．４２ｍＬ）に溶解し、０℃にて８ ｍｏｌ／Ｌ水酸化カリウム水溶液（２．８８ μＬ）、ヨードメタン（３．２７ ｍｇ）を加えた。この混合物を０℃で３時間撹拌後、濃縮した。得られた残渣（３．４７ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（０．２１ ｍＬ）に、氷冷下５５％水素化ナトリウム（１．６８ ｍｇ）を加えた。氷冷下、３０分撹拌後、参考例３の化合物（５．８４ ｍｇ）とヨウ化カリウム（１．７４ ｍｇ）を加え、室温で１２時間撹拌した。その後、反応混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（０．６４ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.00-2.14 (2H, m), 2.20-2.34 (4H, m), 2.63 (2H, t, J = 6.6 Hz), 3.05-3.19 (2H, m), 3.33-3.45 (2H, m), 3.54-3.74 (6H, m), 3.92 (3H, s), 7.26-7.32 (1H, m), 7.41 (1H, s), 7.49-7.59 (2H, m), 7.73 (1H, d, J = 8.3 Hz). Example 101
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1-methyl-5,6,7,8-tetrahydroimidazole [4,5-c ] Azepine-4 (1H) -on

A mixture of the compound of Reference Example 51 (697 mg), 20% palladium hydroxide-carbon (3310 mg) and methanol (7.9 mL) was stirred under a hydrogen atmosphere (1 atm) at 60 ° C. for 1.5 hours. Then, the reaction mixture was filtered and concentrated under reduced pressure. The resulting residue (492 mg), a mixture of triethylamine (2.18 mL) and ethanol (7.9 mL) was heated to reflux for 72 hours. The reaction mixture was concentrated and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). The resulting purified product (5.9 mg) was dissolved in dichloromethane (0.42 mL) and trifluoroacetic acid (0.42 mL) was added. The mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, the residue was dissolved in N, N-dimethylformamide (0.42 mL), and 8 mol / L potassium hydroxide aqueous solution (2.88 μL) and iodomethane (3.27 mg) were added at 0 ° C. added. The mixture was stirred at 0 ° C. for 3 hours and then concentrated. 55% sodium hydride (1.68 mg) was added to an N, N-dimethylformamide solution (0.21 mL) of the obtained residue (3.47 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, the compound of Reference Example 3 (5.84 mg) and potassium iodide (1.74 mg) were added, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.64 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.14 (2H, m), 2.20-2.34 (4H, m), 2.63 (2H, t, J = 6.6 Hz), 3.05-3.19 (2H, m) ), 3.33-3.45 (2H, m), 3.54-3.74 (6H, m), 3.92 (3H, s), 7.26-7.32 (1H, m), 7.41 (1H, s), 7.49-7.59 (2H, m) ), 7.73 (1H, d, J = 8.3 Hz).

実施例６２の化合物（２４．０ ｍｇ）のＮ，Ｎ―ジメチルホルムアミド溶液（０．２５ ｍＬ）に、室温でシアノ化亜鉛（２５．１ ｍｇ）、テトラキストリフェニルホスフィンパラジウム（１１．７ ｍｇ）を加えた。１００℃にて１．５時間撹拌後、反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（９．５ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.66-2.71 (6H, m), 3.01 (2H, t, J = 6.6 Hz), 3.44-3.48 (4H, m), 3.65-3.74 (4H, m), 7.29 (1H, dd, J = 8.0, 7.1 Hz), 7.40 (1H, dd, J = 8.0, 7.1 Hz), 7.49 (1H, s), 7.74 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 9.19 (1H, s). Example 102
7- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -8-oxo-5,6,7,8-tetrahydro-2,7-naphthylidine- 3-Carbonitrile

Zinc cyanide (25.1 mg) and tetrakistriphenylphosphine palladium (11.7 mg) in an N, N-dimethylformamide solution (0.25 mL) of the compound of Example 62 (24.0 mg) at room temperature. Was added. After stirring at 100 ° C. for 1.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (9.5 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.66-2.71 (6H, m), 3.01 (2H, t, J = 6.6 Hz), 3.44-3.48 (4H, m), 3.65-3.74 (4H, m) ), 7.29 (1H, dd, J = 8.0, 7.1 Hz), 7.40 (1H, dd, J = 8.0, 7.1 Hz), 7.49 (1H, s), 7.74 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 9.19 (1H, s).

参考例４７の化合物（７５．０ ｍｇ）のＮ−メチルピロリドン溶液（０．５３ ｍＬ）に、２，２−ジメトキシ−Ｎ−メチルエタン−１−アミン（２５１ ｍｇ）、メタンスルホン酸（２７．４ μＬ）と硫酸マグネシウム（１５２ ｍｇ）を加え、１１０℃で１時間攪拌した。その後、１５０℃で２時間攪拌し、反応混合物に１０％水酸化ナトリウム水溶液を反応混合物ｐＨが９以上になるまで加え、クロロホルムで抽出した。有機層を合わせ無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣に酢酸エチル／ヘキサン（２／１）を加え、水で洗浄した。水層を合わせ、酢酸エチル／ヘキサン（２／１）で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をアミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製した。得られた固体に酢酸エチル（０．９１ ｍＬ）を加え、７０℃ですべて溶解したことを確認後、徐々に室温に冷却し、固体の析出を確認後、氷冷下で２時間攪拌後、ろ取し、０℃で冷却した酢酸エチルで洗浄し、減圧乾燥することで、表題化合物（４６．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.98-2.18 (6H, m), 2.18-2.29 (2H, m), 2.61 (2H, t, J = 6.7 Hz), 2.77 (2H, t, J = 7.0 Hz), 3.01-3.14 (3H, m), 3.43-3.51 (5H, m), 3.69 (2H, t, J = 6.7 Hz), 6.54 (1H, d, J = 2.4 Hz), 6.67 (1H, d, J = 2.4 Hz), 7.24-7.30 (1H, m), 7.47-7.56 (2H, m), 7.71 (1H, d, J = 7.9 Hz). Example 103
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1-methyl-5,6,7,8-tetrahydropyrro [3,2-c ] Azepine-4 (1H) -on

Reference Example 47 compound (75.0 mg) in N-methylpyrrolidone solution (0.53 mL), 2,2-dimethoxy-N-methylethane-1-amine (251 mg), methanesulfonic acid (27.4 mg). μL) and magnesium sulfate (152 mg) were added, and the mixture was stirred at 110 ° C. for 1 hour. Then, the mixture was stirred at 150 ° C. for 2 hours, a 10% aqueous sodium hydroxide solution was added to the reaction mixture until the pH of the reaction mixture became 9 or more, and the mixture was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Ethyl acetate / hexane (2/1) was added to the residue, and the mixture was washed with water. The aqueous layers were combined and extracted with ethyl acetate / hexane (2/1). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by amino silica gel column chromatography (hexane / ethyl acetate). Ethyl acetate (0.91 mL) was added to the obtained solid, and after confirming that it was completely dissolved at 70 ° C., the mixture was gradually cooled to room temperature, and after confirming the precipitation of the solid, stirring under ice cooling for 2 hours was performed. The mixture was collected by filtration, washed with ethyl acetate cooled at 0 ° C., and dried under reduced pressure to give the title compound (46.0 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.98-2.18 (6H, m), 2.18-2.29 (2H, m), 2.61 (2H, t, J = 6.7 Hz), 2.77 (2H, t, J) = 7.0 Hz), 3.01-3.14 (3H, m), 3.43-3.51 (5H, m), 3.69 (2H, t, J = 6.7 Hz), 6.54 (1H, d, J = 2.4 Hz), 6.67 (1H) , d, J = 2.4 Hz), 7.24-7.30 (1H, m), 7.47-7.56 (2H, m), 7.71 (1H, d, J = 7.9 Hz).

実施例６２の化合物（１１４ ｍｇ）のテトラヒドロフラン溶液（６．０ ｍＬ）に、室温で１．１ ｍｏｌ／Ｌ ジエチル亜鉛−ヘキサン溶液（０．３２９ ｍＬ）、[１，１’−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物（１７．７ ｍｇ）を加えた。７０℃にて２時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）にて精製し、表題化合物（６２．３ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.24 (3H, t, J = 7.6 Hz), 2.66 (3H, t, J = 6.4 Hz), 2.67-2.71 (4H, m), 2.77 (2H, q, J = 7.6 Hz), 2.90 (2H, t, J = 6.6 Hz), 3.44-3.47 (4H, m), 3.60 (2H, t, J = 6.6 Hz), 3.67 (2H, t, J = 6.6 Hz), 6.91 (1H, s), 7.28 (1H, dd, J = 8.3, 8.3 Hz), 7.39 (1H, dd, J = 8.3, 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 8.3 Hz), 9.04 (1H, s). Example 104
2- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -6-ethyl-3,4-dihydro-2,7-naphthylidine-1 (2H) − On

In a tetrahydrofuran solution (6.0 mL) of the compound (114 mg) of Example 62, a 1.1 mol / L diethylzinc-hexane solution (0.329 mL) at room temperature, [1,1'-bis (diphenylphos). Fino) ferrocene] palladium (II) dichloride dichloromethane adduct (17.7 mg) was added. After stirring at 70 ° C. for 2 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (62.3 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.6 Hz), 2.66 (3H, t, J = 6.4 Hz), 2.67-2.71 (4H, m), 2.77 (2H, 2H, q, J = 7.6 Hz), 2.90 (2H, t, J = 6.6 Hz), 3.44-3.47 (4H, m), 3.60 (2H, t, J = 6.6 Hz), 3.67 (2H, t, J = 6.6) Hz), 6.91 (1H, s), 7.28 (1H, dd, J = 8.3, 8.3 Hz), 7.39 (1H, dd, J = 8.3, 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 8.3 Hz), 9.04 (1H, s).

実施例６９の化合物（６２．０ ｍｇ）のＮ，Ｎ―ジメチルホルムアミド溶液（０．５０ ｍＬ）に、室温で炭酸カリウム（５４．１ ｍｇ）、トリメチルボロキシン（０．０５００ ｍＬ）、テトラキストリフェニルホスフィンパラジウム（１５．１ ｍｇ）を加えた。マイクロウェーブ照射下１５０℃にて撹拌後、反応混合物をセライトろ過し、ろ液を減圧濃縮した。残渣を逆相液体クロマトグラフィー（アセトニトリル／水、０．０５％トリフルオロ酢酸含）にて精製し、表題化合物（１２．３ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.44 (3H, s), 2.65 (2H, t, J = 6.6 Hz), 2.74 (4H, t, J = 5.0 Hz), 2.85 (2H, t, J = 6.9 Hz), 3.51 (4H, t, J = 5.0 Hz), 3.63 (2H, t, J = 6.6 Hz), 3.68 (2H, d J = 6.9 Hz), 3.70 (3H, s), 7.31-7.35 (1H, ddd, J = 8.3, 7.8 0.9 Hz), 7.44 (1H, ddd, J =7.8, 7.8, 0.9 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 8.3 Hz). Example 105
5- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -1,3-dimethyl-1,5,6,7-tetrahydro-4H-pyrazolo [ 4,3-c] Pyridine-4-one

Potassium carbonate (54.1 mg), trimethylboroxin (0.0500 mL), tetrakistri in an N, N-dimethylformamide solution (0.50 mL) of the compound of Example 69 (62.0 mg) at room temperature. Phenylphosphine palladium (15.1 mg) was added. After stirring at 150 ° C. under microwave irradiation, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase liquid chromatography (acetonitrile / water, containing 0.05% trifluoroacetic acid) to give the title compound (12.3 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.44 (3H, s), 2.65 (2H, t, J = 6.6 Hz), 2.74 (4H, t, J = 5.0 Hz), 2.85 (2H, t, J = 6.9 Hz), 3.51 (4H, t, J = 5.0 Hz), 3.63 (2H, t, J = 6.6 Hz), 3.68 (2H, d J = 6.9 Hz), 3.70 (3H, s), 7.31- 7.35 (1H, ddd, J = 8.3, 7.8 0.9 Hz), 7.44 (1H, ddd, J = 7.8, 7.8, 0.9 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J) = 8.3 Hz).

実施例７３の化合物（１４．０ ｍｇ）のメタノール溶液（１．０ ｍＬ）に、室温でナトリウムメトキシド（１５．９ ｍｇ）を加えた。１２０℃にて５時間撹拌後、反応混合物を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（２．１ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.67 (2H, t, J = 6.6 Hz), 2.76 (4H, t, J = 4.8 Hz), 2.83 (2H, t, J = 6.6 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.61 (3H, s), 3.62 (2H, J = 6.6 Hz), 3.67 (2H, J = 6.6 Hz), 4.34 (3H, s), 7.35 (1H, dd, J = 7.6, 7.6 Hz), 7.46 (1H, dd, J = 7.6, 7.6 Hz), 7.81 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 7.6 Hz). Example 106
5- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -3-methoxy-2-methyl-2,5,6,7-tetrahydro-4H- Pyrazolo [4,3-c] Pyridine-4-one

Sodium methoxide (15.9 mg) was added to a methanol solution (1.0 mL) of compound (14.0 mg) of Example 73 at room temperature. After stirring at 120 ° C. for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.1 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.67 (2H, t, J = 6.6 Hz), 2.76 (4H, t, J = 4.8 Hz), 2.83 (2H, t, J = 6.6 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.61 (3H, s), 3.62 (2H, J = 6.6 Hz), 3.67 (2H, J = 6.6 Hz), 4.34 (3H, s), 7.35 (1H, dd) , J = 7.6, 7.6 Hz), 7.46 (1H, dd, J = 7.6, 7.6 Hz), 7.81 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 7.6 Hz).

実施例６２の化合物（６０．０ ｍｇ）の重メタノール溶液（０．５０ ｍＬ）に、氷冷下５５％水素化ナトリウム（１６．６ ｍｇ）を加えた。８０℃にて４時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（３２．２ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J = 4.8 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.60 (2H, s), 3.71 (2H, t, J = 6.4 Hz), 6.49 (1H, s), 7.33 (1H, 1H, dd, J = 8.3, 8.3 Hz), 7.44 (1H, dd, J = 8.3, 8.3 Hz), 7.78 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 8.79 (1H, s). Example 107
2- {2- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] _{^{ethyl} -6 - [(2 H 3}} ) methyloxy] ^(4,4-2 H ₂₎ -3,4-dihydro-2,7-naphthylidine-1 (2H) -on

55% sodium hydride (16.6 mg) was added to a deuterated methanol solution (0.50 mL) of the compound of Example 62 (60.0 mg) under ice-cooling. After stirring at 80 ° C. for 4 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (32.2 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J = 4.8 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.60 (2H, s), 3.71 (2H, t, J = 6.4 Hz), 6.49 (1H, s), 7.33 (1H, 1H, dd, J = 8.3, 8.3 Hz), 7.44 (1H, dd, J = 8.3) , 8.3 Hz), 7.78 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 8.79 (1H, s).

実施例６２の化合物（８４．０ ｍｇ）の１，２−ジメトキシエタン溶液（１．６ ｍＬ）に、室温で炭酸カリウム（９８．０ ｍｇ）、トリメチルボロキシン（０．０８２０ ｍＬ）、テトラキストリフェニルホスフィンパラジウム（４１．１ ｍｇ）を加えた。マイクロウェーブ照射下１００℃にて３時間撹拌後、反応混合物をセライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）にて精製し、表題化合物（７．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.56 (3H, s), 2.71 (2H, t, J = 6.6 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.94 (2H, t, J = 6.6 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.6 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.96 (1H, s), 7.32-7.36 (1H, m), 7.43-7.47 (1H, m), 7.79 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 9.06 (1H, s). Example 108
2- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -6-methyl-3,4-dihydro-2,7-naphthylidine-1 (2H) − On

Potassium carbonate (98.0 mg), trimethylboroxin (0.0820 mL), tetrakistri in a 1,2-dimethoxyethane solution (1.6 mL) of the compound of Example 62 (84.0 mg) at room temperature. Phenylphosphine palladium (41.1 mg) was added. After stirring at 100 ° C. for 3 hours under microwave irradiation, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (7.0 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.56 (3H, s), 2.71 (2H, t, J = 6.6 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.94 (2H, t, J = 6.6 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.6 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.96 (1H, s), 7.32 -7.36 (1H, m), 7.43-7.47 (1H, m), 7.79 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 9.06 (1H, s).

参考例４９の化合物（０．７９０ ｇ）、硫酸ナトリウム（８．００ ｇ）とｐ−トルエンスルホン酸一水和物（０．４２２ ｇ）を２，２−ジメトキシ−Ｎ−メチルエタナミン（２５ ｍＬ）に溶解させ、１５０℃で１２時間攪拌した。その後、反応混合液をセライトろ過しクロロホルムで洗浄した。ろ液に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出し、有機層を硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、逆相精製を行うことで、表題化合物（０．１６１ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.15-2.16 (2H, m), 2.66 (2H, t, J = 6.6 Hz), 2.74 (4H, t, J = 5.0 Hz), 2.79 (2H, t, J = 6.9 Hz), 3.48-3.49 (2H, m), 3.50 (3H, s), 3.56 (4H, t, J = 5.0 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.56 (1H, d, J = 3.2 Hz), 6.68 (1H, d, J = 2.8 Hz), 7.21 (1H, ddd, J = 8.3, 8.0, 0.9 Hz), 7.43-7.48 (2H, m), 7.69 (1H, d, J = 8.3 Hz). Example 109
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -1-methyl-5,6,7,8-tetrahydropyrro [3,2-c ] Azepine-4 (1H) -on

The compound of Reference Example 49 (0.790 g), sodium sulfate (8.00 g) and p-toluenesulfonic acid monohydrate (0.422 g) were added to 2,2-dimethoxy-N-methylethanamine (25). It was dissolved in mL) and stirred at 150 ° C. for 12 hours. Then, the reaction mixture was filtered through Celite and washed with chloroform. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, the mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) and subjected to reverse phase purification to give the title compound (0.161 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.16 (2H, m), 2.66 (2H, t, J = 6.6 Hz), 2.74 (4H, t, J = 5.0 Hz), 2.79 (2H, 2H, t, J = 6.9 Hz), 3.48-3.49 (2H, m), 3.50 (3H, s), 3.56 (4H, t, J = 5.0 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.56 ( 1H, d, J = 3.2 Hz), 6.68 (1H, d, J = 2.8 Hz), 7.21 (1H, ddd, J = 8.3, 8.0, 0.9 Hz), 7.43-7.48 (2H, m), 7.69 (1H) , d, J = 8.3 Hz).

参考例５３の化合物（７０．０ ｍｇ）、参考例５２の化合物（８６．０ ｍｇ）、トリエチルアミン（０．０８２ ｍＬ）とジクロロメタン（２．０ ｍＬ）の混合物に水素化トリアセトキシホウ素ナトリウム（７８．０ ｍｇ）を加え、室温で１時間攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（２．２０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.72-2.81 (6H, m), 3.11 (2H, t, J = 6.4 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.72-3.81 (4H, m), 7.36 (1H, dd, J = 7.3, 7.3 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.54 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 9.29 (1H, s). Example 110
2- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -6- (trifluoromethyl) -3,4-dihydro-2,7-naphthylidine- 1 (2H) -on

Sodium borohydride (78) in a mixture of the compound of Reference Example 53 (70.0 mg), the compound of Reference Example 52 (86.0 mg), triethylamine (0.082 mL) and dichloromethane (2.0 mL). .0 mg) was added, and the mixture was stirred at room temperature for 1 hour. Then, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.20 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.72-2.81 (6H, m), 3.11 (2H, t, J = 6.4 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.72-3.81 ( 4H, m), 7.36 (1H, dd, J = 7.3, 7.3 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.54 (1H, s), 7.81 (1H, d, J = 8.3 Hz) ), 7.90 (1H, d, J = 8.3 Hz), 9.29 (1H, s).

オキセタン−３−オール（８３．０ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（０．２１ ｍＬ）に、氷冷下５５％水素化ナトリウム（３６．９ ｍｇ）を加えた。室温で１５分間撹拌後、反応混合物に実施例６２の化合物（５０．０ ｍｇ）を加えた。８０℃にて１時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）にて精製し、表題化合物（１１．４ ｍｇ）を得た。
¹H-NMR (400 MHz,CDCl₃) δ: 2.72 (2H, t, J = 6.6 Hz), 2.77 (4H, t, J = 4.6 Hz), 2.96 (2H, t, J = 6.6 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.64 (2H, t, J = 6.6 Hz), 3.73 (2H, t, J = 6.6 Hz), 4.71 (2H, dd, J = 8.0, 5.3 Hz), 5.00 (2H, t, J = 7.3 Hz), 5.63-5.69 (1H, m), 6.58 (1H, s), 7.36 (1H, dd, J = 8.3, 8.3 Hz), 7.47 (1H, ddd, J = 8.3, 8.3, 0.9 Hz), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 8.71 (1H, s). Example 111
2- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -6-[(oxetane-3-yl) oxy] -3,4-dihydro-2 , 7-naphthylidine-1 (2H) -on

55% sodium hydride (36.9 mg) was added to N, N-dimethylformamide (0.21 mL) of oxetane-3-ol (83.0 mg) under ice-cooling. After stirring at room temperature for 15 minutes, the compound of Example 62 (50.0 mg) was added to the reaction mixture. After stirring at 80 ° C. for 1 hour, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (11.4 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.72 (2H, t, J = 6.6 Hz), 2.77 (4H, t, J = 4.6 Hz), 2.96 (2H, t, J = 6.6 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.64 (2H, t, J = 6.6 Hz), 3.73 (2H, t, J = 6.6 Hz), 4.71 (2H, dd, J = 8.0, 5.3 Hz), 5.00 (2H, t, J = 7.3 Hz), 5.63-5.69 (1H, m), 6.58 (1H, s), 7.36 (1H, dd, J = 8.3, 8.3 Hz), 7.47 (1H, ddd, J = 8.3) , 8.3, 0.9 Hz), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 8.71 (1H, s).

実施例６１の化合物（２８６ ｍｇ）のメタノール溶液（３．６ ｍＬ）にフマル酸（８４．０ ｍｇ）を加え、室温で２時間攪拌した。その後、析出した固体をろ取することで、固体（３００ ｍｇ）を得た。得られた固体（３００ ｍｇ）、Ｎ−フルオロベンゼンスルホンイミド（３７０ ｍｇ）とアセトニトリル（２．９ ｍＬ）の混合物を室温で１．５時間攪拌した。反応混合物を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、さらに、分取薄層クロマトグラフィー（クロロホルム／メタノール）で分離精製することで、表題化合物（３．７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.67 (2H, t, J = 6.6 Hz), 2.72-2.79 (6H, m), 3.41 (3H, s), 3.54 (4H, t, J = 4.8 Hz), 3.61-3.74 (4H, m), 5.86 (1H, d, J = 4.1 Hz), 7.36 (1H, dd, J = 7.6, 7.6 Hz), 7.47 (1H, dd, J = 7.3, 7.3 Hz), 7.81 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 8.3 Hz). Example 112
5- {2- [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] ethyl} -2-fluoro-1-methyl-1,5,6,7-tetrahydro-4H- Pyrrolo [3,2-c] Pyridine-4-one

Fumaric acid (84.0 mg) was added to a methanol solution (3.6 mL) of the compound (286 mg) of Example 61, and the mixture was stirred at room temperature for 2 hours. Then, the precipitated solid was collected by filtration to obtain a solid (300 mg). The resulting solid (300 mg), a mixture of N-fluorobenzenesulfonimide (370 mg) and acetonitrile (2.9 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, the obtained residue was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by preparative thin layer chromatography (chloroform / methanol) to give the title compound (3.7). mg) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.67 (2H, t, J = 6.6 Hz), 2.72-2.79 (6H, m), 3.41 (3H, s), 3.54 (4H, t, J = 4.8) Hz), 3.61-3.74 (4H, m), 5.86 (1H, d, J = 4.1 Hz), 7.36 (1H, dd, J = 7.6, 7.6 Hz), 7.47 (1H, dd, J = 7.3, 7.3 Hz) ), 7.81 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 8.3 Hz).

実施例３の化合物（１０４ｍｇ）の１，４−ジオキサン溶液（１．０ｍＬ）に、２，３−ジクロロ−５，６−ジシアノ−ｐ−ベンゾキノン（６０．３ｍｇ）を加えた。１００℃で１時間攪拌後、反応混合物へ飽和炭酸水素ナトリウム水溶液を加え、ろ過した後、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、さらに、アミノシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で分離精製し、表題化合物（１０．５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.64 (3H, s), 2.73 (4H, t, J = 4.9 Hz), 2.81 (2H, t, J = 6.4 Hz), 3.54 (4H, t, J = 4.9 Hz), 4.13 (2H, t, J = 6.4 Hz), 6.34 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.17-7.22 (1H, m), 7.27 (1H, d, J = 7.3 Hz), 7.41-7.50 (2H, m), 7.64 (1H, d, J = 7.9 Hz), 9.49 (1H, s). Example 113
2- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -6-methyl-2,7-naphthylidine-1 (2H) -one

2,3-Dichloro-5,6-dicyano-p-benzoquinone (60.3 mg) was added to a 1,4-dioxane solution (1.0 mL) of the compound of Example 3 (104 mg). After stirring at 100 ° C. for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was filtered, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by amino silica gel column chromatography (ethyl acetate / methanol) to give the title compound (10.5 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.64 (3H, s), 2.73 (4H, t, J = 4.9 Hz), 2.81 (2H, t, J = 6.4 Hz), 3.54 (4H, t, J = 4.9 Hz), 4.13 (2H, t, J = 6.4 Hz), 6.34 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.17-7.22 (1H, m), 7.27 (1H, 1H, d, J = 7.3 Hz), 7.41-7.50 (2H, m), 7.64 (1H, d, J = 7.9 Hz), 9.49 (1H, s).

実施例１と同様の手法により、参考例３の化合物と２，４−ジメチル−ピリド［４，３−ｄ］ピリミジン−５（６Ｈ）−オンより表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.95-2.08 (4H, m), 2.25-2.35 (2H, m), 2.69 (3H, s), 2.72 (2H, t, J = 6.1 Hz), 2.98 (3H, s), 2.99-3.10 (3H, m), 4.05 (2H, t, J = 6.4 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (3H, m), 7.63 (1H, d, J = 7.9 Hz). Example 114
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2,4-dimethylpyrido [4,3-d] pyrimidine-5 (6H) -one

The title compound was obtained from the compound of Reference Example 3 and 2,4-dimethyl-pyrido [4,3-d] pyrimidin-5 (6H) -one by the same method as in Example 1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.95-2.08 (4H, m), 2.25-2.35 (2H, m), 2.69 (3H, s), 2.72 (2H, t, J = 6.1 Hz), 2.98 (3H, s), 2.99-3.10 (3H, m), 4.05 (2H, t, J = 6.4 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44 -7.52 (3H, m), 7.63 (1H, d, J = 7.9 Hz).

Examples 115-139
According to the method described in Example 3, the compounds of Examples 115 to 139 were obtained from the corresponding compounds of the reference example.

Examples 140-152
According to the method described in Example 22, the compounds of Examples 140 to 152 were obtained from the corresponding compounds of the reference example.

実施例３２に記載の方法に準じ、対応する参考例の化合物より、表題化合物を得た。
LC-MS: R.T. = 1.22 min, ObsMS = 379 [M+1] Example 153
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} -7,8-dihydro-1,6-naphthalidine-5 (6H) -one

The title compound was obtained from the corresponding reference compound according to the method described in Example 32.
LC-MS: RT = 1.22 min, ObsMS = 379 [M + 1]

Examples 154 to 175
According to the method described in Example 37, the compounds of Examples 154 to 175 were obtained from the corresponding compounds of the reference example.

Examples 176-179
According to the method described in Example 88, the compounds of Examples 176 to 179 were obtained from the corresponding compounds of the reference example.

Examples 180-182
According to the method described in Example 93, the compounds of Examples 180 to 182 were obtained from the corresponding compounds of the reference example.

Examples 183 to 185
According to the method described in Example 108, the compounds of Examples 183 to 185 were obtained from the corresponding compounds of Example 144 or Example 146.

Examples 186-187
According to the method described in Example 106, the compounds of Examples 186 to 187 were obtained from the corresponding compounds of Example 144 or Example 146.

実施例１４６の化合物（１０．０ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（０．５ ｍＬ）にフッ化セシウム（１８．５ ｍｇ）を加えた。マイクロウェーブ照射下、２００℃で２時間攪拌後、反応混合物に水を加え、クロロホルムで抽出し、合わせた有機層を濃縮した。濃縮残渣を分取薄層クロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１．６ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.99-2.16 (4H, m), 2.29 (2H, t, J = 11.5 Hz), 2.73 (2H, t, J = 6.2 Hz), 3.05 (2H, t, J = 6.6 Hz), 3.09-3.18 (3H, m), 3.73 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.2 Hz), 7.02 (1H, dd, J = 8.3, 3.2 Hz), 7.28-7.33 (1H, m), 7.51-7.59 (2H, m), 7.66-7.74 (2H, m). Example 188
7- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2-fluoro-6,7-dihydro-1,7-naphthylidine-8 (5H) − On

Cesium fluoride (18.5 mg) was added to an N, N-dimethylformamide solution (0.5 mL) of the compound of Example 146 (10.0 mg). After stirring at 200 ° C. for 2 hours under microwave irradiation, water was added to the reaction mixture, the mixture was extracted with chloroform, and the combined organic layer was concentrated. The concentrated residue was separated and purified by preparative thin layer chromatography (chloroform / methanol) to give the title compound (1.6 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.16 (4H, m), 2.29 (2H, t, J = 11.5 Hz), 2.73 (2H, t, J = 6.2 Hz), 3.05 (2H, 2H, t, J = 6.6 Hz), 3.09-3.18 (3H, m), 3.73 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.2 Hz), 7.02 (1H, dd, J = 8.3) , 3.2 Hz), 7.28-7.33 (1H, m), 7.51-7.59 (2H, m), 7.66-7.74 (2H, m).

参考例５４の化合物（２１０ ｍｇ）のテトラヒドロフラン溶液（６．０ ｍＬ）に５ ｍｏｌ／Ｌ 塩酸（１．２ ｍＬ）を加え、室温で６時間攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製後、さらに、逆相液体クロマトグラフィー（アセトニトリル／水、０．０５％トリフルオロ酢酸含）にて精製し、表題化合物（９６．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.99-2.12 (4H, m), 2.19-2.31 (2H, m), 2.65 (2H, t, J = 6.6 Hz), 2.98 (2H, t, J = 6.7 Hz), 3.04-3.18 (3H, m), 3.64-3.73 (4H, m), 7.24-7.28 (1H, m), 7.48-7.56 (2H, m), 7.69 (1H, d, J = 8.0 Hz), 7.95 (1H, s). Example 189
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] Pyridine-4-one

5 mol / L hydrochloric acid (1.2 mL) was added to a tetrahydrofuran solution (6.0 mL) of the compound (210 mg) of Reference Example 54, and the mixture was stirred at room temperature for 6 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by amino silica gel column chromatography (chloroform / methanol) and then further purified by reverse phase liquid chromatography (acetonitrile / water, including 0.05% trifluoroacetic acid), and the title compound (96.0 mg) was purified. ) Was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.12 (4H, m), 2.19-2.31 (2H, m), 2.65 (2H, t, J = 6.6 Hz), 2.98 (2H, t, J) = 6.7 Hz), 3.04-3.18 (3H, m), 3.64-3.73 (4H, m), 7.24-7.28 (1H, m), 7.48-7.56 (2H, m), 7.69 (1H, d, J = 8.0) Hz), 7.95 (1H, s).

実施例１１０および参考例５２と同様の手法により、３−（ピペリジン−４−イル）ベンゾ［ｄ］イソオキサゾール塩酸塩から表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.92-2.09 (4H, m), 2.14-2.24 (2H, m), 2.59 (2H, t, J = 6.4 Hz), 2.98-3.09 (5H, m), 3.61 (2H, t, J = 6.4 Hz), 3.76 (2H, t, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.77 (1H, s). Example 190
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine- 4 (5H) -on

The title compound was obtained from 3- (piperidine-4-yl) benzo [d] isooxazole hydrochloride by the same procedure as in Example 110 and Reference Example 52.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-2.09 (4H, m), 2.14-2.24 (2H, m), 2.59 (2H, t, J = 6.4 Hz), 2.98-3.09 (5H, m) ), 3.61 (2H, t, J = 6.4 Hz), 3.76 (2H, t, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.77 (1H, s).

６，７−ジヒドロ−３Ｈ−イミダゾ［４，５−ｃ］ピリジン−４（５Ｈ）−オン（７８．５ ｍｇ）のテトラヒドロフラン溶液（２．０ ｍＬ）にジ−ｔｅｒｔ−ブチルジカーボネイト（１８７ ｍｇ）を加えた。室温で２４時間攪拌後、反応混合物を濃縮し、得られた残渣をシリカゲルクロマトグラフィー（クロロホルム／メタノール）で分離精製した。得られた固体（１７．０ ｍｇ）と参考例３の化合物（１９．９ ｍｇ）のトルエン溶液（０．４ ｍＬ）にテトラブチルアンモニウムブロマイド（７．６２ ｍｇ）と水酸化カリウム（６．０３ ｍｇ）を加え、室温で６時間攪拌した。その後、４ ｍｏｌ／Ｌ 塩酸−酢酸エチル（０．５ ｍＬ）を加えた。室温で２４時間攪拌後、反応混合物をアミノシリカゲルカラムクロマトグラフィーおよびシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１４．４ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 2.01-2.13 (4H, m), 2.25-2.37 (2H, m), 2.80 (2H, t, J = 6.4 Hz), 2.94 (2H, t, J = 7.0 Hz), 3.00-3.16 (3H, m), 3.61 (2H, td, J = 7.1, 2.6 Hz), 4.44 (2H, t, J = 6.3 Hz), 5.23 (1H, s), 7.26-7.32 (1H, m), 7.50-7.59 (2H, m), 7.63 (1H, s), 7.73 (1H, d, J = 7.9 Hz). Example 191
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -6,7-dihydro [1,3] imidazolo [4,5-c] pyridine- 4 (5H) -on

Di-tert-butyl dicarbonate (187 mg) in tetrahydrofuran solution (2.0 mL) of 6,7-dihydro-3H-imidazole [4,5-c] pyridine-4 (5H) -one (78.5 mg). ) Was added. After stirring at room temperature for 24 hours, the reaction mixture was concentrated, and the obtained residue was separated and purified by silica gel chromatography (chloroform / methanol). Tetrabutylammonium bromide (7.62 mg) and potassium hydroxide (6.03) were added to a toluene solution (0.4 mL) of the obtained solid (17.0 mg) and the compound of Reference Example 3 (19.9 mg). mg) was added, and the mixture was stirred at room temperature for 6 hours. Then 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added. After stirring at room temperature for 24 hours, the reaction mixture was separated and purified by amino silica gel column chromatography and silica gel column chromatography (chloroform / methanol) to give the title compound (14.4 mg).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.01-2.13 (4H, m), 2.25-2.37 (2H, m), 2.80 (2H, t, J = 6.4 Hz), 2.94 (2H, t, J) = 7.0 Hz), 3.00-3.16 (3H, m), 3.61 (2H, td, J = 7.1, 2.6 Hz), 4.44 (2H, t, J = 6.3 Hz), 5.23 (1H, s), 7.26-7.32 (1H, m), 7.50-7.59 (2H, m), 7.63 (1H, s), 7.73 (1H, d, J = 7.9 Hz).

５５％水素化ナトリウム（３１．６ ｍｇ）のＮ，Ｎ−ジメチルホルムアミド懸濁液（１．３ ｍＬ）に、３−ブロモ−１−（４−メトキシベンジル）−６，７−ジヒドロ−１Ｈ−ピラゾロ［４，３−ｃ］ピリジン−４（５Ｈ）−オン（１７７ ｍｇ）を氷冷下で加えた。氷冷下１時間攪拌後、ヨウ化カリウム（４３．７ ｍｇ）と参考例３の化合物（１４６ ｍｇ）を加え、室温で７２時間攪拌した。その後、反応混合物に水（３０ ｍＬ）を加え、クロロホルム（３０ ｍＬ×２）で抽出後、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で分離精製した。得られた生成物にトリフルオロ酢酸（１．０ ｍＬ）を加え、７５℃で２時間攪拌した。その後、反応混合物をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（４７．８ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.99-2.14 (4H, m), 2.24-2.32 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 3.02 (2H, t, J = 6.6 Hz), 3.06-3.14 (1H, m), 3.14-3.21 (2H, m), 3.65-3.73 (4H, m), 7.27-7.31 (1H, m), 7.50-7.58 (2H, m), 7.70 (1H, d, J = 7.8 Hz). Example 192
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -3-bromo-1,5,6,7-tetrahydro-4H-pyrazolo [4, 3-c] Pyridine-4-one

3-Bromo-1- (4-methoxybenzyl) -6,7-dihydro-1H- in an N, N-dimethylformamide suspension (1.3 mL) of 55% sodium hydride (31.6 mg). Pyrazolo [4,3-c] pyridine-4 (5H) -one (177 mg) was added under ice-cooling. After stirring under ice-cooling for 1 hour, potassium iodide (43.7 mg) and the compound of Reference Example 3 (146 mg) were added, and the mixture was stirred at room temperature for 72 hours. Then, water (30 mL) was added to the reaction mixture, the mixture was extracted with chloroform (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (ethyl acetate). Trifluoroacetic acid (1.0 mL) was added to the obtained product, and the mixture was stirred at 75 ° C. for 2 hours. Then, the reaction mixture was separated and purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (47.8 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.14 (4H, m), 2.24-2.32 (2H, m), 2.68 (2H, t, J = 6.4 Hz), 3.02 (2H, t, J) = 6.6 Hz), 3.06-3.14 (1H, m), 3.14-3.21 (2H, m), 3.65-3.73 (4H, m), 7.27-7.31 (1H, m), 7.50-7.58 (2H, m), 7.70 (1H, d, J = 7.8 Hz).

実施例１７９の化合物（１００ ｍｇ）の１，４−ジオキサン溶液（０．７ ｍＬ）にジメチルジオキシラン（３７．８ ｍｇ）を加えた。１００℃で２時間攪拌後、反応混合物に飽和炭酸水素ナトリウム水溶液（３０ ｍＬ）を加え、クロロホルム（３０ ｍＬ×２）で抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製後、さらに、分取薄層カラムクロマトグラフィー（酢酸エチル／メタノール）で分離精製し、表題化合物（８．１０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.67 (4H, t, J = 4.9 Hz), 2.74 (2H, t, J = 6.1 Hz), 2.77 (3H, s), 3.49 (4H, t, J = 4.9 Hz), 4.08 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 7.12-7.17 (1H, m), 7.36-7.44 (2H, m), 7.47 (1H, d, J = 7.3 Hz), 7.60 (1H, d, J = 8.5 Hz), 9.49 (1H, s). Example 193
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperazin-1-yl] ethyl} -2-methylpyrido [4,3-d] pyrimidine-5 (6H) -one

Dimethyldioxirane (37.8 mg) was added to a 1,4-dioxane solution (0.7 mL) of compound (100 mg) of Example 179. After stirring at 100 ° C. for 2 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, the mixture was extracted with chloroform (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by preparative thin layer column chromatography (ethyl acetate / methanol) to give the title compound (8.10 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.67 (4H, t, J = 4.9 Hz), 2.74 (2H, t, J = 6.1 Hz), 2.77 (3H, s), 3.49 (4H, t, J = 4.9 Hz), 4.08 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 7.12-7.17 (1H, m), 7.36-7.44 (2H, m), 7.47 ( 1H, d, J = 7.3 Hz), 7.60 (1H, d, J = 8.5 Hz), 9.49 (1H, s).

実施例１９３と同様の手法により、実施例１５０の化合物から表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.91-2.08 (4H, m), 2.22-2.32 (2H, m), 2.71 (2H, t, J = 6.1 Hz), 2.77 (3H, s), 2.95-3.08 (3H, m), 4.06 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (3H, m), 7.62 (1H, d, J = 7.9 Hz), 9.49 (1H, s). Example 194
6- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2-methylpyrido [4,3-d] pyrimidine-5 (6H) -one

The title compound was obtained from the compound of Example 150 by the same method as in Example 193.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-2.08 (4H, m), 2.22-2.32 (2H, m), 2.71 (2H, t, J = 6.1 Hz), 2.77 (3H, s), 2.95-3.08 (3H, m), 4.06 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (3H, m) , 7.62 (1H, d, J = 7.9 Hz), 9.49 (1H, s).

Example 195
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo [ 4,3-c] Pyridine-4-one form B
A suspension of the compound of Example 37 (10.0 mg) and water (100 μL) was shaken at room temperature for 2 weeks. Then, the solid was collected by filtration to obtain the title compound.
Powder XRD (°, 2θ ± 0.2)
4.67, 9.04, 11.86, 12.80, 13.24, 13.54, 14.19, 15.65, 16.00, 17.37, 17.75, 18.61, 18.92, 19.39, 21.09, 21.91, 22.38, 22.68, 23.35, 23.70, 24.37, 24.61, 25.62, 26.14, 26.64, 27.20, 28.02, 28.38, 29.06 (Of these, 10 characteristic peaks are 9.04, 11.86, 15.65, 16.00, 17.75, 19.39, 21.91, 23.35, 24.61, 26.14, and 4 more characteristic peaks are 9.04. , 16.00, 17.75, 21.91.)

Example 196
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo [ 4,3-c] Pyridine-4-one form C
Heptane (200 μL) was added to a mixture of the compound of Example 37 (5.0 mg) and ethanol (50 μL) under heating and reflux, and the mixture was further heated under reflux for 1 hour. The title compound was then obtained by spontaneous evaporation of the solvent from the mixture at room temperature.
Powder XRD (°, 2θ ± 0.2)
9.86, 11.54, 12.45, 14.55, 15.96, 18.16, 19.13, 19.71, 20.19, 21.06, 22.59, 23.17, 23.30, 23.58, 24.51, 25.00, 25.60, 25.84, 26.60, 27.14, 27.46, 29.20 (Of these, characteristic The 10 peaks were 9.86, 11.54, 12.45, 14.55, 19.13, 21.06, 23.17, 23.58, 25.84, 27.46, and the more characteristic 4 peaks were 12.45, 14.55, 19.13, 25.84.)

３−（ピペラジン−1−イル）ベンゾ［ｄ］イソオキサゾール塩酸塩（５．４４ ｇ）、水酸化カリウム（３．８２ ｇ）、１−ブロモ−２−クロロエタン（９．４１ ｍＬ）、テトラヒドロフラン（１００ ｍＬ）と水（１００ ｍＬ）の混合物を室温で２４時間撹拌した。その後、反応混合物に水を加え、クロロホルムで抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥後、ろ過して、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（３．４５ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.56-2.92 (6H, m), 3.42-3.76 (6H, m), 7.17-7.23 (1H, m), 7.42-7.50 (2H, m), 7.66 (1H, d, J = 7.9 Hz). Reference example 1
3- [4- (2-chloroethyl) piperazine-1-yl] -1,2-benzoisoxazole

3- (Piperazine-1-yl) benzo [d] isoxazole hydrochloride (5.44 g), potassium hydroxide (3.82 g), 1-bromo-2-chloroethane (9.41 mL), tetrahydrofuran ( A mixture of 100 mL) and water (100 mL) was stirred at room temperature for 24 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.45 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.56-2.92 (6H, m), 3.42-3.76 (6H, m), 7.17-7.23 (1H, m), 7.42-7.50 (2H, m), 7.66 (1H, d, J = 7.9 Hz).

３−（ピペラジン−１−イル）ベンゾ［ｄ］イソチアゾール（２５．０ ｇ）、水酸化カリウム（１２．８ ｇ）、テトラヒドロフラン（６０ ｍＬ）と水（７．５ ｍＬ）の混合物に、１−ブロモ−２−クロロエタン（３７．８ ｍＬ）を加え、室温で７２時間撹拌した。その後、反応混合物に水を加え、クロロホルムで抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥後、ろ過して、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（２２．３ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.76 (4H, t, J = 5.0 Hz), 2.84 (2H, t, J = 7.1 Hz), 3.58 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.9 Hz), 7.33-7.39 (1H, m), 7.44-7.50 (1H, m), 7.79-7.83 (1H, m), 7.88-7.92 (1H, m). Reference example 2
3- [4- (2-chloroethyl) piperazine-1-yl] -1,2-benzoisothiazole

1 in a mixture of 3- (piperazine-1-yl) benzo [d] isothiazole (25.0 g), potassium hydroxide (12.8 g), tetrahydrofuran (60 mL) and water (7.5 mL) -Bromo-2-chloroethane (37.8 mL) was added, and the mixture was stirred at room temperature for 72 hours. Then, water was added to the reaction mixture, the mixture was extracted with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (22.3 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.76 (4H, t, J = 5.0 Hz), 2.84 (2H, t, J = 7.1 Hz), 3.58 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.9 Hz), 7.33-7.39 (1H, m), 7.44-7.50 (1H, m), 7.79-7.83 (1H, m), 7.88-7.92 (1H, m).

３−（ピペリジン−４−イル）ベンゾ［ｄ］イソオキサゾール塩酸塩（２．０１ ｇ）、テトラヒドロフラン（４．０ ｍＬ）と水（２．４ ｍＬ）の混合物に水酸化カリウム（１．４２ ｇ）を加え、室温で３０分間攪拌した。その後、１−ブロモ−２−クロロエタン（２．７９ ｍＬ）を加え、室温で２４時間攪拌した。反応混合物に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で分離精製し、表題化合物（１．１０ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.04-2.20 (4H, m), 2.27-2.36 (2H, m), 2.80 (2H, t, J = 7.1 Hz), 3.04-3.15 (3H, m), 3.64 (2H, t, J = 7.1 Hz), 7.27-7.32 (1H, m), 7.51-7.59 (2H, m), 7.74-7.78 (1H, m). Reference example 3
3- [1- (2-chloroethyl) piperidine-4-yl] -1,2-benzoisoxazole

Potassium hydroxide (1.42 g) in a mixture of 3- (piperidine-4-yl) benzo [d] isoxazole hydrochloride (2.01 g), tetrahydrofuran (4.0 mL) and water (2.4 mL) ) Was added, and the mixture was stirred at room temperature for 30 minutes. Then, 1-bromo-2-chloroethane (2.79 mL) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (1.10 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.20 (4H, m), 2.27-2.36 (2H, m), 2.80 (2H, t, J = 7.1 Hz), 3.04-3.15 (3H, m) ), 3.64 (2H, t, J = 7.1 Hz), 7.27-7.32 (1H, m), 7.51-7.59 (2H, m), 7.74-7.78 (1H, m).

Reference examples 4-5
The compounds of Reference Examples 4 to 5 were obtained using the corresponding starting materials according to the method described in Reference Example 3.

Reference example 6
3- [1- (2-chloroethyl) piperidine-4-yl] -6-fluoro-5-methyl-1,2-benzoisoxazole

a) Production of tert-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate (Compound IN-1-1) 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (5.00 g) , N, O-dimethylhydroxyamine hydrochloride (3.19 g), N1-((ethylimino) methylene) -N3, N3-dimethylpropan-1,3-diamine hydrochloride (5.02 g), triethylamine (4) A mixture of .41 g) and N, N-dimethylformamide (100 mL) was stirred at room temperature for 1.5 hours. Then, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed twice with saturated aqueous ammonium chloride solution and saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.52 g). ..
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.63-1.76 (4H, m), 2.70-2.86 (3H, m), 3.19 (3H, s), 3.72 (3H, s) ), 4.03-4.24 (2H, m).

b) Production of tert-butyl 4- (2,4-difluoro-5-methylbenzoyl) piperidine-1-carboxylate (Compound IN-1-2) 1-bromo-2,4-difluoro-5-methylbenzene (1-bromo-2,4-difluoro-5-methylbenzene) 1.63 mol / L n-butyllithium / hexane (7.43 mL) was added dropwise to a solution of 2.28 g) in tetrahydrofuran (36 mL) at −78 ° C. for 3 minutes. After stirring at −78 ° C. for 1 hour, compound IN-1-1 (1.50 g) was added, and the mixture was stirred at −78 ° C. for 2.5 hours. Then, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.01 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.59-1.69 (2H, m), 1.83-1.92 (2H, m), 6.80-6.87 (1H, m), 7.17-7.25 (1H, m).

c) Production of tert-butyl 4- (6-fluoro-5-methyl-1,2-benzoisoxazole-3-yl) piperidine-1-carboxylate (Compound IN-1-3) Compound IN1-2 A mixture of (731 mg), hydroxylamine hydrochloride (599 mg), sodium acetate (707 mg) and ethanol (10 mL) was stirred at 60 ° C. for 4 hours. Then, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). A mixture of the resulting product (335 mg), cesium carbonate (615 mg) and acetonitrile (9.0 mL) was stirred in a sealed tube at 130 ° C. for 3.5 hours. Then, the reaction mixture was filtered, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (90.8 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.87-1.99 (2H, m), 2.01-2.10 (2H, m), 2.38 (3H, d, J = 1.7 Hz), 2.89-3.03 (2H, m) ), 3.16-3.26 (1H, m), 4.11-4.36 (2H, m), 7.21 (1H, d, J = 9.0 Hz), 7.47 (1H, d, J = 7.1 Hz).

d) Production of 3- [1- (2-chloroethyl) piperidine-4-yl] -6-fluoro-5-methyl-1,2-benzoisoxazole (Reference Example 6) Compound IN-1--3 (131 mg) ) To a solution of dichloromethane (1.0 mL) was added 4 mol / L hydrochloric acid / ethyl acetate (1.0 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give a solid (114 mg). A mixture of the resulting solid (114 mg), potassium carbonate (232 mg), 1-bromo-2-chloroethane (301 mg), tetrahydrofuran (1.7 mL) and water (0.42 mL) was added at room temperature. Stirred overnight. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (41.8 mg).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.98-2.45 (9H, m), 2.76-2.88 (2H, m), 3.00-3.15 (3H, m), 3.58-3.75 (2H, m), 7.20 (1H, d, J = 9.2 Hz), 7.52 (1H, d, J = 7.0 Hz).

参考例６と同様の手法により、１−フルオロ−２−ヨード−４−メチルベンゼンから表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.97-2.25 (4H, m), 2.27-2.42 (2H, m), 2.45 (3H, s), 2.71-2.97 (2H, m), 2.99-3.22 (3H, m), 3.58-3.80 (2H, m), 7.24-7.27 (1H, m), 7.33 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz). Reference example 7
3- [1- (2-chloroethyl) piperidine-4-yl] -5-methyl-1,2-benzoisoxazole

The title compound was obtained from 1-fluoro-2-iodo-4-methylbenzene by the same method as in Reference Example 6.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.97-2.25 (4H, m), 2.27-2.42 (2H, m), 2.45 (3H, s), 2.71-2.97 (2H, m), 2.99-3.22 (3H, m), 3.58-3.80 (2H, m), 7.24-7.27 (1H, m), 7.33 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz).

Reference example 8
3- (Piperidin-4-yl) -1,2-benzoisothiazole

a) Production of tert-butyl 4- [2- (benzyl sulfanyl) benzoyl] piperidine-1-carboxylate (Compound IN2-1) tert-butyl 4- (2-fluorobenzoyl) piperidine-1-carboxylate ( Anhydrous sodium sulfide (554 mg) was added to a solution of 664 mg) of dimethyl sulfoxide (5.0 mL), and the mixture was stirred at 80 ° C. for 2 hours. Then, anhydrous sodium sulfide (560 mg) was further added, and the mixture was stirred at 110 ° C. for 3 hours. Potassium carbonate (895 mg) and benzyl bromide (0.270 mL) were added to the reaction mixture. After stirring at room temperature for 5 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (391 mg).
LC-MS: RT = 2.12 min ObsMS = 412 [M + 1]

b) Preparation of tert-butyl 4- (1,2-benzoisothiazole-3-yl) piperidine-1-carboxylate (Compound IN-2-2) A dichloromethane solution of compound IN-2-1 (391 mg) ( Sulfuryl chloride (0.081 mL) was added to 5.0 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Then, the reaction mixture was concentrated, 2 mol / L ammonia-ethanol (4.75 mL) was added to a tetrahydrofuran solution (5.0 mL) of the obtained residue, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (187 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.86-2.10 (4H, m), 2.85-3.04 (2H, m), 3.31-3.44 (1H, m), 4.15-4.35 (2H, m), 7.38-7.44 (1H, m), 7.47-7.53 (1H, m), 7.92 (1H, d, J = 8.0 Hz), 7.97 (1H, d, J = 8.0 Hz).

c) Production of 3- (piperidin-4-yl) -1,2-benzoisothiazole (Reference Example 8) 4 mol / mol / in a chloroform solution (5.0 mL) of compound IN-2-2 (173 mg). L Hydrochloric acid-ethyl acetate (5.0 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was then concentrated to give the title compound (119 mg).
LC-MS: RT = 1.28 min ObsMS = 219 [M + 1]

Reference example 9
6-Fluoro-3- (piperazine-1-yl) -1,2-benzoisothiazole

a) Production of tert-butyl 4- (6-fluoro-1,2-benzoisothiazole-3-yl) piperazine-1-carboxylate (compound IN-3-1) 6-fluorobenzo [d] isothiazole- A mixture of 3 (2H) -one (2.00 g), triethylamine (8.22 mL) and 1,4-dioxane (59 mL) with bromotri (pyrrolidin-1-yl) phosphonium hexafluorophosphofate (V) ) (6.06 g) was added. After stirring at room temperature for 1 hour, tert-butylpiperazin-1-carboxylate (6.61 g) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 48 hours. Then, water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.260 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.50 (9H, s), 3.46 (4H, t, J = 5.0 Hz), 3.65 (4H, t, J = 5.0 Hz), 7.12 (1H, ddd, J = 8.7, 8.7, 2.3 Hz), 7.47 (1H, dd, J = 8.3, 2.3 Hz), 7.84 (1H, dd, J = 8.9, 4.8 Hz).

b) Production of 6-fluoro-3- (piperazine-1-yl) -1,2-benzoisothiazole (Reference Example 9) In a dichloromethane solution (6.8 mL) of compound IN-3-1 (912 mg). Trifluoroacetic acid (6.8 mL) was added, and the mixture was stirred at room temperature for 13 hours. Then, the reaction mixture was concentrated, saturated sodium hydrogen carbonate was added, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (639 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.12 (4H, t, J = 5.0 Hz), 3.50 (4H, t, J = 4.8 Hz), 7.10 (1H, ddd, J = 8.7, 8.7, 2.3 Hz), 7.46 (1H, dd, J = 8.3, 1.8 Hz), 7.85 (1H, dd, J = 8.9, 4.8 Hz).

２８％ナトリウムメトキシド−メタノール溶液（５０．０ ｍＬ）に、室温下６−ブロモ−３，４−ジヒドロ−２，７−ナフチリジン−１（２Ｈ）−オン（５．００ ｇ）を加えた。７０℃にて２時間撹拌後、０℃にて反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題化合物（３．６８ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.92 (2H, t, J = 6.4 Hz), 3.53 (2H, td, J = 6.5, 3.1 Hz), 3.96 (3H, s), 6.06 (1H, br s), 6.53 (1H, d, J = 0.9 Hz), 8.80 (1H, s). Reference example 10
6-Methoxy-3,4-dihydro-2,7-naphthylene-1 (2H) -one

To a 28% sodium methoxide-methanol solution (50.0 mL) was added 6-bromo-3,4-dihydro-2,7-naphthylidine-1 (2H) -one (5.00 g) at room temperature. After stirring at 70 ° C. for 2 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture at 0 ° C., and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.68 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.92 (2H, t, J = 6.4 Hz), 3.53 (2H, td, J = 6.5, 3.1 Hz), 3.96 (3H, s), 6.06 (1H, s) br s), 6.53 (1H, d, J = 0.9 Hz), 8.80 (1H, s).

Reference example 11
5-Methyl-6,7-dihydro-1,7-naphthalene-8 (5H) -one

a) Preparation of methyl 3- (cyanomethyl) pyridin-2-carboxylate (Compound IN-4-1) N-bromo in a chloroform solution (27 mL) of methyl 3-methylpicolinate (1.00 g) at room temperature. Succinimide (1.53 g) and benzoyl peroxide (0.214 g) were added. After stirring at 70 ° C. for 16 hours, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). Sodium cyanide (0.0712 g) was added to a solution of the resulting product (0.304 g) in N, N-dimethylformamide (3.3 mL) at room temperature. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.0440 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.01 (3H, s), 4.28 (2H, s), 7.55 (1H, dd, J = 7.8, 4.6 Hz), 8.01 (1H, dd, J = 7.8) , 1.4 Hz), 8.73 (1H, dd, J = 4.6, 1.4 Hz).

b) Preparation of methyl 3- (1-cyanoethyl) pyridin-2-carboxylate (Compound IN-4-2) Ice in a tetrahydrofuran solution (1.2 mL) of compound IN-4-1 (63.0 mg). 55% sodium hydride (15.6 mg) was added cold. After stirring at 0 ° C. for 30 minutes, a tetrahydrofuran solution (0.30 mL) of methyl iodide (0.0291 mL) was added dropwise. After stirring at 0 ° C. for 30 minutes, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (35.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.66 (3H, d, J = 7.2 Hz), 4.00 (3H, s), 5.09 (1H, q, J = 7.2 Hz), 7.55 (1H, dd, J = 7.6, 4.4 Hz), 8.08 (1H, dd, J = 7.6, 1.2 Hz), 8.70 (1H, dd, J = 4.4, 1.2 Hz).

c) Production of 5-methyl-6,7-dihydro-1,7-naphthylidine-8 (5H) -one (Reference Example 11) Ethanol solution (2.17) of compound IN-4-2 (35.0 mg). Raney nickel (15.8 mg) under ice-cooling was added to mL). After stirring at 50 ° C. for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (22.3 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (3H, d, J = 7.2 Hz), 3.10-3.21 (1H, m), 3.26-3.32 (1H, m), 3.60-3.65 (1H, m) ), 7.34 (1H, dd, J = 8.0, 4.8 Hz), 7.56-7.58 (1H, m), 7.80 (1H, br s), 8.64 (1H, dd, J = 4.6, 1.4 Hz).

Reference example 12
1-Methyl-1,5,6,7-Tetrahydro-4H-imidazole [4,5-c] Pyridine-4-one

a) Production of 1-methyl-1,5-dihydro-4H-imidazole [4,5-c] pyridin-4-one (compound IN-5-1) 4-chloro-1-methyl-1H-imidazole [4] , 5-C] A mixture of pyridine (100 mg) and formic acid (1.40 mL) was heated under reflux for 5 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (127 mg).
^{1 1} H-NMR (300 MHz, CD ₃ OD) δ: 4.03 (3H, s), 6.91 (1H, d, J = 7.3 Hz), 7.55 (1H, d, J = 7.3 Hz), 8.07 (1H, s) ), 9.20 (1H, s).

b) Production of 1-methyl-1,5,6,7-tetrahydro-4H-imidazole [4,5-c] pyridin-4-one (Reference Example 12) Compound IN-5-1 (0.106 g) A mixture of 20% palladium hydroxide-carbon (1.25 g) and acetic acid (7.1 mL) was stirred under a hydrogen atmosphere (1 atm) at 70 ° C. for 8 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (13.9 mg).
^{1 1} H-NMR (300 MHz, CD ₃ OD) δ: 3.01-2.91 (2H, m), 3.74 (3H, s), 3.66-3.57 (2H, m), 7.97 (1H, s).

ピペリジン−２，４−ジオン（１９．０ ｇ）、酢酸（１．０１ ｇ）とＮ，Ｎ−ジメチルホルムアミド（８０ ｍＬ）の混合物にメチルヒドラジン（７．７４ ｇ）を０℃で加え２０分間した。その後、室温で１時間攪拌後、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール（４４．０ ｇ）を加えた。６０℃で２時間攪拌後、反応混合物を室温へ冷却し、ジエチルエーテル（１００ ｍＬ）を加え、０℃で３０分間攪拌した。析出した固体をろ取することで、表題化合物（１４．４ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.91 (2H, t, J = 6.6 Hz), 3.57 (2H, td, J = 6.6, 2.6 Hz), 3.90 (3H, s), 5.85 (1H, s), 7.78 (1H, s). Reference example 13
2-Methyl-2,5,6,7-Tetrahydro-4H-Pyrazolo [4,3-c] Pyridine-4-one

Methylhydrazine (7.74 g) was added to a mixture of piperidine-2,4-dione (19.0 g), acetic acid (1.01 g) and N, N-dimethylformamide (80 mL) at 0 ° C. for 20 minutes. did. Then, after stirring at room temperature for 1 hour, N, N-dimethylformamide dimethylacetal (44.0 g) was added. After stirring at 60 ° C. for 2 hours, the reaction mixture was cooled to room temperature, diethyl ether (100 mL) was added, and the mixture was stirred at 0 ° C. for 30 minutes. The precipitated solid was collected by filtration to give the title compound (14.4 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.91 (2H, t, J = 6.6 Hz), 3.57 (2H, td, J = 6.6, 2.6 Hz), 3.90 (3H, s), 5.85 (1H, 1H, s), 7.78 (1H, s).

参考例１３と同様の手法により、シクロプロピルヒドラジン一塩酸塩を用いて表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.03-1.15 (4H, m), 2.91 (2H, t, J = 6.6 Hz), 3.55-3.60 (2H, m), 5.56 (1H, brs), 7.87 (1H, s). Reference example 14
2-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one

The title compound was obtained using cyclopropylhydrazine monohydrochloride by the same method as in Reference Example 13.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.03-1.15 (4H, m), 2.91 (2H, t, J = 6.6 Hz), 3.55-3.60 (2H, m), 5.56 (1H, brs), 7.87 (1H, s).

ピペリジン−２，４−ジオン（５００ ｍｇ）のエタノール溶液（９．０ ｍＬ）に、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール（６３２ ｍｇ）を加えて２時間還流させた。その後、氷冷下メチルヒドラジン（２２４ ｍｇ）を滴下して２時間室温で撹拌した。その後８０℃で１時間攪拌した後、ジエチルエーテル（１５ ｍＬ）を加えてトリチュレーションし固体をろ取することで、表題化合物（５６５ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.91 (2H, t, J = 6.6 Hz), 3.63 (2H, td, J = 6.8, 2.4 Hz), 3.84 (3H, s), 6.10 (1H, s), 7.87 (1H, s). Reference example 15
1-Methyl-1,5,6,7-Tetrahydro-4H-Pyrazolo [4,3-c] Pyridine-4-one

N, N-Dimethylformamide dimethylacetal (632 mg) was added to an ethanol solution (9.0 mL) of piperidine-2,4-dione (500 mg), and the mixture was refluxed for 2 hours. Then, methylhydrazine (224 mg) under ice-cooling was added dropwise, and the mixture was stirred at room temperature for 2 hours. Then, after stirring at 80 ° C. for 1 hour, diethyl ether (15 mL) was added, trituration was performed, and the solid was collected by filtration to give the title compound (565 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.91 (2H, t, J = 6.6 Hz), 3.63 (2H, td, J = 6.8, 2.4 Hz), 3.84 (3H, s), 6.10 (1H, s) s), 7.87 (1H, s).

参考例１５と同様の手法により、５−メチル−２，４−ピペリジンジオンを用いて表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.33 (3H, d, J = 6.9 Hz), 3.06-3.14 (1H, m), 3.29 (1H, dq, J = 12.5, 2.2 Hz), 3.79 (1H, dd, J = 12.4, 5.0 Hz), 3.85 (3H, s), 5.29 (1H, brs), 7.86 (1H, s). Reference example 16
1,7-Dimethyl-1,5,6,7-Tetrahydro-4H-pyrazolo [4,3-c] Pyridine-4-one

The title compound was obtained using 5-methyl-2,4-piperidinedione by the same method as in Reference Example 15.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.33 (3H, d, J = 6.9 Hz), 3.06-3.14 (1H, m), 3.29 (1H, dq, J = 12.5, 2.2 Hz), 3.79 ( 1H, dd, J = 12.4, 5.0 Hz), 3.85 (3H, s), 5.29 (1H, brs), 7.86 (1H, s).

Reference example 17
1-Methyl-5,6,7,8-Tetrahydropyrazolo [4,3-c] Azepine-4 (1H) -on

a) Production of N- (1-methyl-1,5,6,7-tetrahydro-4H-indazole-4-iriden) hydroxylamine (compound IN-6-1) 1-methyl-6,7-dihydro-1H A mixture of -indazole-4 (5H) -one (855 mg), hydroxylamine hydrochloride (475 mg), sodium acetate (560 mg) and ethanol (28 mL) was stirred at 60 ° C. for 14 hours. The reaction mixture was then filtered and concentrated. The concentrated residue was triturated with hexane: ethyl acetate (1: 1), collected by filtration and dried to give the title compound (635 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.08 (2H, m), 2.48 (2H, t, J = 6.2 Hz), 2.73 (2H, t, J = 6.2 Hz), 3.81 (3H, 3H, s), 8.19 (1H, s).

b) Production of 1-methyl-5,6,7,8-tetrahydropyrazolo [4,3-c] azepine-4 (1H) -one (Reference Example 17) Compound IN-6-1 (7.86 g) ), P-Toluenesulfonyl chloride (10.4 g) was added to a mixture of triethylamine (9.95 mL) and dichloromethane (95 mL), and the mixture was heated under reflux for 30 minutes. Then, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. Ethyl acetate (18 mL) was added to the residue and heated at 80 ° C. to confirm that all the solids had dissolved, then gradually cooled to room temperature, and hexane (18 mL) and ethyl acetate (3.0 mL) were added in that order. added. After stirring at room temperature for 1 hour, the precipitated solid is collected by filtration, washed with hexane: ethyl acetate (2: 3,50 mL) and hexane (20 mL), and dried to obtain a solid (13.6 g). rice field. The mixture of the obtained solid (13.6 g) and trifluoroacetic acid (22.9 mL) was heated to reflux for 30 minutes. The reaction mixture was then concentrated and purified by amino silica gel column chromatography (chloroform / methanol). Ethanol (60 mL) was added to the obtained solid, and the mixture was stirred at 80 ° C. for 1 hour, gradually cooled to room temperature, stirred at 0 ° C. for 1 hour, and then collected by filtration. The obtained solid was washed with ethanol: hexane (1: 1,10 mL) and dried to give the title compound (5.52 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.13-2.20 (2H, m), 2.91 (2H, t, J = 6.4 Hz), 3.38 (2H, td, J = 5.0, 5.0 Hz), 3.79 ( 3H, s), 6.10 (1H, brs), 7.99 (1H, s).

参考例１７と同様の手法により、１，３−ジメチル−１，５，６，７−テトラヒドロ−４Ｈ−インダゾール−４−オンから表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.06-2.13 (2H, m), 2.44 (3H, s), 2.86 (2H, t, J = 6.7 Hz), 3.26-3.33 (2H, m), 3.69 (3H, s), 6.18 (1H, brs). Reference example 18
1,3-Dimethyl-5,6,7,8-Tetrahydropyrazolo [4,3-c] Azepine-4 (1H) -on

The title compound was obtained from 1,3-dimethyl-1,5,6,7-tetrahydro-4H-indazole-4-one by the same method as in Reference Example 17.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.06-2.13 (2H, m), 2.44 (3H, s), 2.86 (2H, t, J = 6.7 Hz), 3.26-3.33 (2H, m), 3.69 (3H, s), 6.18 (1H, br s).

Reference example 19
6-Methyl-3,4-dihydro-2,7-naphthylene-1 (2H) -one

a) Preparation of methyl 4-chloro-6-methylpyridine-3-carboxylate (Compound IN-7-1) Toluene solution of 4-hydroxy-6-methylnicotinic acid (1.00 g) (6.5 mL) To (N, N-dimethylformamide (0.0200 mL) was added at room temperature, and then oxalyl chloride (3.00 mL) was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Toluene (3.0 mL) was added to the residue, and then methanol (10 mL) was added at 0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.20 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.57 (3H, s), 3.93 (3H, s), 7.27 (1H, s), 8.92 (1H, s).

b) Preparation of methyl 4- {2-[(tert-butoxycarbonyl) amino] ethyl} -6-methylpyridine-3-carboxylate (Compound IN-7-2) Compound IN-7-1 (5.03 g) ) And toluene / water (3: 1,54 mL), potassium tert-butyl N- [2- (trifluoroboranuidyl) ethyl] carbamate (10.2 g), cesium carbonate (22.1 g) at room temperature. g), 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane adduct (1.98 g) was added. After stirring at 100 ° C. for 3 hours under a nitrogen atmosphere, water (55 mL) and ethyl acetate (30 mL) were added to the reaction mixture, the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (7.84 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.39 (9H, s), 2.57 (3H, s), 3.11-3.17 (2H, m), 3.36-3.42 (2H, m), 3.90 (3H, s) ), 7.08 (1H, s), 8.97 (1H, s).

c) Production of 6-methyl-3,4-dihydro-2,7-naphthylidine-1 (2H) -one (Reference Example 19) Ethyl acetate / methanol solution of compound IN-7-2 (1.25 g) (reference example 19) To 1: 1,4.2 mL) was added 4 mol / L hydrochloric acid-ethyl acetate (21.2 mL, 85.0 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5.0 mL) and a 28% sodium methoxide-methanol solution (3.27 g) was added at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. 2 mol / L hydrochloric acid (10.0 ml) was added to the residue, and the aqueous layer was washed with ethyl acetate. After neutralizing by adding 1 mol / L aqueous sodium hydroxide solution to the aqueous layer, the mixture was extracted with chloroform / methanol (4: 1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethanol / hexane to give the title compound (519 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.60 (3H, s), 2.97 (2H, t, J = 6.6 Hz), 3.59 (2H, td, J = 6.6, 2.9 Hz), 6.36 (1H, 1H, s), 7.03 (1H, s), 9.08 (1H, s).

Reference example 20
6'-Methyl-2', 3'-Dihydro-1'H-Spiro [Cyclopropane-1,4'-[2,7] Diazanaphthalene] -1'-On

a) Preparation of methyl 6-chloro-4- (cyanomethyl) pyridine-3-carboxylate (Compound IN-8-1) N, N-dimethylformamide solution of methyl 4,6-dichloronicotinate (5.00 g) To (49 mL) was added potassium carbonate (6.71 g) and tert-butyl cyanoacetate (3.77 g) at room temperature. After stirring at 100 ° C. for 2 hours, water (100 mL) was added to the reaction mixture, the mixture was neutralized with 2 mol / L hydrochloric acid (35 mL), and extracted with toluene (100 mL × 4). The organic layer was washed with 0.1 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until the solvent reached 300 mL, and p-toluenesulfonic acid monohydrate (p-toluenesulfonic acid monohydrate). 0.462 g) was added. After stirring at 100 ° C. for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.35 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (3H, s), 4.28 (2H, s), 7.65 (1H, s), 9.02 (1H, s).

b) Preparation of methyl 4- (cyanomethyl) -6-methylpyridine-3-carboxylate (Compound IN-8-2) A 1,2-dimethoxyethane solution (17) of compound IN-8-1 (2.55 g). To (mL), potassium carbonate (2.51 g), trimethylboroxin (5.08 mL), and tetrakistriphenylphosphine palladium (1.40 g) were added at room temperature. After stirring at 100 ° C. for 2 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (465 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.66 (3H, s), 3.95 (3H, s), 4.25 (2H, s), 7.44 (1H, s), 9.11 (1H, s).

c) Preparation of methyl 4- (1-cyanocyclopropyl) -6-methylpyridine-3-carboxylate (Compound IN-8-3) Acetonitrile solution (1.8 mL) of compound IN-8-2 (101 mg). ), 1,2-Dibromoethane (0.0554 mL) and potassium carbonate (220 mg) were added at room temperature. After stirring at 70 ° C. for 48 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (67.1 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (2H, dd, J = 7.8, 5.5 Hz), 1.76 (2H, t, J = 3.7 Hz), 2.60 (3H, s), 3.99 (3H, s), 7.18 (1H, s), 9.05 (1H, s).

d) Production of 6'-methyl-2', 3'-dihydro-1'H-spiro [cyclopropane-1,4'-[2,7] diazanaphthalene] -1'-on (Reference Example 20) Compound IN To an ethanol solution (3.3 mL) of -8-3 (61.0 mg) was added 50% lanenickyl-aqueous suspension (0.17 mL) under ice-cooling. After stirring at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (35.4 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.07 (2H, t, J = 2.9 Hz), 1.12 (2H, t, J = 2.9 Hz), 2.55 (3H, s), 3.39 (2H, d, J = 2.7 Hz), 6.59 (1H, s), 7.40 (1H, brs), 9.06 (1H, s).

参考例２０と同様の手法により、化合物ＩＮ−８−２からヨウ化メチルを用いて表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.36 (6H, s), 2.62 (3H, s), 3.34 (2H, d, J = 0.8 Hz), 6.52 (1H, brs), 7.09 (1H, s), 9.09 (1H, s). Reference example 21
4,4,6-trimethyl-3,4-dihydro-2,7-naphthylene-1 (2H) -one

The title compound was obtained from compound IN-8-2 using methyl iodide by the same method as in Reference Example 20.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (6H, s), 2.62 (3H, s), 3.34 (2H, d, J = 0.8 Hz), 6.52 (1H, brs), 7.09 (1H, 1H, s), 9.09 (1H, s).

Reference example 22
7- (2-Hydroxy-2-methoxyethyl) -6,7-dihydro-1,7-naphthalene-8 (5H) -one

a) Production of 7- (prop-2-en-1-yl) -6,7-dihydro-1,7-naphthylinen-8 (5H) -one (compound IN-9-1) 6,7-dihydro- To a solution of 1,7-naphthylidine-8 (5H) -one (1.29 g) in N, N-dimethylformamide (20 mL), add 55% sodium hydride (0.456 g) under ice-cooling, and add 1 Stirred for hours. Then, allyl iodide (0.949 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. Toluene was added to the residue and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.97 g).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.03 (2H, t, J = 6.6 Hz), 3.56 (2H, t, J = 6.6 Hz), 4.23-4.29 (2H, m), 5.20-5.32 ( 2H, m), 5.80-5.95 (1H, m), 7.34 (1H, dd, J = 7.7, 4.6 Hz), 7.56 (1H, d, J = 7.7 Hz), 8.71 (1H, d, J = 4.6 Hz) ).

b) Production of 7- (2-Hydroxy-2-methoxyethyl) -6,7-dihydro-1,7-naphthylidine-8 (5H) -one (Reference Example 22) Compound IN-9-1 (1.69) To a mixture of g), tetrahydrofuran (44 mL) and water (22 mL) was added sodium periodate (4.80 g) and osmium tetroxide (0.183 g) under ice-cooling. After stirring under ice-cooling for 6 hours, the reaction mixture was filtered through Celite and washed with chloroform / methanol (4/1). A saturated aqueous sodium thiosulfate solution was added to the filtrate, extracted with chloroform / methanol (4 / 1,50 mL × 12 times), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.65 g).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.02-3.11 (2H, m), 3.43 (3H, s), 3.68 (2H, dd, J = 13.8, 5.1 Hz), 3.75-3.89 (2H, m) ), 4.61-4.72 (1H, m), 4.80-4.88 (1H, m), 7.36 (1H, dd, J = 7.7, 4.8 Hz), 7.55-7.60 (1H, m), 8.68-8.72 (1H, m) ).

Reference example 23-25
The compounds of Reference Examples 23 to 25 were obtained using the corresponding starting materials according to the method described in Reference Example 22.

Reference example 26
2-Methyl-6,7-dihydro [1,3] oxazolo [5,4-c] pyridine-4 (5H) -one

a) Preparation of ethyl 5-{[(benzyloxy) carbonyl] amino} -3-oxopentanoate (compound IN-10-1) 3-([(benzyloxy) carbonyl] amino) propionic acid (10.0) g) was dissolved in tetrahydrofuran (180 mL) and carbonyl-1,1'-diimidazole (7.99 g) was added. After stirring at room temperature for 1.5 hours, ethyl potassium malonate (9.91 g) was added, and then magnesium chloride (5.54 g) was slowly added. After stirring for 15 minutes, the mixture was heated and stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (8.58 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.14 (3H, t, J = 7.1 Hz), 2.08-2.20 (2H, m), 3.22-3.34 (2H, m), 3.98 (2H, q, J) = 6.9 Hz), 4.72 (1H, s), 5.00 (2H, s), 5.25 (1H, brs), 7.27-7.37 (5H, m).

b) Preparation of ethyl 5-{[(benzyloxy) carbonyl] amino} -2-chloro-3-oxopentanoate (Compound IN-10-2) Compound IN-10-1 (8.58 g) is chloride. It was dissolved in methylene (150 mL) and sulfyl chloride (2.38 mL) was added dropwise at 0 ° C. After stirring at 0 ° C. for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with methylene chloride, the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the title compound (9.47) was added. g) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.96-3.03 (2H, m), 3.46-3.53 (2H, m), 4.27 (2H, q, J) = 7.3 Hz), 4.77 (1H, s), 5.09 (2H, s), 5.16 (1H, brs), 7.29-7.43 (5H, m).

c) Production of ethyl 2- (acetyloxy) -5-{[(benzyloxy) carbonyl] amino} -3-oxopentanoate (Compound IN-10-3) Compound IN-10-2 (1.50 g) ) Was dissolved in acetonitrile (5.0 mL), acetic acid (0.786 mL) and triethylamine (3.19 mL) were added, and the mixture was stirred overnight at room temperature. Then, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.57 g).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 2.22 (3H, s), 2.89-2.97 (2H, m), 3.45-3.53 (2H, m), 4.26 (2H, q, J = 7.2 Hz), 5.08 (2H, s), 5.18 (1H, brs), 5.47 (1H, s), 7.30-7.37 (5H, m).

d) Ethyl 4- (2-{[(benzyloxy) carbonyl] amino} ethyl) -2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-4) Production Compound IN-10- 3 (9.11 g) and ammonium acetate (4.00 g) were dissolved in acetic acid (40 mL) and heated at 120 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (8.74 g).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 2.47 (3H, s), 3.02 (2H, t, J = 6.2 Hz), 3.53 (2H, td, J = 6.1, 6.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 5.06 (2H, s), 5.30 (1H, s), 7.26-7.36 (5H, m).

e) Preparation of ethyl 4- (2-aminoethyl) -2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-5) Compounds IN-10-4 (3.44 g) and 5 % Pd-C (2.00 g) was dissolved in ethanol (25 mL). Then, the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.78 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1 Hz), 2.22 (3H, s), 2.51 (3H, s), 2.99 (2H, dd, J = 10.1, 3.7) Hz), 3.05-3.08 (2H, m), 4.38 (2H, q, J = 7.2 Hz).

f) Preparation of 2-methyl-6,7-dihydro [1,3] oxazolo [5,4-c] pyridine-4 (5H) -one (Reference Example 26) Compound IN-10-5 (0.749 g) ), Potassium carbonate (0.627 g), dimethoxyethane (1.0 mL) and water (1.0 mL) were stirred for 3 days at room temperature, and the solvent was distilled off. Then, the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.322 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.55 (3H, s), 2.90 (2H, t, J = 7.1 Hz), 3.65 (2H, td, J = 7.1, 2.3 Hz), 5.96 (1H, 1H, s).

Reference example 27-30
Compounds of Reference Examples 27 to 30 were obtained using the corresponding starting materials according to the method described in Reference Example 26.

Reference example 31
2-Methyl-6,7-dihydro [1,3] oxazolo [4,5-c] Pyridine-4 (5H) -one

a) Ethyl 5- (2-{[(benzyloxy) carbonyl] amino} ethyl) -1,3-oxazole-4-carboxylate (Compound IN-11-1) 3-([(benzyloxy) carbonyl ] To a solution of amino) propionic acid (5.00 g) in tetrahydrofuran (50 mL) was added carbonyl-1,1'-diimidazole (4.00 g) at room temperature. After stirring at room temperature for 1.5 hours, triethylamine (4.06 mL) and ethyl isocyanoacetate (3.20 mL) were added. After stirring at 65 ° C. for 24 hours, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.99 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 3.27 (2H, t, J = 6.4 Hz), 3.53 (2H, dd, J = 6.4, 6.4 Hz) , 4.35 (2H, q, J = 7.1 Hz), 5.00 (1H, brs), 5.05 (2H, s), 7.29-7.33 (5H, m), 7.74 (1H, s).

b) Ethyl 5-(2-{[(benzyloxy) carbonyl] amino} ethyl) -2-iodo-1,3-oxazole-4-carboxylate (Compound IN-11-2) Production Compound IN-11- To 1 (446 mg) in tetrahydrofuran solution (2.1 mL) was added 1.0 mol / L bis (trimethylsilyl) amidolithium-tetrahydrofuran solution (3.08 mL) at −40 ° C. After stirring at −40 ° C. for 15 minutes, a 0.5 mol / L zinc chloride-tetrahydrofuran solution (6.17 mL) was added, the temperature was raised to 0 ° C. in 45 minutes, and then iodine (462 mg) was added. .. After stirring at room temperature for 1 hour, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (510 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 3.27 (2H, t, J = 6.4 Hz), 3.52 (2H, dd, J = 6.4, 6.4 Hz) , 4.34 (2H, q, J = 7.1 Hz), 5.00 (1H, brs), 5.07 (2H, s), 7.32 (5H, dd, J = 10.1, 8.3 Hz).

c) Production of ethyl 5- (2-{[(benzyloxy) carbonyl] amino} ethyl) -2-methyl-1,3-oxazole-4-carboxylate (Compound IN-11-3) Compound IN-11- Potassium carbonate (247 mg), trimethylboroxin (97.0 mg), tetrakistriphenylphosphine palladium (68.9 mg) at room temperature in 2 (265 mg) N, N-dimethylformamide solution (1.5 mL). ) Was added. After reacting at 120 ° C. for 1.5 hours under microwave irradiation, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (100 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 3.16 (2H, t, J = 6.6 Hz), 3.46 (2H, dd, J = 6.3, 6.3 Hz), 4.28 (2H, q, J = 7.2 Hz), 5.01 (2H, s), 5.00-5.03 (1H, br s) 7.27-7.35 (5H, m).

d) Preparation of 2-methyl-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-4 (5H) -one (Reference Example 31) of compound IN-11-3 (710 mg). Palladium on carbon (227 mg) was added to the ethanol solution (11 mL) at room temperature. After stirring at room temperature for 15 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
Potassium carbonate (384 mg) was added to the obtained residue (423 mg) of 1,2-dimethoxyethane / aqueous solution (1 / 1,1.9 mL) at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (209 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.48 (3H, s), 2.99 (2H, t, J = 7.1 Hz), 3.64 (2H, td, J = 7.1, 2.5 Hz), 5.40 (1H, 1H, brs).

参考例３１と同様の手法により、４−（［（ベンジルオキシ）カルボニル］アミノ）ブタン酸から表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.07-2.13 (2H, m), 2.44 (3H, s), 2.94 (2H, t, J = 6.7 Hz), 3.37 (2H, dd, J = 9.8, 5.4 Hz), 6.12 (1H, brs). Reference example 32
2-Methyl-5,6,7,8-Tetrahydro-4H- [1,3] Oxazolo [4,5-c] Azepine-4-one

The title compound was obtained from 4-([(benzyloxy) carbonyl] amino) butanoic acid by the same method as in Reference Example 31.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.07-2.13 (2H, m), 2.44 (3H, s), 2.94 (2H, t, J = 6.7 Hz), 3.37 (2H, dd, J = 9.8) , 5.4 Hz), 6.12 (1H, brs).

Reference example 33
1-Methyl-4,5,6,7-Tetrahydropyrazolo [3,4-c] Azepine-8 (1H) -on

a) Methyl 4- (3-{[(benzyloxy) carbonyl] amino} prop-1-in-1-yl) -1-methyl-1H-pyrazole-5-carboxylate (Compound IN-12-1) Production Methyl-4-iodo-1-methyl-1H-pyrazol-5-carboxylate (600 mg) in N, N-dimethylformamide solution (5.0 mL) with benzylprop-2-in-1-ylcarbamate (5.0 mL). 640 mg), triethylamine (2.20 mL), bis (triphenylphosphine) palladium (II) dichloride (158 mg) and copper (I) iodide (43.0 mg) were added, and the mixture was stirred at 90 ° C. for 3 hours. .. Then, water (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate / toluene (1/1), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (610 mg).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.89 (3H, s), 4.15 (3H, s), 4.24 (2H, d, J = 5.3 Hz), 4.99 (1H, brs), 5.15 (2H, s), 7.29-7.43 (5H, m), 7.54 (1H, s).

b) Production of 1-methyl-4,5,6,7-tetrahydropyrazolo [3,4-c] azepine-8 (1H) -one (Reference Example 33) Compound IN-12-1 (610 mg) 10% Palladium-carbon (600 mg) was added to a methanol solution (10 mL), and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) for 6 hours. The reaction mixture was filtered through Celite and concentrated. Triethylamine (0.519 mL) was added to an ethanol solution (10 mL) of the obtained residue, and the mixture was heated under reflux for 140 hours. The reaction mixture was concentrated and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (130 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.07 (2H, m), 2.86 (2H, t, J = 7.1 Hz), 3.28-3.34 (2H, m), 4.14 (3H, s), 5.93 (1H, brs), 7.31 (1H, s).

参考例３３と同様の手法により、メチル４−ヨード−１−メチル−１Ｈ−ピラゾール−３−カルボキシレートから表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.00-2.09 (2H, m), 2.83 (2H, t, J = 6.8 Hz), 3.33-3.40 (2H, m), 3.95 (3H, s), 6.11 (1H, brs), 7.23 (1H, s). Reference example 34
2-Methyl-4,5,6,7-Tetrahydropyrazolo [3,4-c] Azepine-8 (2H) -on

The title compound was obtained from methyl4-iodo-1-methyl-1H-pyrazole-3-carboxylate by the same method as in Reference Example 33.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.09 (2H, m), 2.83 (2H, t, J = 6.8 Hz), 3.33-3.40 (2H, m), 3.95 (3H, s), 6.11 (1H, brs), 7.23 (1H, s).

Reference example 35
3-Methyl-5,6,7,8-Tetrahydroimidazole [4,5-c] Azepine-4 (3H) -one

a) Methyl 4- (3-{[(benzyloxy) carbonyl] amino} prop-1-in-1-yl) -1-methyl-1H-imidazole-5-carboxylate (Compound IN-13-1) Preparation A mixture of methyl 4-imidazole carboxylate (375 mg), N-bromosuccinimide (529 mg) and acetonitrile (15 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). To a solution of the obtained purified product (0.267 g) in N, N-dimethylformamide (6.5 mL) was added 55% sodium hydride (0.0680 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, iodomethane (0.277 g) was added, and the mixture was stirred at room temperature for 4 hours. Methanol was added to the reaction mixture, the mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). The obtained purified product (176 mg), N- (tert-butoxycarbonyl) propargylamine (228 mg), copper (I) iodide (15.3 mg), triethylamine (0.569 g), bis (triphenyl). A mixture of phosphine) palladium (II) dichloride (56.4 mg) and N, N-dimethylformamide (15 mL) was stirred at 100 ° C. for 1.5 hours under microwave irradiation. Then, the reaction mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (101 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.79-3.91 (5H, m), 4.27 (2H, d, J = 5.1 Hz), 5.13 (3H, s), 7.28-7.42 (5H, m), 7.49-7.61 (1H, m).

b) Preparation of 3-methyl-5,6,7,8-tetrahydroimidazo [4,5-c] azepine-4 (3H) -one (Reference Example 35) Compound IN-13-1 (101 mg), 20 A mixture of% palladium hydroxide-carbon (0.173 g) and methanol (1.7 mL) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. Then, the reaction mixture was filtered and concentrated. The resulting residue (60.9 mg), a mixture of triethylamine (125 mg) and ethanol (1.6 mL) was stirred at 100 ° C. for 72 hours. The reaction mixture was concentrated and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (6.6 mg).
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 1.97-2.08 (2H, m), 2.91-3.00 (2H, m), 3.26-3.36 (2H, m), 3.87 (3H, s), 7.71 ( 1H, s).

２，４−ピペリジンジオン（２００ ｍｇ）、メチルアミノアセトアルデヒドジメチルアセタール（２５３ ｍｇ）、ｐ−トルエンスルホン酸一水和物（３３．６ ｍｇ）とトルエン（８．８ ｍＬ）の混合物をＤｅａｎ−Ｓｔａｒｋ装置存在下、１４０℃で１時間撹拌した。その後、反応混合物を減圧濃縮し、室温にてトリフルオロ酢酸（１．６ ｍＬ）を加えた。室温で２４時間撹拌後、トルエンを加え、溶媒を共沸して留去した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１９４ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.81 (2H, t, J = 6.9 Hz), 3.55-3.62 (5H, m), 5.34 (1H, brs), 6.54 (1H, d, J = 5.0 Hz), 6.55 (1H, d, J = 4.6 Hz). Reference example 36
1-Methyl-1,5,6,7-Tetrahydro-4H-pyrrolo [3,2-c] Pyridine-4-one

Dean-Stark is a mixture of 2,4-piperidindione (200 mg), methylaminoacetaldehyde dimethyl acetal (253 mg), p-toluenesulfonic acid monohydrate (33.6 mg) and toluene (8.8 mL). In the presence of the device, the mixture was stirred at 140 ° C. for 1 hour. Then, the reaction mixture was concentrated under reduced pressure, and trifluoroacetic acid (1.6 mL) was added at room temperature. After stirring at room temperature for 24 hours, toluene was added and the solvent was azeotropically distilled off. The residue was separated and purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (194 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.81 (2H, t, J = 6.9 Hz), 3.55-3.62 (5H, m), 5.34 (1H, brs), 6.54 (1H, d, J = 5.0) Hz), 6.55 (1H, d, J = 4.6 Hz).

参考例３６と同様の手法により、５−メチル−２，４−ピペリジンジオンを用いて表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (3H, d, J = 7.3 Hz), 3.01-3.09 (1H, m), 3.39-3.46 (1H, m), 3.62 (3H, s), 3.82 (1H, dd, J = 13.1, 5.3 Hz), 6.52 (1H, d, J = 3.2 Hz), 6.57 (1H, d, J = 3.2 Hz), 8.82 (1H, brs). Reference example 37
1,7-Dimethyl-1,5,6,7-Tetrahydro-4H-pyrrolo [3,2-c] Pyridine-4-one

The title compound was obtained using 5-methyl-2,4-piperidinedione by the same method as in Reference Example 36.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (3H, d, J = 7.3 Hz), 3.01-3.09 (1H, m), 3.39-3.46 (1H, m), 3.62 (3H, s), 3.82 (1H, dd, J = 13.1, 5.3 Hz), 6.52 (1H, d, J = 3.2 Hz), 6.57 (1H, d, J = 3.2 Hz), 8.82 (1H, brs).

ピペリジン−２，４−ジオン（１０．０ ｇ, ８８．０ ｍｍｏｌ）のＮ，Ｎ―ジメチルホルムアミド溶液（４４ ｍＬ）に、氷冷下メチルヒドラジン（４．７０ ｍＬ，８８．０ ｍｍｏｌ）を加えた。室温で１時間撹拌後、反応混合物にＮ，Ｎ−ジメチルアセトアミドジメチルアセタール（６５．４ ｍＬ，４４２ ｍｍｏｌ）を加えた。１３０℃にて３時間撹拌後、反応混合物を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）にて精製し、表題化合物（１１．２ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.51 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.51 (2H, td, J = 6.6, 2.8 Hz), 3.74 (3H, s), 5.34 (1H, s). Reference example 38
2,3-Dimethyl-2,5,6,7-Tetrahydro-4H-pyrazolo [4,3-c] Pyridine-4-one

To a solution of piperidine-2,4-dione (10.0 g, 88.0 mmol) in N, N-dimethylformamide (44 mL), add methylhydrazine (4.70 mL, 88.0 mmol) under ice-cooling. rice field. After stirring at room temperature for 1 hour, N, N-dimethylacetamide dimethyl acetal (65.4 mL, 442 mmol) was added to the reaction mixture. After stirring at 130 ° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol) to give the title compound (11.2 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.51 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.51 (2H, td, J = 6.6, 2.8 Hz), 3.74 (3H, 3H, s), 5.34 (1H, s).

Reference Example 39 and Reference Example 40
3-Bromo-1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one (Reference Example 39)
3-Bromo-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one (Reference Example 40)

a) Production of 3-bromo-1,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridine-4-one (compound IN-14-1) 1,5,6,7-tetrahydro -4H-Pyrazolo [4,3-c] pyridine-4-one (600 mg), sodium acetate (1.44 g), ethanol (21 mL) and water (14 mL) in a mixture under ice-cooled bromine (4,3-c) 0.451 mL) was added. After stirring for 2 hours under ice-cooling, sodium acetate (1.44 g) and bromine (0.451 mL) were further added. Further, after stirring under ice-cooling for 2 hours, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, the mixture was filtered through Celite, and concentrated under reduced pressure. The residue was dissolved in methanol, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.02 g).
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 2.96 (2H, t, J = 6.9 Hz), 3.54 (2H, t, J = 6.9 Hz).

b) 3-Bromo-1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one (Reference Example 39) and 3-bromo-2-methyl-2 , 5,6,7-Tetrahydro-4H-pyrazolo [4,3-c] Pyridine-4-one (Reference Example 40) N, N-dimethylformamide of compound IN-14-1 (1.02 g) To the solution (10 mL) was added potassium carbonate (1.31 g) and methyl iodide (0.354 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Reference Example 39 (341 mg) and Reference Example 40 (205 mg).
Reference example 39: ¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.88 (2H, t, J = 6.9 Hz), 3.37 (2H, td, J = 6.9, 2.6 Hz), 3.73 (3H, s) ), 7.34 (1H, brs).
Reference example 40: ¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.73 (2H, t, J = 6.6 Hz), 3.34 (2H, td, J = 6.6, 3.1 Hz), 3.78 (3H, s) ), 7.47 (1H, brs).

参考例１３の化合物（１００ ｍｇ）、ビス（（（トリフルオロメチル）スルフィニル）オキシ）ジンク（４３９ ｍｇ）、ジクロロメタン（３．０ ｍＬ）と水（１．２ ｍＬ）の混合物に７０％ ２−ヒドロペルオキシド−２−メチルプロパン水溶液（０．３６２ ｍＬ）を氷冷下滴下した。室温で１６時間撹拌後、１０％チオ硫酸ナトリウム水溶液を反応混合物に加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（０．０４００ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.92 (2H, t, J = 6.6 Hz), 3.56 (2H, td, J = 6.6, 3.2 Hz), 4.04 (3H, q, J = 1.4 Hz), 5.79 (1H, brs). Reference example 41
2-Methyl-3- (trifluoromethyl) -2,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one

70% 2- in a mixture of compound (100 mg), bis (((trifluoromethyl) sulfinyl) oxy) zinc (439 mg), dichloromethane (3.0 mL) and water (1.2 mL) of Reference Example 13. An aqueous solution of hydroperoxide-2-methylpropane (0.362 mL) was added dropwise under ice-cooling. After stirring at room temperature for 16 hours, a 10% aqueous sodium thiosulfate solution was added to the reaction mixture, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (0.0400 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.92 (2H, t, J = 6.6 Hz), 3.56 (2H, td, J = 6.6, 3.2 Hz), 4.04 (3H, q, J = 1.4 Hz) , 5.79 (1H, brs).

Reference example 42
2-Methyl-7,8-dihydropyrido [4,3-d] pyrimidine-5 (6H) -one

a) (3E) -3-[(Dimethylamino) methylidene] Piperidine-2,4-dione (Compound IN-15-1) Production Piperidine-2,4-dione (2.50 g) N, N-dimethyl N, N-dimethylformamide dimethylacetal (3.52 mL) was added to the formamide solution (50 mL), and the mixture was stirred at 90 ° C. for 4 hours. Then, the reaction mixture was concentrated to obtain the title compound (3.72 g).
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.28 (2H, t, J = 6.5 Hz), 3.05 (3H, s), 3.12-3.18 (2H, m), 3.28 (3H, s), 7.12 (1H, brs), 7.82 (1H, s).

b) Preparation of 2-methyl-7,8-dihydropyrido [4,3-d] pyrimidin-5 (6H) -one (Reference Example 42) Compound IN-15-1 (150 mg), N, N-diisopropylethylamine A mixture of (300 mg), acetamidine monohydrate (101 mg) and ethanol (4.5 mL) was stirred at 100 ° C. for 2 hours. Then, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (87.9 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.78 (3H, s), 3.13 (2H, t, J = 6.6 Hz), 3.68 (2H, td, J = 6.6, 2.8 Hz), 5.97 (1H, 1H, s), 9.15 (1H, s).

Reference example 43-44
Compounds of Reference Examples 43 to 44 were obtained using the corresponding reagents according to the method described in Reference Example 42.

Reference example 45
2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethane-1-amine dihydrochloride

a) Production of tert-butyl {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} carbamate (compound IN-16-1) 3- (piperidine-4-yl) Il) Benz-butyl (2-bromoethyl) carbamate (6.65 g), tetrabutylammonium bromide (0) in a mixture of benzo [d] isoxazole (3.00 g), tetrahydrofuran (56 mL) and water (18 mL). .956 g) and potassium carbonate (10.3 g) were added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (5.70 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.05-2.13 (4H, m), 2.13-2.25 (2H, m), 2.52 (2H, t, J = 6.0 Hz), 3.00-3.16 (3H, m), 3.21-3.33 (2H, m), 5.05 (1H, brs), 7.28-7.33 (1H, m), 7.51-7.60 (2H, m), 7.75 (1H, d, J) = 7.8 Hz).

b) Production of 2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethane-1-amine dihydrochloride (Reference Example 45) The same method as in the production of Reference Example 8. Obtained the title compound from compound IN-16-1.
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.16-2.32 (2H, m), 2.33-2.46 (2H, m), 3.15-3.29 (1H, m), 3.30-3.44 (4H, m) , 3.45-3.59 (2H, m), 3.63-3.78 (2H, m), 7.41 (1H, dd, J = 7.4, 7.4 Hz), 7.66 (1H, dd, J = 7.7, 7.7 Hz), 7.75 (1H) , d, J = 8.5 Hz), 8.14 (1H, d, J = 8.0 Hz), 8.46 (3H, brs), 11.35 (1H, brs).

Reference example 46
Methyl 1-methyl-4- (2-oxoethyl) -1H-pyrazole-5-carboxylate

a) Production of methyl 4-[(Z) -2-ethoxyethenyl] -1-methyl-1H-pyrazole-5-carboxylate (Compound IN-17-1) Similar to the production of compound IN-12-1. The title compound was obtained from methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate by the procedure.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 3.91 (3H, s), 3.99 (2H, q, J = 7.1 Hz), 4.13 (3H, s) , 5.79 (1H, d, J = 6.6 Hz), 6.24 (1H, d, J = 6.8 Hz), 8.02 (1H, s).

b) Preparation of methyl 1-methyl-4- (2-oxoethyl) -1H-pyrazole-5-carboxylate (Reference Example 46) Hydrochloric acid solution (1.1 mL) of compound IN-17-1 (95.8 mg). ), 1 mol / L hydrochloric acid (1.1 mL) was added under ice-cooling, and the mixture was stirred at 40 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (79.2 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.78 (2H, d, J = 1.4 Hz), 3.88 (3H, s), 4.19 (3H, s), 7.42 (1H, s), 9.68 (1H, 1H, t, J = 1.6 Hz).

Reference example 47
1- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} azepane-2,4-dione

a) Production of 1,4-dioxa-8-azaspiro [4.6] undecane-7-one (Compound IN-18-1) Atoluene solution (15 mL) of azepan-2,4-dione (1.07 g) ) Was added with ethane-1,2-diol (0.570 mL) and methanesulfonic acid (0.0270 mL), and the mixture was heated under reflux for 4 hours under a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, hexane (15 mL) was added, the mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected by filtration and washed with toluene / hexane = 1/1 (2.0 mL). 1.37 g) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.82-1.90 (2H, m), 1.93-1.99 (2H, m), 2.83 (2H, s), 3.24-3.31 (2H, m), 3.93-4.11 (4H, m), 5.95 (1H, brs).

b) Production of 1- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} azepane-2,4-dione (Reference Example 47) Compound IN-18- To 1 (375 mg) of N, N-dimethylformamide solution (4.4 mL) was added 55% sodium hydride (96.0 mg) under ice-cooling. After stirring for 20 minutes under ice-cooling, the compound of Reference Example 3 (580 mg) and potassium iodide (109 mg) were added, and the mixture was stirred at 50 ° C. for 4 hours. Water was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. In order to distill off the residual N, N-dimethylformamide, the concentration operation by adding toluene to the residue was repeated twice. Tetrahydrofuran (7.3 mL) and 6 mol / L hydrochloric acid (7.30 mL) were added to the obtained concentrated residue, and the mixture was stirred at 60 ° C. for 1 hour. Then, a 2 mol / L sodium hydroxide aqueous solution was added to the reaction mixture, the pH was adjusted to 7 or higher, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (630 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.96-2.15 (6H, m), 2.17-2.29 (2H, m), 2.54-2.63 (2H, m), 2.67 (2H, t, J = 7.3 Hz) ), 3.02-3.14 (3H, m), 3.55 (2H, s), 3.62 (4H, t, J = 5.8 Hz), 7.25-7.30 (1H, m), 7.48-7.57 (2H, m), 7.70 ( 1H, d, J = 7.9 Hz).

実施例４７と同様の手法により、ピペリジン−２，４−ジオンを用いて表題化合物を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.89-1.97 (2H, m), 2.01-2.08 (4H, m), 2.18-2.25 (2H, m), 2.55-2.60 (2H, m), 2.59 (2H, s), 3.04-3.08 (3H, m), 3.45 (2H, t, J = 6.4 Hz), 3.52 (2H, t, J = 6.4 Hz), 3.92-4.00 (4H, m), 7.24-7.28 (2H, m), 7.48-7.55 (2H, m), 7.69-7.73 (1H, m). Reference example 48
8- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -1,4-dioxa-8-azaspiro [4.5] decane-7-one

The title compound was obtained using piperidine-2,4-dione by the same procedure as in Example 47.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.89-1.97 (2H, m), 2.01-2.08 (4H, m), 2.18-2.25 (2H, m), 2.55-2.60 (2H, m), 2.59 (2H, s), 3.04-3.08 (3H, m), 3.45 (2H, t, J = 6.4 Hz), 3.52 (2H, t, J = 6.4 Hz), 3.92-4.00 (4H, m), 7.24- 7.28 (2H, m), 7.48-7.55 (2H, m), 7.69-7.73 (1H, m).

化合物ＩＮ−１８−１（１．２０ ｇ）のＮ，Ｎ−ジメチルホルムアミド溶液（２０ ｍＬ）に、氷冷下５５％水素化ナトリウム（０．４２１ ｇ）を加えた。氷冷下、３０分撹拌後、参考例１の化合物（１．８６ ｇ）とヨウ化カリウム（０．５８２ ｇ）を加え、６０℃で４時間撹拌した。その後、反応混合物に２ ｍｏｌ／Ｌ塩酸を加えて９０℃で１時間攪拌した。その後、反応液に４ ｍｏｌ／Ｌ水酸化ナトリウム水溶液をｐＨ９になるまで加えて、クロロホルムで抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で分離精製し、表題化合物（１．１７ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.06-2.11 (1H, m), 2.62-2.73 (7H, m), 3.54 (4H, t, J = 10.3 Hz), 3.64 (4H, tt, J = 8.3, 4.8 Hz), 4.81 (4H, s), 7.22 (1H, ddd, J = 8.3, 8.0, 0.9 Hz), 7.44-7.51 (2H, m), 7.68 (1H, dd, J = 8.3, 0.9 Hz). Reference example 49
1- {2- [4- (1,2-benzoisoxazole-3-yl) piperazine-1-yl] ethyl} azepane-2,4-dione

To a solution of compound IN-18-1 (1.20 g) in N, N-dimethylformamide (20 mL) was added 55% sodium hydride (0.421 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, the compound of Reference Example 1 (1.86 g) and potassium iodide (0.582 g) were added, and the mixture was stirred at 60 ° C. for 4 hours. Then, 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was stirred at 90 ° C. for 1 hour. Then, a 4 mol / L sodium hydroxide aqueous solution was added to the reaction solution until the pH reached 9, extracted with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.17 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.06-2.11 (1H, m), 2.62-2.73 (7H, m), 3.54 (4H, t, J = 10.3 Hz), 3.64 (4H, tt, J) = 8.3, 4.8 Hz), 4.81 (4H, s), 7.22 (1H, ddd, J = 8.3, 8.0, 0.9 Hz), 7.44-7.51 (2H, m), 7.68 (1H, dd, J = 8.3, 0.9) Hz).

Reference example 50
Methyl 4- [2-({2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} amino) ethyl] -1-[(4-methoxyphenyl) methyl] -1H-pyrazole-3-carboxylate

a) Preparation of methyl 4-iodo-1-[(4-methoxyphenyl) methyl] -1H-pyrazol-3-carboxylate (Compound IN-19-1) Methyl 4-iodo-1H-pyrazol-5-carboxylate To a mixture of (413 mg) and acetonitrile (8.2 mL) was added potassium carbonate (339 mg) and 4-methoxybenzyl chloride (0.268 mL), and the mixture was stirred at 50 ° C. for 2 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (467 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.95 (3H, s), 5.30 (2H, s), 6.90 (2H, d, J = 9.2 Hz), 7.22 (2H, d, J = 8.7 Hz), 7.38 (1H, s).

b) Production of methyl 1-[(4-methoxyphenyl) methyl] -4- (2-oxoethyl) -1H-pyrazole-3-carboxylate (Compound IN-19-2) by the same method as in Reference Example 46. The title compound was obtained from compound IN-19-1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 3.86 (2H, d, J = 0.9 Hz), 3.93 (3H, s), 5.30 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.33 (1H, s), 9.72 (1H, t, J = 1.4 Hz).

c) Methyl 4- [2-({2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} amino) ethyl] -1-[(4-methoxyphenyl) Preparation of Methyl] -1H-Pyrazole-3-carboxylate (Reference Example 50) N, N-diisopropylethylamine (0.144 mL) was added to a dichloromethane solution (1.7 mL) of the compound (105 mg) of Reference Example 45. In addition, it was stirred at room temperature for 5 minutes. Then, compound IN-19-2 (47.6 mg) and acetic acid (0.0283 mL) were added, and the mixture was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (70.0 mg) was added, and 12 at room temperature. Stirred for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to give the title compound (26.2 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.23 (6H, m), 2.52 (2H, t, J = 6.2 Hz), 2.75 (2H, t, J = 10.0 Hz), 2.84 (2H, 2H, t, J = 6.9 Hz), 2.93 (2H, t, J = 6.6 Hz), 2.98-3.12 (3H, m), 3.79 (3H, s), 3.92 (3H, s), 5.27 (2H, s), 6.87 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 7.8 Hz), 7.27-7.32 (1H, m), 7.50-7.59 (3H, m), 7.75 (1H, d, J = 8.3 Hz).

メチル ４−ブロモ−１Ｈ−イミダゾール−５−カルボキシレート（４５０ ｍｇ）、２−（トリメチルシリル）エトキシメチルクロライド（５．４９ ｇ）、トリエチルアミン（３．３３ ｇ）とアセトニトリル（１１ ｍＬ）の混合物を室温で３時間撹拌した。その後、反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製した。得られた精製物（５２８ ｍｇ）、Ｎ−（ベンジルオキシカルボニル）プロパルギルアミン（５９６ ｍｇ）、ヨウ化銅（Ｉ）（６０．０ ｍｇ）、トリエチルアミン（１．５９ ｇ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロライド（２２１ ｍｇ）とＮ，Ｎ−ジメチルホルムアミド（７．９ ｍＬ）の混合物をマイクロウェーブ照射下、１３０℃で１．５時間撹拌した。その後、反応混合物をろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で分離精製し、表題化合物（４０１ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: -0.08-0.01 (9H, m), 0.81-0.99 (2H, m), 1.99-2.08 (3H, m), 3.42-3.65 (2H, m), 3.77-3.96 (2H, m), 4.04-4.18 (2H, m), 4.96-5.22 (2H, m), 7.28-7.42 (5H, m), 7.72 (1H, s). Reference example 51
Methyl 4- (3-{[(benzyloxy) carbonyl] amino} prop-1-in-1-yl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-5-carboxylate

A mixture of methyl 4-bromo-1H-imidazol-5-carboxylate (450 mg), 2- (trimethylsilyl) ethoxymethyl chloride (5.49 g), triethylamine (3.33 g) and acetonitrile (11 mL) at room temperature. Was stirred for 3 hours. Then, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). The obtained purified product (528 mg), N- (benzyloxycarbonyl) propargylamine (596 mg), copper (I) iodide (60.0 mg), triethylamine (1.59 g), bis (triphenylphosphine). A mixture of palladium (II) dichloride (221 mg) and N, N-dimethylformamide (7.9 mL) was stirred at 130 ° C. for 1.5 hours under microwave irradiation. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (401 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: -0.08-0.01 (9H, m), 0.81-0.99 (2H, m), 1.99-2.08 (3H, m), 3.42-3.65 (2H, m), 3.77-3.96 (2H, m), 4.04-4.18 (2H, m), 4.96-5.22 (2H, m), 7.28-7.42 (5H, m), 7.72 (1H, s).

Reference example 52
[4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] acetaldehyde

a) Production of 3- [4- (2,2-diethoxyethyl) piperazin-1-yl] -1,2-benzoisothiazole (compound IN-20-1) 3- (piperazine-1-yl) benzo [D] Iodide with 2-bromo-1,1-diethoxyethane (2.16 g) and potassium carbonate (2.52 g) in an acetonitrile solution (9.1 mL) of isothiazole (2.00 g). Potassium (0.151 g) was added. After heating under reflux for 13 hours, ethyl acetate (30 mL) was added to the reaction mixture, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.04 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.22 (6H, t, J = 6.9 Hz), 2.63 (2H, d, J = 5.0 Hz), 2.77 (4H, t, J = 4.8 Hz), 3.50 -3.61 (6H, m), 3.65-3.74 (2H, m), 4.69 (1H, t, J = 5.3 Hz), 7.30-7.35 (1H, m), 7.42-7.47 (1H, m), 7.79 (1H) , d, J = 7.8 Hz), 7.89 (1H, d, J = 8.3 Hz).

b) Production of [4- (1,2-benzoisothiazole-3-yl) piperazine-1-yl] acetaldehyde (Reference Example 52) Compound IN-20-1 (3.04 g) with 47% hydrogen bromide Acid (15.0 mL) was added and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was poured into ice water (40 mL), 20% aqueous sodium hydroxide solution (27 mL) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.48 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.77 (4H, t, J = 5.0 Hz), 3.27 (2H, d, J = 1.4 Hz), 3.61 (4H, t, J = 5.0 Hz), 7.32 -7.37 (1H, m), 7.43-7.48 (1H, m), 7.80 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 9.75 (1H, t, J = 1.4) Hz).

Reference example 53
Methyl 4- (2-aminoethyl) -6- (trifluoromethyl) pyridine-3-carboxylate monohydrochloride

a) Methyl 4- {2-[(tert-butoxycarbonyl) amino] ethyl} -6- (trifluoromethyl) pyridine-3-carboxylate (Compound IN-21-1) Production of Compound IN-7-2 The title compound was obtained from methyl 4-iodo-6-trifluoromethylpyridine-3-carboxylate by the same procedure as in the production.
LC-MS: RT = 1.693 min ObsMS = 249 [M + 1]

b) Preparation of methyl 4- (2-aminoethyl) -6- (trifluoromethyl) pyridine-3-carboxylate monohydrochloride (Reference Example 53) Compound IN-21-1 (1.13 g), ethyl acetate To a mixture of (3.0 mL) and methanol (6.0 mL) was added 4 mol / L hydrochloric acid-ethyl acetate (20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give the title compound (0.942 g).
LC-MS: RT = 1.002 min ObsMS = 249 [M + 1]

Reference example 54
5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2- (triphenylmethyl) -2,5,6,7-tetrahydro-4H- Pyrazolo [4,5-c] Pyridine-4-one

a) Preparation of 2- (triphenylmethyl) -2,5,6,7-tetrahydro-4H-pyrazolo [4,3-c] pyridin-4-one (compound IN-22-1) 6,7-dihydro -1H-Pyrazolo [4,3-c] Pyridine-4 (5H) -one (0.500 g) in N, N-dimethylformamide solution (7.0 mL) with triethylamine (0.762 mL), trityl chloride (1.02 g) was added. After stirring at room temperature for 18 hours, water and hexane were added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound (0.796 g).
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.77 (2H, t, J = 6.6 Hz), 3.36-3.41 (2H, m), 7.03-7.09 (6H, m), 7.33-7.41 (9H) , m), 7.46-7.50 (2H, m).

b) 5- {2- [4- (1,2-benzoisoxazole-3-yl) piperidine-1-yl] ethyl} -2- (triphenylmethyl) -2,5,6,7-tetrahydro- Production of 4H-Pyrazolo [4,3-c] Pyridine-4-one (Reference Example 54) The title compound was obtained from the compound of Reference Example 3 and compound IN-21-1 by the same method as in Example 3. ..
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.76-1.88 (2H, m), 1.98-2.05 (2H, m), 2.12-2.21 (2H, m), 2.50-2.54 (2H, m) , 2.87 (2H, t, J = 6.6 Hz), 2.99-3.06 (2H, m), 3.08-3.18 (1H, m), 3.52 (2H, t, J = 6.8 Hz), 3.65 (2H, t, J) = 6.8 Hz), 7.04-7.10 (6H, m), 7.32-7.41 (10H, m), 7.49 (1H, s), 7.59-7.64 (1H, m), 7.70 (1H, d, J = 8.3 Hz) , 7.92 (1H, d, J = 7.8 Hz).

Test Example 1: Evaluation of binding activity to _{human 5-HT 1A} receptor, human 5-HT _2A receptor and human D _{2 receptor Human 5-HT 1A} receptor, human 5-HT of the compound of the present invention the binding affinity _2A receptor and human D ₂ receptors was measured by the following method.
CHO cell membrane fractions expressing human 5-HT _1A receptor, human 5-HT _2A receptor and human D ₂ receptor were purchased from PerkinElmer. In the binding evaluation test, the test compound dissolved in dimethylsulfoxide (DMSO), various receptor membrane specimens diluted with a buffer, and [3H] 8-OH-DPAT, 5-HT for 5- _{HT1A receptor. 2A} for receptors [3H] Ketanserin, for _{D 2} receptors [3H] spiperone (above all from Perkin Elmer) were mixed and after incubation for 60 minutes at room temperature, respectively, 0.3% polyethylene imine solution It was immediately added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with the above, and suction filtered. The radioactivity remaining on the filter was measured using a liquid scintillation counter (manufactured by PerkinElmer). The binding inhibition rate was calculated by the following formula.

5-HT _1A receptor binding inhibition rate (%) = 100-100 × {([ ³ H] 8-OH-DPAT binding amount in the presence of test substance)}-(10 μmol / L 8-OH-DPAT presence) ^{[3 H] 8-OH-} DPAT binding amount)} / {(test substance in the absence ^{[3 H] 8-OH-} DPAT binding amount)} under - (10μmol / L 8-OH -DPAT present ^{[3 H] 8-OH-} DPAT binding amount under)}

5-HT _2A receptor binding inhibition rate (%) = 100-100 × {( ^{amount of [3 H] Ketanserin bound in the presence of test substance)}-([3} H] Ketanserin in the presence of 10 μmol / L Mianserin binding amount)} / {(test substance in the absence ^[3 H] Ketanserin binding ^{amount)} - (10μmol / L [} 3 H] Ketanserin binding amount in the Mianserin presence)}

D ₂ binding inhibition rate to the receptor (%) = 100-100 × {( [3 H] Spiperone binding amount under test substance ^{exists)} - ([3 H]} Spiperone binding amount in the presence of 10 .mu.mol / L spiperone )} / {(test substance in the absence ^[3 H] spiperone binding ^{amount)} - (10μmol / L [} 3 H] spiperone binding amount of spiperone presence)}

The IC ₅₀ value, Hill analysis (Physiology, 1910, 40, 190-200 ) was calculated by. The Ki of each compound was calculated by the following formula.
Binding inhibition constant (Ki) = IC ₅₀ / (1 + S / Kd)
Here, S represents the concentration of the added ligand. The Kd value represents the binding dissociation constant of the ligand to the membrane, and the value calculated from the saturated binding experiment separately performed using the same cell membrane was used. The smaller the Ki value, the stronger the binding to the receptor.

Test Example 2: was purchased CHO membrane fraction was expressed similar human 5-HT _1A receptor as used in agonistic activity Evaluation Test Example 1 for the human 5-HT _1A receptor. A test compound dissolved in DMSO, various receptor membrane specimens diluted with the buffer solution, and [ ³⁵ S] Guanosine 5'-O- [gamma-thio] triphosphate (GTPγS) are mixed in a buffer solution containing guanosine diphosphate. After incubation for 60 minutes at room temperature, the mixture was rapidly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) and suction filtered. The radioactivity bound to the receptor was measured using a liquid scintillation counter. The agonist activity was calculated by the following formula.

Agonist activity against 5- _HT1A receptor (%) = 100 × {([ ^{35 S] GTPγS binding amount in the presence of test substance)}-([35} S] GTPγS binding amount in the presence of 20 μmol / L GTPγS) ^{} / {([35} S] GTPγS binding amount in the presence of 100 μmol / L 5-HT ^)-([35 S] GTPγS binding amount in the presence of 20 μmol / L GTPγS)}
Here, the agonist activity in the presence of 10 μM of each compound was defined as the maximum activity (E _max ) of each compound, and the concentration showing half the activity of _{E max} was calculated as _{EC 50.}

Test Example 3: antagonistic activity rating aequorin against human _{5-HT 2A} receptor, Gal6 proteins, each receptor transiently in CHO-K1 cells (Chinese hamster ovary) overnight in a CO ₂ incubator were expressed in 37 After culturing at ° C., the cells were seeded on a 384-well plate and allowed to stand at room temperature for 2 hours or more. Various compounds dissolved in DMSO were added, and changes in the amount of luminescence were measured with an FDSS / μCELL drug discovery screening support system (manufactured by Hamamatsu Photonics). The antagonist activity was calculated by the following formula.

Antagonist activity (%) = 100 × {(amount of light emitted from the well in the presence of 1 nmol / L 5-HT-amount of light emitted from the solvent-added well)-(amount of light emitted from the well in the presence of the test substance and 1 nmol / L 5-HT) Amount-Emission amount of solvent-added well)} / (Emission amount of well in the presence of 1 nmol / L 5-HT-Emission amount of solvent-added well)
Here, the concentration of the test substance when the antagonist activity became 50% was calculated as _{IC 50.} The results are shown in the table below.

Test Example 4: Human hepatic microsome metabolic stability test The human hepatic microsome metabolic stability of the compound of the present invention was evaluated by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and the test substance were mixed in 25 mmol / L phosphate buffer (pH 7.4) to the following concentrations and incubated at 37 ° C. for 30 minutes.
-Human liver microsomes: 0.1 mg / mL
-NAPDH: 3.2 mmol / L,
-Test substance: 0.1 μmol / L
The residual rate of the test substance in the sample after 30 minutes was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated from the following formula.
Human liver microsome metabolic stability (mL / min / mg protein) = -LN (residual rate) / 30 / 0.1
The results are shown in the table below.

Test Example 5: Human Half-Life Prediction Test The elimination half-life of the compound of the present invention in humans was predicted by the following method.
The compound of the present invention is intravenously administered to cynomolgus monkeys in a 0.01 mol / L hydrochloric acid aqueous solution, and blood is spilled 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration. Collected. Plasma was obtained from the collected blood, the plasma drug concentration was measured by LC-MS, and the monkey distribution volume was calculated from this concentration transition.
The unbound fraction of the compound of the present invention in humans and monkeys was measured using equilibrium dialysis.
The half-life in humans was calculated by applying the following formula using the results of monkey distribution volume, human and monkey serum unbound fractions, and human hepatic microsome metabolic stability obtained in Test Example 3.
-Human volume of distribution = Monkey distribution volume x Human serum unbound fraction / Monkey serum unbound fraction-Human liver clearance = (Human liver blood flow x Human serum unbound fraction x 56.7 x Human hepatic microsome metabolic stability) / (human hepatic blood flow + unbound volume of distribution in human serum x 56.7 x human hepatic mylosome metabolic stability)
-Human half-life = 0.693 x human volume of distribution / human liver clearance The results are shown in the table below.

Test Example 6-1: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory effect of the compound of the present invention was auto-expressed using CHO cells in which the hERG channel involved in _{the human rapidly activated delayed rectified potassium current (I Kr) was forcibly expressed.} It was measured by the whole cell patch clamp method using a patch clamp system.
(Preparation of cell suspension)
The hERG-CHO cells purchased from ChanTest were cultured in a CO ₂ incubator at 37 ° C. and exfoliated from the flask using trypsin immediately before the measurement of the hERG current to prepare a cell suspension.
(Solution preparation)
The extracellular fluid and intracellular fluid used for the measurement were prepared as follows.
Extracellular fluid: 2 mmol / L CaCl ₂ , 1 mmol / L MgCl ₂ , 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose
Intracellular fluid: 5.4 mmol / L CaCl ₂ , 1.8 mmol / L MgCl ₂ , 10 mmol / L HEPES, 31 mmol / L KOH, 10 mmol / L EGTA, 120 mmol / L KCl, 4 mmol / L Na _2- ATP
Test substance solution: The test substance was dissolved in DMSO to 2 mmol / L or 20 mmol / L to prepare a test substance solution. Furthermore the test substance solution was diluted 200-fold in the extracellular fluid, it the test substance solution of the concentration required for the calculation of hERG inhibition The IC ₅₀ values by serial dilution with the extracellular solution was prepared and applied.
(Current value measurement and data analysis)
The cell suspension, extracellular fluid, intracellular fluid, and measuring plate were placed in the auto patch clamp system, and hERG current measurement was performed by the whole cell patch clamp method. In the voltage protocol, the holding potential was set to −80 mV, a depolarizing pulse was applied from −50 mV to +20 mV for 5 seconds, and then a repolarized pulse was applied at −50 mV for 5 seconds to return to the holding potential. The interval between each pulse was 15 seconds. Assay software for the Qpatch system (manufactured by Biolin Scientific) was used for data analysis. Four concentrations were gradually applied to each test substance, and the average value of the maximum outward current (Peak tail current) obtained by the final three stimulations of each applied concentration was used as the evaluation data. Further, the inhibition of current at each concentration of each test substance on applying prior value, IC ₅₀ values were calculated by Hill equation using the software (Hill equation).
The results are shown in the table below.

Test Example 6-2: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory effect of the compound of the present invention was auto-expressed using CHO cells in which the hERG channel involved in _{the human rapidly activated delayed rectified potassium current (I Kr) was forcibly expressed.} It was measured by the whole cell patch clamp method using a patch clamp system.
(Preparation of cell suspension)
The hERG-CHO cells purchased from ChanTest _{were cultured in a CO 2} incubator at 37 ° C. and exfoliated from the flask using trypsin immediately before the measurement of the hERG current to prepare a cell suspension.
(Solution preparation)
The extracellular fluid and intracellular fluid used for the measurement were prepared as follows.
Extracellular fluid: 2 mmol / L CaCl ₂ , 1 mmol / L MgCl ₂ , 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose
Intracellular fluid: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF
Test substance solution: The test substance was dissolved in DMSO to 2 mmol / L or 20 mmol / L to prepare a test substance solution. Furthermore the test substance solution was diluted 200-fold in the extracellular fluid, it the test substance solution of the concentration required for the calculation of hERG inhibition The IC ₅₀ values by serial dilution with the extracellular solution was prepared and applied.
(Current value measurement and data analysis)
The cell suspension, extracellular fluid, intracellular fluid, and measuring plate were placed in the auto patch clamp system, and hERG current measurement was performed by the whole cell patch clamp method. In the voltage protocol, the holding potential was set to −80 mV, a depolarizing pulse was applied from −50 mV to +20 mV for 5 seconds, and then a repolarized pulse was applied at −50 mV for 5 seconds to return to the holding potential. The interval between each pulse was 15 seconds. For data analysis, analysis software for Qube (manufactured by Sophion Sophion) was used. Four concentrations were gradually applied to each test substance, and the average value of the maximum outward current (Peak tail current) obtained by the final three stimulations of each applied concentration was used as the evaluation data. Further, the inhibition of current at each concentration of each test substance on applying prior value, IC ₅₀ values were calculated by Hill equation using the software (Hill equation).
The results are shown in the table below.

Test Example 7: MK-801-induced hyperkinesia suppression test 7-week-old male SD rats were used. A 0.5% methylcellulose solution was used as a solvent to prepare the administration solution of the test compound, and the mixture was turbid and used. The administration solution of MK-801 was prepared by dissolving and using physiological saline as a solvent.
The MK-801-induced hyperkinetic suppression test was carried out as follows using SuperMex manufactured by Muromachi Kikai Co., Ltd., a data acquisition program CompACT AMS, and a transparent plastic cage.
The animals were placed in the cage described above and the momentum measurement was started. Forty-five minutes later, the rat was gently taken out together with the cage, and the compound administration solution (solvent or test compound turbid solution) and MK-801 administration solution (solvent or MK-801 solution) were orally administered and subcutaneously administered, respectively, and the cage was measured. I returned it to the position. The measurement was completed 2 hours and 30 minutes after the start of the momentum measurement. The 90-minute data from 1 hour (15 minutes after administration of the compound, MK-801) to 2 hours and 30 minutes after the start of the exercise measurement was used as the test result, and the exercise amount of each individual for 90 minutes was totaled.
The analysis of the test results was carried out as follows.
Parametric Dunnett's multiple comparisons (significance level: 5% on both sides) were performed between the test compound administration group and the solvent administration group. When the test compound administration group showed a significant suppression of the amount of exercise as compared with the solvent administration group, it was judged to have an antipsychotic effect.
The results of the above tests are shown in FIGS. 1 and 2.

Test Example 8: Evaluation of binding activity to side effect-related receptors The binding affinity of the compound of the present invention to side effect-related receptors (for example, adrenaline α receptor, histamine receptor, muscarinic receptor, etc.) shall be measured by the following method. Can be done.
Using the CHO cell membrane fraction expressing the human-type target receptor, a binding evaluation test is carried out as follows. After mixing the test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and the [3H] -labeled ligand having strong binding activity to each target receptor, and incubating each at room temperature. , Immediately add to a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) and filter under reduced pressure. A liquid scintillation counter (manufactured by PerkinElmer) is used to measure the radioactivity remaining on the filter. The binding inhibition rate is calculated by the following formula. To calculate the amount of non-specific binding to the receptor membrane specimen, a control compound having strong binding activity to the target receptor is used instead of the test substance.

Binding inhibition rate to the target receptor (%) = 100-100 × {( [3 H] labeled ligand binding amount under test substance present)} - (in the presence of 10 .mu.mol / L control compound ^[3 H] labeled ligand binding amount)} / {(test substance in the absence ^{[3 H]} labeled ligand binding amount)} - ^{([3 H]} labeled ligand binding amount in the presence of 10 .mu.mol / L control compound)}

Test Example 9: Evaluation of P-gp Substrate Property NFR (Net Flux Ratio), which is an index of P-gp substrate property, can be calculated by the following method. Appearance from the luminal side (A side) to the basal membrane side (B side) using MDCKII (Madin-Darby canine kidney strain II) cells and MDR1-MDCKII cells overexpressing MDR1 (multidrug resistance protein 1). Permeation coefficient (Papp AB) and apparent permeation coefficient (Papp BA) from the basal membrane side (B side) to the luminal side (A side) were measured for each of MDCKII cells and MDR1-MDCKII cells. did. NFR (Net Lux Ratio) was calculated from the ratio of the apparent permeability coefficient of MDR1-MDCKII cells to Rio (Papp BA / Papp AB) and the apparent permeability coefficient of MDCKII cells to Rio.

The results of Test Example 9 are shown in the table below.

Test Example 10: Evaluation of intracerebral transfer (rat intracerebral transfer test)
In this test, the intracerebral transferability of the compound of the present invention can be evaluated by the following method. The compound of the present invention is subcutaneously administered in a physiological saline solution or orally administered in a methylcellulose suspension solution to SD or WKY 7-week-old rats, and 0.5 hours, 1 hour, or 2 hours after administration. Plasma and brain were collected from plasma and the drug concentrations in plasma and brain were measured by LC-MS.
The serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
Kp, uu, brain (brain / plasma unbound drug concentration ratio) was determined by applying the plasma and brain compound concentrations and plasma and brain protein binding rates obtained by the above test to the following formulas. Can be calculated.
Kp, uu, brain = (Brain compound concentration x (100-Brain protein binding rate (%)) / 100) / (Plasma compound concentration x (100-Plasma protein binding rate (%)) / 100)

The results of Test Example 10 are shown in the table below.

Test Example 11: Assessment of hepatotoxicity risk (dansylated glutathione (dGSH) trapping assay)
The compound of the present invention was metabolized in hepatic microsomes by the following method, and a reactive metabolite that reacts with dansylated glutathione (dGSH) was detected and quantified from the metabolites produced. The metabolic reaction was measured using a screening robot (manufactured by Tecan), and the concentration of metabolite-dGSH conjugate was measured using a fluorescence detection UPLC system (manufactured by Waters).

(Solution preparation)
The compound of the present invention was dissolved in DMSO to prepare a 10 mmol / L test substance solution. A microsome solution was prepared by mixing 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (manufactured by Xenotech, 20 mg protein / mL), and 1.27 mL of pure water. .. A microsome (dGSH (−)) solution was prepared by adding 0.67 mL of pure water to 3.78 mL of the microsome solution. 1.14 mL of dGSH solution (20 mmol / L) was added to 6.48 mL of microsome solution to prepare a microsome (dGSH (+)) solution. A cofactor solution was prepared by dissolving 80.9 mg of NADPH in 30 mL of pure water. A reaction terminator was prepared by dissolving 33 mg of Tris (2-carboxyethyl) phosphin (TECP) in 115 mL of methanol.

(reaction)
12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL each was dispensed into 6 wells on a 96-well plate. The above 6 wells were divided into 3 groups of 2 wells each, and were designated as a "reaction group", a "unreacted group" and a "dGSH non-added group", respectively. 50 μL of microsome (dGSH (+)) solution was added to the “reaction group” and “unreacted group”, and 50 μL of microsome (dGSH (−)) was added to the “dGSH non-added group”. A cofactor solution was added to the "reaction group" and the "dGSH non-added group", and 50 μL of pure water was added to the "unreacted group". After incubating at 37 ° C. for 60 minutes, the reaction was stopped by adding 450 μL of the reaction terminator solution. Add pure water to the "reaction group" and "dGSH non-added group", add 50 μL of cofactor solution to the "unreacted group", cool the plate at -20 ° C for 1 hour, and then centrifuge (4000 rpm, 10 minutes). went. The supernatant was collected on a separate plate and used for analysis.

(analysis)
The concentration of metabolite-dGSH conjugate was measured under the following conditions using a fluorescence detection UPLC system (manufactured by Waters).
Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 x 10 mm
Elution solvent: A, 0.2% formic acid aqueous solution; B, 0.2% formic acid / acetonitrile gradient: B, 20% (0 min) → 70% (9.33 min) → 90% (10.63 min) → 20% (11 min) → 20% (14 min)
Since the fluorescence intensity changes depending on the organic solvent composition, the correction was made with the organic solvent composition at the time of elution.

The results of Test Example 11 are shown in the table below.

Test Example 12: Evaluation of enzyme-inducing ability The enzyme-inducing ability of the compound of the present invention was measured by the following method.
-Preparation of induction medium A DMSO solution (10 mmol / L) of the test compound was diluted with HepaRG serum-free Induction Medium to prepare an induction medium (containing 0.1% DMSO) of 1 μmol / L or 10 μmol / L.
-Cell culture After thawing HepaRG cells, dilute them with HepaRG Thawing Medium to 1.25 x 106 viable cells / mL ^{and seed each well of the collagen I-coated 96-well plate to 1.0 x 10 5} cells / well. did. Incubation was carried out under 37 ° C. and 5% CO ₂ conditions for 6 hours, and after confirming cell adhesion, the cells were replaced with fresh HepaRG Teawing Medium and _{incubated under 37 ° C. and 5% CO 2} conditions for 3 days. Then, HepaRG Thawing Medium was removed, an induction medium containing each concentration of the test substance was added, and the mixture was incubated for 48 hours. The induction medium was changed every 24 hours.
-MRNA expression fluctuation analysis RNA was purified using RNeasy 96, and cDNA was synthesized using SuperScript IV VILO Master Mix. The mRNA expression level was measured by real-time PCR using TaqMan Gene Expression Assays and TaqMan Fast Advanced Master Mix.
-Calculation of Induction Magnification (Fold Induction) The induction magnification of each CYP molecular species was calculated as follows.
Induction magnification = 2 ^ (-ΔΔCt)
ΔΔCt = ΔCt (test substance treatment) −ΔCt (solvent control treatment)
ΔCt = Ct (target gene) -Ct (endogenous control gene)
Ct: Threshold Cycle at a certain number of fluorescence intensities

The results of Test Example 12 are shown in the table below.

The compound of the present invention is useful as a therapeutic agent for neuropsychiatric disorders because it exhibits _{antagonistic activity against serotonin 5-HT 2A} receptor and agonist activity against serotonin 5-HT _{1A receptor.}

Claims (25)

Equation (1):

[During the ceremony,
V represents ^CR A ^{R B;}
n represents 1 or 2;
Z represents a nitrogen atom, a carbon atom or -CR ^J- ;
t represents 1, 2 or 3;
The bond (a) containing the dashed line represents a single bond or a double bond;
R ^A and ^{R B} are each independently, also independent from each other when ^{the R A} or ^{R B} is more, a hydrogen _{atom, C 1-6 alkyl, C 1-6} alkoxy or _{C 3-10} cycloalkyl (The alkyl, the alkoxy and the cycloalkyl may be independently substituted with the same or different 1 to 3 halogens);
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen or a C _1-6 alkyl which may be substituted with the same or different 1 to 3 halogens;
Ring Q ¹ is expressed by the following equation (2):

{In the formula,
Ring Q ³ are an aromatic heterocycle optionally substituted 5 or 6-membered;
W represents ^CR C ^{R D;}
m represents 0 or 1;
X is, -CR ^E - or ^-CR F ^{R G} - represents;
Y represents a nitrogen atom or -CR ^H- ;
The bond (b) containing the broken line represents the group represented by}, which represents a single bond or a double bond;
Ring ^{Q 2} is the following formula (3a) or (3b):

{In the formula,
R ^2a , R ^2b , R ^2c and R ^2d are independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are independent and the same, respectively). Represents an amino represented by (or may be substituted with 1 to 3 different halogens) or may be substituted with the same or different 1 to 2 C _{1-6 alkyl}.}
^{R C, R D, R E} , R F, R G, R H and ^{R J} are each independently a hydrogen _{atom, C 1-6 alkyl, C 1-6} alkoxy or _{C 3-10} cycloalkyl (said Alkyl, the alkoxy and the cycloalkyl may be independently substituted with the same or different 1-3 halogens), where ^RF and ^RG are C _1-6 alkyl. In some cases, they may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbon ring;
put it here,
When (I) the ring ^{Q 3} is an aromatic heterocyclic ring may 5 membered ^{substituted, R 2a, R 2b, R} 2c and ^{R 2d,} is an both hydrogen atoms;
(II) when ring Q ³ is an aromatic heterocyclic 6-membered optionally substituted, m is 0;
(III) When the bond (a) containing the broken line is a double bond, Z is a carbon atom;
When (IV) bond containing a broken line (b) is a single bond, X is ^-CR F ^{R G} - a and;
(V) when coupling including dashed (b) is a double bond, X is -CR E ^- a is] a compound or a pharmaceutically acceptable medicament containing a salt represented. Ring ^{Q 3} is a hydrogen atom, a halogen, _{cyano, C 1-6 alkyl, C 3-10} cycloalkyl (which alkyl and the cycloalkyl are each independently replaced with the same or different 1 to 3 halogens _(May be), and C 1-6 alkoxy, which is selected from the group consisting of the same or different 1-3 halogens or 4-8 member saturated heterocyclic groups. The medicament according to claim 1, which is a 5- or 6-membered aromatic heterocycle which may be substituted with 1 to 3 identical or different substituents. Equation (1) is the equation (1a):

[In the formula, the ^{bond (a) including Q 1} , Q ² , V, Z, n, R ^1a , R ^1b , R ^1c , R ^1d and a broken line is synonymous with the above], claim 1 or The medicament according to claim 2. The medicament according to any one of claims 1 to 3, wherein R ^1a , R ^1b , R ^1c and R ^{1d are all hydrogen atoms.} R ^A and R ^B are both hydrogen atom, a pharmaceutical as claimed in any one of claims 4. The medicament according to any one of claims 1 to 5, wherein n is 2. The medicament according to any one of claims 1 to 6, wherein the bond (a) including the broken line is a single bond. Equation (1) is the following equation (1b):

Wherein, Q ^1, Q ² and Z has the same meanings as defined above] is represented by the medicament according to claim 1 or claim 2. The medicament according to any one of claims 1 to 8, wherein Z is a nitrogen atom. The medicament according to any one of claims 1 to 8, wherein Z is −CH−. The medicament according to any one of claims 1 to 10, wherein Y is a nitrogen atom. The medicament according to any one of claims 1 to 11, wherein the bond (b) including the broken line is a single bond and X is −CH _2-. Ring Q ¹ has the following equations (4a), (4b), (4c), (4d), (4e) or (4f):

[During the ceremony,
R ^3a and R ^3b are independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are independently the same or different 1-3). _{Represents an amino that may be substituted with one or two C 1-6} alkyls that are the same or different], any one of claims 1 through 12. The medicines described in the section. Ring Q ¹ is the following formula (5a), (5b), (5c), (5d), (5e), (5f) or (5g):

[During the ceremony,
R ^4a represents C _1-6 alkyl or C _1-6 alkoxy.
R ^4b represents a hydrogen atom or C _1-6 alkyl.
R ^4c and R ^4d independently represent a hydrogen atom or C _1-6 alkyl, where ^{when either R 4c} or R ^4d is a hydrogen atom, the other represents a _{C 1-6 alkyl.} , Also, R ^4c and R ^4d may form a 3- to 6-membered saturated carbon ring together with the carbon atom to which they are bonded], any one of claims 1 to 12. The medicines described in the section. Ring Q ² is formula (3a), a pharmaceutical according to any one of claims 14 to claim 1. Ring Q ² is formula (3b), the pharmaceutical according to any one of claims 14 to claim 1. The medicament according to any one of claims 1 to 16, wherein R ^2a , R ^2b , R ^2c and R ^{2d are all hydrogen atoms.} The medicament according to claim 1, wherein the compound represented by the formula (1) is represented by any of the following formulas.

The medicament according to any one of claims 1 to 18, for use in the treatment of a psychiatric disorder or a central nervous system disorder. Psychiatric or central nervous system disorders, including symptomatic organic psychiatric disorders; mental and behavioral disorders due to the use of psychoactive substances; schizophrenia, schizophrenia-type disorders and delusional disorders; mood [emotion] disorders; nerves Symptomatic disorders, stress-related disorders and physical expression disorders; non-organic sleep disorders; not due to sexual dysfunction, organic disorders or illnesses; diffuse developmental disorders; behavioral and emotional disorders that normally occur in childhood and adolescence 19. The medicament according to claim 19, which is a disorder of the extrapyramidal tract and abnormal movements; other degenerative diseases of the nervous system; or a sleep disorder. Psychiatric or central nervous system disorders associated with schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, dementia Psychiatric symptoms, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, psychiatric symptoms associated with Parkinson's disease dementia, psychiatric symptoms associated with Parkinson's disease, or irritation, agitation or aggression associated with Alzheimer's disease. The medicament according to claim 19. Psychiatric or central nervous system disorders are schizophrenia, psychiatric symptoms associated with dementia, psychiatric symptoms associated with Alzheimer's disease, psychiatric symptoms associated with Levy body dementia, or irritation, agitation or aggression associated with Alzheimer's disease. , The medicament according to claim 19. Use of the medicament according to any one of claims 1 to 18, for producing a therapeutic agent for a psychiatric disorder or a central nervous system disease. The medicament according to any one of claims 1 to 18, antidepressants, antidepressants, schizophrenia therapeutic agents, dopamine replacement agents, dopamine receptor agonists, Parkinson's disease therapeutic agents, antiepileptic agents, A combination of at least one drug selected from the group consisting of anticonvulsants, analgesics, hormone preparations, migraine treatments, adrenaline β receptor antagonists, dementia treatments, mood disorder treatments, antiemetics and sleep inducers. A drug for use in the treatment of psychiatric or central nervous system disorders. Antidepressants, anxiolytics, schizophrenia drugs, dopamine replacement drugs, dopamine receptor agonists, Parkinson's disease drugs, antiepileptic drugs, anticonvulsants, analgesics, hormone preparations, migraine drugs, adrenaline β acceptance Claims for treating psychiatric or central nervous system disorders in combination with at least one agent selected from the group consisting of body antagonists, dementia therapeutic agents, mood disorder therapeutic agents, antiemetics and sleep-inducing agents. The medicament according to any one of claims 1 to 18.

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