JP2023008912A - Pharmaceutical composition containing aliphatic acid amide derivative - Google Patents

Abstract

To provide a pharmaceutical composition containing a novel compound useful as a therapeutic agent for neuropsychiatric disorder.SOLUTION: A pharmaceutical composition contains a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, having antagonist activity to serotonin 5-HT2A receptor and serotonin 5-HT7 receptor [where Z is a nitrogen atom or the like, Y is carbonyl or the like, m and n each denote 1 or the like, R1a-R1d, R2a-R2d, R4a-R4d each denote a hydrogen atom or the like, R3 is alkyl or the like, Q is a predetermined bicyclic ring group].SELECTED DRAWING: None

Description

The present invention provides an aliphatic acid amide derivative or a pharmaceutically acceptable salt thereof having antagonistic activity against serotonin 5-HT _2A receptors and serotonin 5-HT ₇ receptors, and psychoneurotic agents containing the derivatives as active ingredients. It relates to therapeutic agents for diseases.

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

The 5-HT _2A receptor, one of the subtypes of the 5-HT receptor, is a Gq/11 protein-coupled receptor and is highly expressed in the cerebral cortex, hippocampus, raphe nuclei, and the like. Drugs with antagonistic activity to the 5-HT _2A receptor include the antidepressants mianserin and mirtazapine. In addition, all atypical antipsychotics have antagonistic activity against 5- _HT2A receptors and are used as therapeutic agents for schizophrenia, bipolar disorder, major depression, autism spectrum disorders, etc. ( Non-Patent Document 1, Non-Patent Document 2).

The 5-HT ₇ receptor is a Gs protein-coupled receptor and is widely expressed in the hypothalamus, thalamus, hippocampus, raphe nucleus, etc. (Non-Patent Document 9). Agents having antagonistic activity to the 5- _HT7 receptor include lurasidone, which is used for the treatment of schizophrenia and bipolar disorder, and vortioxetine, which is used for the treatment of major depression. There are no marketed agents that exhibit antagonistic activity at the 5- _HT7 receptor. Lurasidone is used as a therapeutic agent for schizophrenia and bipolar disorder, and vortioxetine is used as a therapeutic agent for major depression (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5). It is also known that antagonizing the 5- _HT7 receptor shows antidepressant, anxiolytic and cognitive function improving effects in some animal models (Non-Patent Documents 6 and 7). Furthermore, it is also known that 5-HT ₇ receptor-deficient mice exhibit antidepressant effects (Non-Patent Document 8).

As noted above, antagonists to 5-HT _2A receptors and 5-HT ₇ receptors have each been _shown to be useful alone in a variety of neuropsychiatric disorders. There are no reports of drugs that selectively and potently exhibit antagonistic activity against the _HT7 receptor.

P. Seeman, Can. J. Psychiatry.4:27-38, 2002 C. J. Schmidt, Life Science.56(25):2209-2222, 1995 By L. Citrome, J. Clinical Practice.65(2):189-210, 2011 YS. Woo, Neuropsychiatric Disease and Treatment.9:1521-1529, 2013 C. Sanchez, Pharmacology & Therapeutics.145:43-57, 2015 Bonaventure P, J Pharmacol Exp Ther. 321:690-8, 2007 Horisawa T, Behavioral Brain Research. 220:83-90, 2011 M. Guscott, Neuropharmacology. 48:492-502, 2005 T W. Lovenberg, Neuron. 11:449-458, 1993

An object of the present invention is to provide a pharmaceutical composition containing a novel compound that has both serotonin 5-HT _2A receptor and 5-HT ₇ receptor antagonist activity and is useful as a therapeutic agent for neuropsychiatric disorders.

The present inventors have conducted intensive studies to achieve the above objects, and found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as "the compound of the present invention") ) has both serotonin 5-HT _2A receptor and 5-HT ₇ receptor antagonist activity, leading to the completion of the present invention.

[式中、
Ｚは、窒素原子または－ＣＲ^Ａ－を表し、
Ｙは、カルボニルまたはスルホニルを表し、
ｍは、１、２、３、または４を表し、
ｎは、０、１、２、または３を表し、
ただし、Ｙがスルホニルの場合、ｎは０ではなく、
Ｒ^Ａは、水素原子、ヒドロキシ、Ｃ_１－６アルキル、またはＣ_１－６アルコキシを表し、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃおよびＲ^１ｄは、それぞれ独立して、水素原子、ヒドロキシ、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、
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃおよびＲ^２ｄは、それぞれ独立して、Ｒ^２ｃおよびＲ^２ｄが複数ある場合はそれぞれ独立して、水素原子、ハロゲン、またはＣ_１－６アルキル（該アルキルは、ハロゲン、ヒドロキシ、Ｃ_３－８シクロアルキルおよびＣ_１－６アルコキシからなる群より選択される、同一または異なる１～５個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^２ａおよびＲ^２ｂ、または同一炭素に結合するＲ^２ｃおよびＲ^２ｄが、それぞれ独立して、上記のＣ_１－６アルキルである場合、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く、
Ｒ^３は、Ｃ_１－６アルキル（該アルキルは、ハロゲン、ヒドロキシ、シアノ、Ｃ_３－８シクロアルキルおよびＣ_１－６アルコキシからなる群より選択される、同一または異なる１～５個の置換基で置換されていてもよい）を表し、
Ｒ^４ａ、Ｒ^４ｂ、Ｒ^４ｃおよびＲ^４ｄは、それぞれ独立して、Ｒ^４ｃおよびＲ^４ｄが複数ある場合はそれぞれ独立して、水素原子、ハロゲン、Ｃ_１－６アルキル（該アルキルは、ハロゲン、ヒドロキシ、シアノ、Ｃ_３－８シクロアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルエステル、および同一または異なる１もしくは２個のＣ_１－６アルキル（該アルキルは、オキソで置換されていてもよい）で置換されていてもよいアミノからなる群より選択される、同一または異なる１～５個の置換基で置換されていてもよい）、Ｃ_２－６アルキニル、またはアミノ（該アミノは、同一または異なる１もしくは２個のＣ_１－６アルキルで置換されていてもよい）を表し、ここにおいて、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^４ｃおよびＲ^４ｄのいずれかの２つが、それぞれ独立して、上記のＣ_１－６アルキルである場合、これらが結合する炭素原子と一緒になって、該Ｃ_１－６アルキルが置換基を有する場合は、その置換基も環の構成元素として含んでもよく、３～６員の飽和炭素環または４～６員の飽和複素環を形成していてもよく、
ただし、Ｙがスルホニルかつｎが１の場合、Ｒ^４ｃまたはＲ^４ｄのいずれか一方は水素原子であり、Ｙがスルホニルかつｎが２または３の場合、Ｙに隣接する炭素原子と結合するＲ^４ｃまたはＲ^４ｄのいずれか一方は水素原子であり、
環Ｑは、下記式（２ａ）、（２ｂ）、（２ｃ）、（２ｄ）、（２ｅ）または（２ｆ）：

｛式中、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃ、およびＲ^５ｄ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もしくは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し、
Ｒ^６は、水素原子、Ｃ_１－６アルキル、またはＣ_３－８シクロアルキル（該アルキル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）を表す｝で表される基である］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組成物。 That is, the present invention is as follows.
[1] Formula (1):

[In the formula,
Z represents a nitrogen atom or -CR ^A -,
Y represents carbonyl or sulfonyl,
m represents 1, 2, 3, or 4;
n represents 0, 1, 2, or 3;
However, when Y is sulfonyl, n is not 0,
R ^A represents a hydrogen atom, hydroxy, C _1-6 alkyl, or C _1-6 alkoxy;
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, hydroxy, halogen, or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogens;
^Each of R ^2a , R ^2b , R ^2c and R ^2d is ^{independently} a hydrogen atom, a halogen, or a C _1-6 alkyl (wherein the alkyl is a halogen , hydroxy, C _3-8 cycloalkyl and C _1-6 alkoxy, optionally substituted with the same or different 1 to 5 substituents), wherein R ^2a and When R ^2b , or R ^2c and R ^2d attached to the same carbon are each independently the above C _1-6 alkyl, together with the carbon atom to which they are attached, a 3- to 6-membered saturated carbon may form a ring,
R ³ is C _1-6 alkyl, wherein the alkyl is 1 to 5 identical or different substituents selected from the group consisting of halogen, hydroxy, cyano, C _3-8 cycloalkyl and C _1-6 alkoxy; may be substituted with),
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, hydroxy, cyano, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkyl esters, and 1 or 2 identical or different C _1-6 alkyls, which may be substituted with oxo optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of optionally substituted amino), C _2-6 alkynyl, or amino (wherein said amino is optionally substituted with 1 or 2 identical or different C _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently In the case of the above C _1-6 alkyl, when the C _1-6 alkyl has a substituent together with the carbon atoms to which they are bonded, the substituent may also be included as a ring-constituting element, may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring,
provided that when Y is sulfonyl and n is 1, either one of R ^4c or R ^4d is a hydrogen atom, and when Y is sulfonyl and n is 2 or 3, R ^4c bonded to the carbon atom adjacent to Y or either one of R ^4d is a hydrogen atom,
Ring Q is the following formula (2a), (2b), (2c), (2d), (2e) or (2f):

{In the formula,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are each independently optionally substituted by the same or different 1 to 3 halogens), or amino optionally substituted by the same or different 1 or 2 C _1-6 alkyl,
R ⁶ is a hydrogen atom, C _1-6 alkyl, or C _3-8 cycloalkyl (the alkyl and the cycloalkyl may each independently be substituted with 1 to 3 halogen atoms which are the same or different); ) represents a group represented by]] or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

[2] R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms;
The pharmaceutical composition according to item [1].

[3] R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms;
The pharmaceutical composition according to item [1] or item [2].

[4] m is 1;
The pharmaceutical composition according to any one of items [1] to [3].

[5] R ³ is C _1-6 alkyl;
The pharmaceutical composition according to any one of items [1] to [4].

[6] Z is -CR ^A -,
The pharmaceutical composition according to any one of items [1] to [5].

[7] R ^A is a hydrogen atom;
The pharmaceutical composition according to any one of items [1] to [6].

[8] R ^5a , R ^5b , R ^5c , and R ^5d are each independently a hydrogen atom, halogen, or C _1-6 alkyl;
The pharmaceutical composition according to any one of items [1] to [7].

[9] R ^5a , R ^5c and R ^5d are hydrogen atoms;
The pharmaceutical composition according to any one of items [1] to [8].

[10] R ^5b is a hydrogen atom, halogen, or C _1-6 alkyl;
The pharmaceutical composition according to any one of items [1] to [9].

[11] R ⁶ is a hydrogen atom;
The pharmaceutical composition according to any one of items [1] to [10].

[12] R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, or C _1-6 alkyl (the alkyl is optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of halogen, hydroxy, and C _1-6 alkoxy;
The pharmaceutical composition according to any one of items [1] to [11].

[13] n is 0 or 1;
The pharmaceutical composition according to any one of items [1] to [12].

[14] Y is carbonyl,
The pharmaceutical composition according to any one of items [1] to [13].

[15] Y is sulfonyl;
The pharmaceutical composition according to any one of items [1] to [13].

[16] The item [1], wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is a compound represented by any of the following formulas or a pharmaceutically acceptable salt thereof: pharmaceutical composition of

[17] A medicament containing the compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof as an active ingredient.

[18] A therapeutic agent for psychiatric disorders or central nervous system disorders, comprising the pharmaceutical composition of any one of [1] to [16].

[19] neurological symptoms or cognition associated with psychiatric disease or central nervous system disease, schizophrenia, bipolar disorder, sleep disorder, autism spectrum disorder, major depression, treatment-resistant depression, Alzheimer's disease or Parkinson's disease The therapeutic agent according to item [18], which is a disease.

[20] comprising administering a therapeutically effective amount of the compound of any one of [1] to [16] or a pharmaceutically acceptable salt thereof to a patient in need of treatment; , a method for treating a psychiatric disorder or a central nervous system disorder.

[21] Use of the pharmaceutical composition according to any one of [1] to [16] for manufacturing a therapeutic agent for psychiatric disorders or central nervous system disorders.

[22] The pharmaceutical composition of any one of [1] to [16], which is used for treating psychiatric disorders or central nervous system disorders.

[23] The pharmaceutical composition according to any one of [1] to [16], a therapeutic drug for developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, an antipsychotic drug, and a therapeutic drug for schizophrenia , drugs for bipolar disorder, antidepressants, anti-anxiety drugs, drugs for obsessive-compulsive disorder, drugs for stress disorders such as post-traumatic stress disorder, drugs for mood disorders, drugs for eating disorders, insomnia, narcolepsy, Drugs for sleep disorders such as sleep apnea syndrome and circadian rhythm disorders, drugs for sexual dysfunction, drugs for drug dependence, drugs for dementia such as Alzheimer's disease, drugs for behavioral and psychological symptoms associated with dementia, brain metabolism A combination of at least one drug selected from the group consisting of circulation improving drugs, movement disorder improving drugs such as Parkinson's disease, analgesics, antiepileptic drugs, anticonvulsants, migraine therapeutic drugs, anesthetics, and central stimulants A therapeutic agent for psychiatric disorders or central nervous system disorders, comprising:

[24] Developmental disorder therapeutic agents such as autism spectrum disorders and attention deficit hyperactivity disorder, antipsychotic agents and schizophrenia therapeutic agents, bipolar disorder therapeutic agents, antidepressants, anti-anxiety agents, obsessive-compulsive disorder therapeutic agents, psychotropic Drugs for stress disorders such as post-traumatic stress disorder, drugs for mood disorders, drugs for eating disorders, drugs for sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome, and circadian rhythm disorders, drugs for sexual dysfunction , drugs to treat drug dependence, drugs to treat dementia such as Alzheimer's disease, drugs to treat behavioral and psychological symptoms associated with dementia, drugs to improve brain metabolism and circulation, drugs to improve movement disorders such as Parkinson's disease, analgesics, antiepileptic drugs, antiepileptic drugs Items [1] to [1] for treating psychiatric disorders or central nervous system disorders in combination with at least one drug selected from the group consisting of convulsive drugs, antimigraine drugs, anesthetics, and central stimulants A therapeutic agent comprising the pharmaceutical composition of any one of [16].

[25] A crystal of the compound of Example 17, 77, 78, 79, or 80, comprising 4 or more (preferably 10 or more) 2θ selected from powder XRD peaks measured in each Example A crystal characterized by a powder XRD pattern with ±0.2.

The compounds of the invention possess antagonistic activity against the 5-HT _2A and 5-HT ₇ receptors. Therefore, the compounds of the present invention are useful as therapeutic agents for neuropsychiatric disorders and central nervous system disorders.

FIG. 10 shows the results of a fear conditioning test (Test Example 6) of the compound of Example 17. FIG. FIG. 10 is a diagram showing the results of rat brain glutamic acid release measurement of the compound of Example 17 (Test Example 7). 1 shows a powder XRD measurement chart of the compound of Example 78. FIG.

The present invention will be described in more detail below. In the present specification, the number of carbon atoms 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.

"Halogen" includes fluorine, chlorine, bromine and iodine atoms. A fluorine atom or a chlorine atom is preferred.

“C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. "C _1-6 alkyl" preferably includes "C _1-4 alkyl", more preferably "C _1-3 alkyl". Specific examples of “C _1-3 alkyl” include methyl, ethyl, propyl, 1-methylethyl and the like. Specific examples of "C _1-4 alkyl" include, in addition to those listed above as specific examples of "C _1-3 alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methyl propyl and the like. Specific examples of “C _1-6 alkyl” include, in addition to those listed above as specific examples of “C _1-4 alkyl”, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1 -methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.
In the present invention, "alkyl is substituted with oxo" means that any carbon atom constituting alkyl forms a keto form (C=O).

“C _3-8 cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, including partially unsaturated bonds and crosslinked structures. “C _3-8 cycloalkyl” preferably includes “C _3-6 cycloalkyl”. Specific examples of “C _3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Specific examples of “C _3-8 cycloalkyl” include, in addition to those exemplified above for “C _3-6 cycloalkyl”, cycloheptyl, cyclooctyl and the like.

"C _1-6 alkoxy" has the same meaning as "C _1-6 alkyloxy", and the "C _1-6 alkyl" moiety has the same meaning as the aforementioned "C _1-6 alkyl". "C _1-6 alkoxy" preferably includes "C _1-4 alkoxy", more preferably "C _1-3 alkoxy". Specific examples of “C _1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy and the like. Specific examples of "C _1-4 alkoxy" include, in addition to those listed above as specific examples of "C _1-3 alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl propoxy and the like. Specific examples of "C _1-6 alkoxy" include, in addition to those listed above as specific examples of "C _1-4 alkoxy", penthyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

“C _1-6 alkyl ester” means an ester in which the R′ portion of ester (—COOR′) is the above “C _1-6 alkyl”. "C _1-6 alkyl ester" preferably includes "C _1-4 alkyl ester", more preferably "C _1-3 alkyl ester". Specific examples of “C _1-3 alkyl ester” include methyl ester, ethyl ester, propyl ester, 1-methylethyl ester and the like. Specific examples of the "C _1-4 alkyl ester" include, in addition to the specific examples of the above "C _1-3 alkyl ester", butyl ester, 1,1-dimethylethyl ester, 1-methylpropyl ester, 2-methylpropyl ester and the like. Specific examples of the "C _1-6 alkyl ester" include, in addition to the specific examples of the above "C _1-4 alkyl ester", pentyl ester, 1,1-dimethylpropyl ester, 1,2- dimethylpropyl ester, 1-methylbutyl ester, 2-methylbutyl ester, 4-methylpentyl ester, 3-methylpentyl ester, 2-methylpentyl ester, 1-methylpentyl ester, hexyl ester and the like.

“C _2-6 alkynyl” means an unsaturated hydrocarbon group containing a straight or branched triple bond and having 2 to 6 carbon atoms. The C _2-6 alkynyl preferably includes “C _2-4 alkynyl”, more preferably “C _2-3 alkynyl”. Specific examples of “C _2-3 alkynyl” include ethynyl, propynyl and the like. Specific examples of “C _2-4 alkynyl” include, in addition to the specific examples of “C _2-3 alkynyl” above, butynyl and the like. Specific examples of “C _2-6 alkynyl” include pentynyl, hexynyl and the like in addition to the specific examples of “C _2-4 alkynyl”.

The “3- to 6-membered saturated carbocyclic ring” means a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, including partially unsaturated bonds and crosslinked structures. The “3- to 6-membered saturated carbocyclic ring” preferably includes a “5- or 6-membered monocyclic saturated carbocyclic ring”. Specific examples of the "5- or 6-membered monocyclic saturated carbocyclic ring" include cyclopentane and cyclohexane. Specific examples of the "3- to 6-membered saturated carbocyclic ring" include, in addition to the specific examples of the "5- or 6-membered monocyclic saturated carbocyclic ring", cyclopropane, cyclobutane, and the like. be done.

"4- to 6-membered saturated heterocyclic group" means, in addition to carbon atoms, 4 to 6 atoms containing 1 or 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms and includes partially unsaturated bonds and crosslinked structures. The "4- to 6-membered saturated heterocyclic group" preferably includes a "5- or 6-membered monocyclic saturated heterocyclic group". Specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group" include tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl , thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxoxazolidinyl, dioxoxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyltetrahydropyranyl and the like. Examples of the "4- to 6-membered saturated heterocyclic ring" include, in addition to the specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group", oxetanyl, azetidinyl and the like.

Z, Y, m, n, R ^A , R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c , R ^2d , R ³ , R in the compound represented by formula (1) ^4a , R ^4b , R ^4c , R ^4d , Q, R ^5a , R ^5b , R ^5c , R ^5d and R ⁶ are preferably as follows, but the technical scope of the present invention is the following compounds is not limited to the range of

One embodiment of Z includes -CR ^A -. Another aspect of Z is a nitrogen atom.

One embodiment of Y includes carbonyl. Another embodiment of Y is sulfonyl.

Preferred embodiments of m include 1 or 2. 1 is mentioned as a more preferable aspect.

Preferred embodiments of n include 0, 1, or 2. 0 or 1 is mentioned as a more preferable aspect. 1 is mentioned as a particularly preferable aspect.

Preferred embodiments of R ^A include a hydrogen atom, hydroxy, or C _1-6 alkyl. A more preferred embodiment includes a hydrogen atom or C _1-3 alkyl. More preferred embodiments include a hydrogen atom, ethyl, or methyl. A most preferred embodiment is a hydrogen atom.

Preferred embodiments of R ^1a , R ^1b , R ^1c and R ^1d each independently include a hydrogen atom, hydroxy, halogen, or C _1-6 alkyl. More preferred embodiments include a hydrogen atom, halogen, or C _1-3 alkyl. More preferred embodiments include a hydrogen atom, fluorine atom, chlorine atom, ethyl, or methyl. A particularly preferred embodiment includes a hydrogen atom, a fluorine atom, or methyl. A most preferred embodiment is a hydrogen atom.

Preferred embodiments of R ^2a , R ^2b , R ^2c and R ^2d each independently include a hydrogen atom, halogen, or C _1-6 alkyl. More preferred embodiments include a hydrogen atom, halogen, or C _1-3 alkyl. More preferred embodiments include a hydrogen atom, fluorine atom, chlorine atom, ethyl, or methyl. A particularly preferred embodiment includes a hydrogen atom, a fluorine atom, or methyl. A most preferred embodiment is a hydrogen atom.

Preferred embodiments of R ³ include C _1-6 alkyl. A more preferred embodiment includes C _1-3 alkyl. More preferred embodiments include ethyl or methyl. A particularly preferred embodiment includes ethyl.

Preferred embodiments of R ^4a , R ^4b , R ^4c and R ^4d each independently include a hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkynyl, or the same or different 1 or 2 C Amino optionally substituted with _1-6 alkyl is exemplified. More preferred embodiments include a hydrogen atom, halogen, C _1-6 alkyl, or amino optionally substituted with 1 or 2 identical or different C _1-6 alkyls. More preferred embodiments include a hydrogen atom, halogen, or C _1-6 alkyl. A particularly preferred embodiment includes a hydrogen atom or C _1-6 alkyl. A particularly preferred embodiment includes a hydrogen atom, methyl, or methoxymethyl. A most preferred embodiment is a hydrogen atom.

Preferred embodiments of Q include (2a), (2c), (2d), (2e) or (2f). More preferred embodiments include (2a), (2d), or (2e). A particularly preferred embodiment is (2a).

Preferred embodiments of R ^5a , R ^5b , R ^5c and R ^5d each independently include a hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, or the same or different 1 or 2 and amino optionally substituted with C _1-6 alkyl. More preferred embodiments include a hydrogen atom, halogen, cyano, C _1-6 alkyl, or C _1-6 alkoxy. A more preferred embodiment includes a hydrogen atom, a fluorine atom, or a chlorine atom. A particularly preferred embodiment includes a hydrogen atom or a fluorine atom.

Preferred embodiments of R ⁶ include a hydrogen atom, C _1-6 alkyl, or C _3-8 cycloalkyl. A more preferred embodiment includes a hydrogen atom or C _1-6 alkyl. More preferred embodiments include a hydrogen atom or C _1-3 alkyl. A particularly preferred embodiment is a hydrogen atom.

｛式中、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃ、およびＲ^５ｄが、それぞれ独立して、水素原子、ハロゲン、またはＣ_１－６アルキルであり、
Ｒ^６が、水素原子またはＣ_１－６アルキルである｝で表される基である、化合物またはその製薬学的に許容される塩。 One mode of the compound represented by Formula (1) includes the following (A).
(A)
Z is a nitrogen atom or -CR ^A -,
Y is carbonyl or sulfonyl,
m is 1 or 2,
n is 0, 1, 2, or 3;
However, when Y is sulfonyl, n is not 0,
R ^A is a hydrogen atom or C _1-6 alkyl,
R ^1a , R ^1b , R ^1c and R ^1d are each independently a hydrogen atom or C _1-6 alkyl;
R ^2a , R ^2b , R ^2c and R ^{2d are} each independently ^a hydrogen atom or C _1-6 alkyl;
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
provided that when Y is sulfonyl and n is 1, either one of R ^4c or R ^4d is a hydrogen atom, and when Y is sulfonyl and n is 2 or 3, R ^4c bonded to the carbon atom adjacent to Y or either one of R ^4d is a hydrogen atom,
Ring Q is the following formula (2a), (2b), (2c), (2d), (2e) or (2f):

{In the formula,
R ^5a , R ^5b , R ^5c , and R ^5d are each independently a hydrogen atom, halogen, or C _1-6 alkyl;
R ⁶ is a hydrogen atom or C _1-6 alkyl}, or a pharmaceutically acceptable salt thereof.

｛式中、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃ、およびＲ^５ｄが、それぞれ独立して、水素原子、ハロゲン、またはＣ_１－６アルキルであり、
Ｒ^６が、水素原子またはＣ_１－６アルキルである｝で表される基である、化合物またはその製薬学的に許容される塩。 One mode of the compound represented by formula (1) includes the following (B).
(B)
Z is a nitrogen atom or -CR ^A -,
Y is carbonyl;
m is 1 or 2,
n is 0, 1, 2, or 3;
R ^A is a hydrogen atom or C _1-6 alkyl,
R ^1a , R ^1b , R ^1c and R ^1d are each independently a hydrogen atom or C _1-6 alkyl;
R ^2a , R ^2b , R ^2c and R ^{2d are} each independently ^a hydrogen atom or C _1-6 alkyl;
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently the above C _1-6 alkyl In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, and a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
Ring Q is the following formula (2a), (2b), (2c), (2d), (2e) or (2f):

{In the formula,
R ^5a , R ^5b , R ^5c , and R ^5d are each independently a hydrogen atom, halogen, or C _1-6 alkyl;
R ⁶ is a hydrogen atom or C _1-6 alkyl}, or a pharmaceutically acceptable salt thereof.

｛式中、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃ、およびＲ^５ｄが、それぞれ独立して、水素原子、ハロゲン、またはＣ_１－６アルキルであり、
Ｒ^６が、水素原子またはＣ_１－６アルキルである｝で表される基である、化合物またはその製薬学的に許容される塩。 One aspect of the compound represented by formula (1) includes the following (C).
(C)
Z is a nitrogen atom or -CR ^A -,
Y is sulfonyl,
m is 1 or 2,
n is 1, 2, or 3;
R ^A is a hydrogen atom or C _1-6 alkyl,
R ^1a , R ^1b , R ^1c and R ^1d are each independently a hydrogen atom or C _1-6 alkyl;
R ^2a , R ^2b , R ^2c and R ^{2d are} each independently ^a hydrogen atom or C _1-6 alkyl;
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
provided that when n is 1, either one of R ^4c or R ^4d is a hydrogen atom, and when n is 2 or 3, either one of R ^4c or R ^4d bonded to the carbon atom adjacent to Y is is a hydrogen atom,
Ring Q is the following formula (2a), (2b), (2c), (2d), (2e) or (2f):

{In the formula,
R ^5a , R ^5b , R ^5c , and R ^5d are each independently a hydrogen atom, halogen, or C _1-6 alkyl;
R ⁶ is a hydrogen atom or C _1-6 alkyl}, or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by Formula (1) includes the following (D).
(D)
Z is -CR ^A -,
Y is carbonyl;
m is 1;
n is 0 or 1,
^RA is a hydrogen atom,
R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms,
R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms,
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
A compound or a pharmaceutically acceptable salt thereof, wherein ring Q is (2a).

One mode of the compound represented by Formula (1) includes the following (E).
(E)
Z is -CR ^A -,
Y is carbonyl;
m is 1;
n is 0 or 1,
^RA is a hydrogen atom,
R ^1a , R ^1b , R ^1c and R ^1d are each independently a hydrogen atom;
R ^2a , R ^2b , R ^2c and R ^2d are each independently a hydrogen atom;
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
A compound or a pharmaceutically acceptable salt thereof, wherein ring Q is (2d).

One aspect of the compound represented by formula (1) includes the following (F).
(F)
Z is -CR ^A -,
Y is carbonyl;
m is 1;
n is 0 or 1,
^RA is a hydrogen atom,
R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms,
R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms,
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
A compound or a pharmaceutically acceptable salt thereof, wherein ring Q is represented by (2e).

One aspect of the compound represented by Formula (1) includes the following (G).
(G)
Z is -CR ^A -,
Y is sulfonyl,
m is 1;
n is 1;
^RA is a hydrogen atom,
R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms,
R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms,
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
provided that either one of R ^4c or R ^4d is a hydrogen atom,
A compound or a pharmaceutically acceptable salt thereof, wherein ring Q is (2a).

One aspect of the compound represented by Formula (1) includes the following (H).
(H)
Z is -CR ^A -,
Y is sulfonyl,
m is 1;
n is 1;
^RA is a hydrogen atom,
R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms,
R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms,
R ³ is C _1-6 alkyl,
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted by hydroxy, C _1-6 alkoxy, C _1-6 alkyl ester, and 1 or 2 of the same or different C _1-6 alkyl (which alkyl may be optionally substituted by oxo) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of amino), C _2-6 alkynyl, or amino (wherein said amino is the same or different 1 or 2 C optionally substituted with _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently C _1-6 alkyl as described above In some cases, when the C _1-6 alkyl has a substituent together with the carbon atom to which they are attached, the substituent may also be included as a ring-constituting element, a 3- to 6-membered saturated carbocyclic ring or may form a 4- to 6-membered saturated heterocyclic ring,
provided that either one of R ^4c or R ^4d is a hydrogen atom,
A compound or a pharmaceutically acceptable salt thereof, wherein ring Q is (2e).

The compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compounds of the present invention include not only racemic forms of the compounds represented by formula (1), but also optically active forms of these compounds. Stereoisomerism may occur when the compound represented by formula (1) has two or more asymmetric carbon atoms. Accordingly, the compounds of the present invention also include stereoisomers of these compounds and mixtures thereof.

In addition, the compound represented by formula (1) also includes a deuterium conversion product obtained by converting ¹ H in any one or more of the compounds represented by formula (1) to ² H(D). .

Since the compound represented by formula (1) and its pharmaceutically acceptable salts may exist in the form of hydrates and/or solvates, 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 include all aspects of crystalline forms.

Examples of pharmaceutically acceptable salts include, when the compound represented by formula (1) has an acidic group, alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts; metal salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids;

When the compound represented by formula (1) has a basic group, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; acetate, propionate, Succinate, Lactate, Malate, Tartrate, Citrate, Maleate, Fumarate, Methanesulfonate, p-Toluenesulfonate, Benzenesulfonate, Ascorbate, Orotate and organic acid salts such as

The method for producing the compound of the present invention will be described below with reference to examples, but the present invention is by no means limited to these.

Production Method The compounds of the present invention are synthesized by a combination of the production methods shown below and known synthesis methods.
The compounds in the reaction scheme may each form a salt, and examples of the salt include those similar to the salts of the compound represented by formula (1). These reactions are merely examples, and the compounds of the present invention can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

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

As the protecting group, the usual protecting groups described in the literature (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) can be used. can be used. More specifically, amino-protecting groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like. Protection of hydroxy group includes, for example, trialkylsilyl, acetyl, benzyl and the like.

The introduction and elimination of protective groups are performed by methods commonly used in synthetic organic chemistry (for example, T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999 ) or a similar method.

〔式中、Ｚ、ｍ、ｎ、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ、Ｒ^３、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^４ｃ、Ｒ^４ｄ、および環Ｑは、前記〔１〕と同義である。〕 Manufacturing method 1
Among the compounds represented by formula (1), the compound represented by formula (1a) can be produced, for example, by the method shown below.

[In the formula, Z, m, n, R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c , R ^2d , R ³ , R ^4a , R ^4b , R ^4c , R ^4d , and Ring Q has the same definition as the above [1]. ]

Compound (1a) can be produced by reacting compound (4) with a carboxylic acid represented by formula (5) in a suitable inert solvent in the presence of a suitable condensing agent. The reaction may be performed in the presence of a suitable 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 the reaction temperature, the condensing agent used, the raw materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl- tris(dimethylamino)phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldimidazole (CDI), benzotriazol-1-yl-N,N,N',N '-Tetramethyluronium hexafluorophosphide salt (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphide salt (HATU) and the like.
optionally, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. additives may be added.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of inert solvents 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 dimethylsulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

〔式中、Ｚ、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ、Ｒ^３、および環Ｑは、前記〔１〕と同義であり、ｌは、０、１、２、または３を表す。〕 Manufacturing method 2
Among the compounds represented by formula (4), the compound represented by formula (4a) can be produced, for example, by the method shown below.

[Wherein, Z, R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c , R ^2d , R ³ , and ring Q are as defined in [1] above, and l is Represents 0, 1, 2, or 3. ]

Compound (8) can be produced by a reductive amination reaction in a suitable inert solvent using compound (6), an aldehyde represented by formula (7) and a suitable reducing agent. The reaction may be carried out in the presence of a suitable base or a suitable acid, if necessary. The reaction temperature usually ranges from about -20°C to the boiling point of the solvent used. The reaction time is usually 10 minutes to 48 hours, although it varies depending on conditions such as the reaction temperature, the reducing agent used, the raw materials, and the solvent.

Specific examples of the reducing agent include complex hydrogen compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride; borane complexes (borane-dimethylsulfide complex or borane-tetrahydrofuran complexes, etc.).

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of acids 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 inert solvents include water; acetonitrile; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; alcoholic solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone; and mixed solvents thereof.

Compound (4a) can be produced by treating compound (8) with a suitable acid in a suitable inert solvent. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent used. The reaction time is usually 10 minutes to 48 hours, varying depending on conditions such as reaction temperature, acid used, raw materials and solvent.

Specific examples of acids include organic acids such as trifluoroacetic acid; inorganic acids such as hydrochloric acid and sulfuric acid;

Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents; 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.

〔式中、Ｚ、ｍ、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ、Ｒ^３、および環Ｑは、前記〔１〕と同義であり、ＬＧは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。〕 Manufacturing method 3
The compound represented by formula (8) can be produced, for example, by the method shown below.

[In the formula, Z, m, R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c , R ^2d , R ³ , and ring Q are as defined in [1] above, and LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.), etc.). ]

Compound (8) can be produced by reacting compound (6) with an alkylating agent represented by formula (9) in a suitable inert solvent. The reaction may optionally be carried out in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst. 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 materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogensulfate and the like.

Specific examples of inert solvents 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

Compound (11) can be produced by reacting compound (6) with an alkylating agent represented by formula (10) in a suitable inert solvent. The reaction may optionally be carried out in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst. 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 materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogensulfate and the like.

Specific examples of inert solvents 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

Compound (8) can be produced by reacting compound (11) with an alkylating agent represented by formula (12) in a suitable inert solvent. The reaction may optionally be carried out in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst. 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 materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogensulfate and the like.

Specific examples of inert solvents 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

〔式中、Ｚ、ｍ、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ、Ｒ^３、Ｒ^４ａ、Ｒ^４ｂ、Ｒ^４ｃ、および環Ｑは、前記〔１〕と同義である。〕 Manufacturing method 4
Among the compounds represented by formula (1), the compound represented by formula (1f) can be produced, for example, by the method shown below.

[Wherein, Z, m, R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c , R ^2d , R ³ , R ^4a , R ^4b , R ^4c , and ring Q are Same as [1]. ]

Compound (14) can be produced by reacting compound (4) with a sulfonyl chloride represented by formula (13) in a suitable inert solvent. The reaction may further be carried out in the presence of a suitable 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 the reaction temperature, raw materials used, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of inert solvents 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 dimethylsulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

Compound (1f) can be produced by reacting compound (14) with a hydroxide such as tetrabutylammonium hydroxide or sodium hydroxide in a suitable inert solvent. 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 the reaction temperature, raw materials used, and solvent, but is usually 10 minutes to 48 hours.

Examples of inert solvents include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2 -Aprotic polar solvents such as pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

〔式中、Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃ、およびＲ^５ｄは、前記〔１〕と同義であり、Ａはヨウ素原子、臭素原子、または塩素原子を表す。〕 Manufacturing method 5
Among the compounds represented by formula (6), the compound represented by formula (6a) can be produced, for example, by the method shown below.

[In the formula, R ^5a , R ^5b , R ^5c and R ^5d are as defined in [1] above, and A represents an iodine atom, a bromine atom, or a chlorine atom. ]

Compound (15) is prepared by reacting 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid with N,O-dimethylhydroxyamine or its hydrochloride in a suitable inert solvent in the presence of a suitable condensing agent. It can be produced by reacting. The reaction may be performed in the presence of a suitable 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 the reaction temperature, the condensing agent used, the raw materials and the solvent, but is usually 10 minutes to 48 hours.

Further, compound (15) can be prepared by reacting N,O-dimethylhydroxyamine or a salt thereof with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in the presence of a suitable base in a suitable inert solvent. It can also be produced by reacting with a derived acid halide or 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 conditions such as the reaction temperature, the condensing agent used, the raw materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl- tris(dimethylamino)phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldimidazole (CDI), benzotriazol-1-yl-N,N,N',N '-tetramethyluronium hexafluorophosphide salt (HBTU) and the like. optionally, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. can be added to carry out the reaction.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of inert solvents 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 dimethylsulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

Compound (17) can be produced by reacting compound (15) with a lithiated product generated by treating compound (16) with an organic lithium such as n-butyllithium in a suitable inert solvent. can. The reaction temperature is usually in the range of about -78°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents, starting materials and solvents used, but is usually 10 minutes to 48 hours.

Specific examples of inert solvents 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 (18) can be produced by reacting compound (17) with hydroxylamine or a salt thereof in the presence of a suitable base, 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 materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; sodium acetate etc.

Specific examples of solvents include 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; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone; water; and mixed solvents thereof.

Compound (19) can be produced by treating compound (18) with a suitable base 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 the reaction temperature, the base used, the raw materials and the solvent, but is usually 10 minutes to 48 hours.

Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; be done.

Specific examples of inert solvents 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

Compound (6a) can be produced by treating compound (19) with a suitable acid in a suitable inert solvent. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent used. The reaction time is usually 10 minutes to 48 hours, varying depending on conditions such as reaction temperature, acid used, raw materials and solvent.

Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents; 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.

Specific examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

By appropriately combining the above production methods, the compound of the present invention having desired substituents at desired positions can be obtained. Isolation and purification of intermediates and products in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. can be done. In addition, intermediates can be subjected to the next reaction without particular purification.

Depending on the reaction conditions and the like, the raw material compounds or intermediates in the above production methods may exist in the form of salts such as hydrochlorides, but they can be used as they are or in free form. When starting compounds or intermediates are obtained in the form of salts and it is desired to use or obtain the starting compounds or intermediates in free form, they are dissolved or suspended in an appropriate solvent, for example, aqueous sodium bicarbonate solution or the like. It can be converted into a free form by neutralizing with a base or the like.

Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, there are tautomers such as ketoenol forms, positional isomers, geometric isomers or isomers such as optical isomers. However, all possible isomers including these and mixtures of said isomers in any ratio are included in the present invention.

In addition, optical isomers can be separated by carrying out known separation steps such as a method using an optically active column and a fractional crystallization method in an appropriate step of the above production method. Moreover, an optically active substance can also be used as a starting material.

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

The compound of the present invention has both 5-HT _2A receptor antagonist activity and 5-HT ₇ receptor antagonist activity, and has a mechanism of action different from that of existing drugs for the treatment of psychiatric disorders. New treatment options can be provided. Thus, the compounds of the present invention are effective in treating psychiatric disorders. The compounds of the present invention are also effective against central nervous system diseases.

Psychiatric disorders or central nervous system disorders expected to be effective include, for example, F00-F09: organic psychiatric disorders including symptomatic disorders, F10-F19: psychoactive substances in the 10th edition of the International Classification of Diseases (ICD-10) Mental and Behavioral Disorders from Use, F20-F29: Schizophrenia, Schizophrenic Disorders and Delusional Disorders, F30-F39: Mood [Emotional] Disorders, F40-F48: Neurotic Disorders, Stress-Related Disorders and Physical Expressive disorders, F51: Non-organic sleep disorders, F52: Sexual dysfunction, not due to organic disorder or disease, F84: Pervasive developmental disorders, F90-F98: Behavioral and Emotional disorders, G20-G26: Extrapyramidal disorders and abnormal movements, G30-G32: Other degenerative disorders of the nervous system, G47: Sleep disorders, and the like.
F00-F09: Organic mental disorders, including symptomatic, include mental disorders and brain dysfunction associated with diseases such as Alzheimer's disease, vascular dementia, Lewy body dementia, Parkinson's disease dementia and brain damage. and other mental disorders due to physical illness.
F10-F19: Mental and behavioral disorders due to psychoactive substance use include delirium tremens, psychotic disorders and amnestic syndrome due to various substance use.
F20-F29: Schizophrenia, schizophrenic disorders and delusional disorders include paranoid schizophrenia, simple schizophrenia, and delusional disorders.
F30-F39: Mood [affective] disorders include, for example, manic episodes, bipolar affective disorder, and depressive episodes.
F40-F48: Neurotic, stress-related, and somatoform disorders include, for example, phobic anxiety disorders, obsessive-compulsive disorders, and somatoform disorders.
F51: Nonorganic sleep disorders include, for example, nonorganic insomnia, sleepwalking, and nightmares.
F52: Sexual dysfunction, non-organic disorder or disease includes, for example, lack or loss of libido, unspecified sexual dysfunction.
F84: Pervasive developmental disorders include, for example, autism, mental retardation, and hyperkinetic disorders associated with stereotyped movements.
F90-F98: Hyperactivity Disorders Behavioral and affective disorders that commonly develop in childhood and adolescence include, for example, hyperactivity disorder, conduct disorder and mixed conduct-emotional disorder.
G20-G26: Extrapyramidal disorders and abnormal movements include, for example, Parkinson's disease and secondary parkinsonism.
G30-G32: Other degenerative diseases of the nervous system include, for example, Alzheimer's disease, frontotemporal dementia, frontotemporal dementia, dementia with Lewy bodies and senile brain degeneration.
G47: Sleep disorders include, for example, disorders of sleep induction and maintenance [insomnia], sleep-wake schedule disorders, narcolepsy and cataplexy.
The compounds of the present invention are useful for treating or preventing recurrence of various symptoms associated with these diseases (psychotic symptoms, sleep disorders, depressive symptoms, anxiety symptoms, cognitive impairment, etc.).

Serotonin (5-hydroxytryptamine: 5-HT), which is known as one of the major neurotransmitters in the central nervous system, is known to be involved in various brain functions including emotional response and cognitive function. The 5-HT _2A receptor, which is one of the subtypes of 5-HT receptors, is highly expressed in the cerebral cortex, hippocampus, raphe nuclei, and the like. It is also known that 5-HT _2A receptors expressed in the prefrontal cortex positively regulate dopaminergic pathways in the ventral tegmental area (Non-Patent Document 2). In other words, it is thought that it exhibits an inhibitory effect on psychotic symptoms by inhibiting 5-HT _2A receptors in the prefrontal cortex.

In addition, 5- _HT7 receptors are widely expressed in hypothorax, thalamus, hippocampus, raphe nuclei, etc., and are involved in the regulation of circadian rhythms in mammals (Non-Patent Document 9). Disruption of circadian rhythms has been found to be implicated in many CNS disorders, including depression, seasonal affective disorder, sleep disorders, shift work syndrome and jet lag, among others. In addition, known agents having antagonistic activity to the 5- _HT7 receptor include lurasidone, which is used as a therapeutic agent for schizophrenia and bipolar disorder, and vortioxetine, which is used for the treatment of major depression. , there are no drugs that exhibit antagonistic activity selectively at the 5- _HT7 receptor.

It is also known to exhibit antidepressant, anxiolytic and cognitive function-improving effects by antagonizing 5- _HT7 receptors in some animal models (Non-Patent Documents 6 and 7).

From the above pharmacological point of view, inhibiting 5-HT _2A receptors and simultaneously inhibiting 5-HT ₇ receptors is useful in various neuropsychiatric disorders such as depression, sleep disorders, and psychotic symptoms. Be expected. Moreover, there are no reported examples of drugs that selectively and strongly exhibit antagonistic activity against 5-HT _2A receptors and 5-HT ₇ receptors.

The compounds of the present invention have strong binding affinity to 5-HT _2A receptors and 5-HT ₇ receptors (Test Example 1) and are antagonists to 5-HT _2A receptors and 5-HT ₇ receptors. active. In a preferred embodiment of the invention, the binding affinity to 5-HT _2A and 5 _- HT ₇ receptors is more than 100-fold stronger _than that of D2 receptors, thus D2 antagonism Exhibit pharmacological actions based on 5- _HT2A receptor antagonistic properties and 5- _HT7 receptor antagonistic properties at blood concentrations that do not produce side effects such as extrapyramidal symptoms and hyperprolactinemia that are thought to be caused by can be done.

In addition, in a preferred embodiment of the compound of the present invention, there is a discrepancy between the hERG channel inhibition concentration, which is an expression index of arrhythmia due to QT prolongation, and the expression concentration of the expected pharmacological action (Test Example 5). The impact is expected to be small.

The elimination half-life (T1/2) of a drug is a factor that determines the number of doses to maintain its effect. Multiple doses per day associated with a short T1/2 may lead to forgetting to take or failing to take the drug, and may interfere with appropriate drug treatment. In addition, there is concern that an increase in the number of doses will increase the incidence of side effects, or that tolerability will decrease as a result of restrictions on high-dose administration. From the above point of view, it can be expected that achieving a long T1/2 will lead to the creation of a long-acting drug with little concern as described above, leading to a reduction in the burden on patients who take the drug.
In a preferred embodiment of the compound of the present invention, the predicted human elimination half-life (T1/2) is as long as 8 hours or more (Test Example 4), and thus the drug efficacy is long lasting in vivo in humans and is It is expected to improve drug adherence in patients and to exhibit high tolerability during administration.

The compounds of the invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical agents, injections, transdermal agents, intranasal agents, and the like. Oral or rectal dosage forms include, for example, capsules, tablets, pills, powders, cachets, suppositories, liquids and the like. Injections include, for example, sterile solutions or suspensions. Topical agents include, for example, creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.

The above dosage forms are prepared in the usual manner with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients and additives include carriers, binders, flavoring agents, buffering agents, thickeners, coloring agents, stabilizers, emulsifiers, dispersing agents, 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, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter. etc. Capsules can be formulated by placing the compound of the invention therein together with a pharmaceutically acceptable carrier. The compounds of the invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachet preparations can also be produced in a similar manner.

Injectable solutions include solutions, suspensions, emulsions and the like. Examples thereof include an aqueous solution and a water-propylene glycol solution. Liquid formulations can also be prepared in the form of solutions of polyethylene glycol and/or propylene glycol, which may contain water. Liquid preparations suitable for oral administration can be prepared by adding the compounds of the present invention to water and adding colorants, flavoring agents, stabilizers, sweeteners, solubilizers, thickeners and the like as required. Liquid formulations suitable for oral administration can also be prepared by adding a compound of the present invention to water with a dispersant and thickening. Thickening agents include, for example, pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, known suspending agents, and the like.

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

The compounds of the present invention can be used in combination with other drugs for the purpose of enhancing their effects and/or reducing side effects. For example, it can be used in combination with anxiolytic agents such as selective serotonin reuptake inhibitors. 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, for example, therapeutic drugs for developmental disorders such as autism spectrum disorders and attention deficit hyperactivity disorder, antipsychotic drugs and therapeutic drugs for schizophrenia, therapeutic drugs for bipolar disorder, antidepressants, antianxiety drugs, Drugs for obsessive-compulsive disorder, drugs for stress disorders such as post-traumatic stress disorder, drugs for mood disorders, drugs for eating disorders, drugs for sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome, and circadian rhythm disorders Drugs, drugs for treating sexual dysfunction, drugs for drug dependence, drugs for treating dementia such as Alzheimer's disease, drugs for treating behavioral and psychological symptoms associated with dementia, drugs for improving brain metabolism and circulation, drugs for improving movement disorders such as Parkinson's disease, analgesics drugs, antiepileptic drugs, anticonvulsants, migraine drugs, anesthetics, central stimulants, and the like.

The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times. A combination drug of the compound of the present invention and a concomitant drug may also be used. 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 subject, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 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 (concomitant drugs) such as antiemetics, sleep-inducing drugs, and anticonvulsants.

The present invention will be described in more detail with reference examples, examples and test examples below, but the present invention is not limited to these. The compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. Abbreviations may be used for simplification of the description, but these abbreviations have the same meanings as those described above.
The compounds were identified using proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), LC-MS and the like. An amino column manufactured by Yamazen Co., Ltd. was used for amino chromatography in Reference Examples and Examples. LC-MS was measured using various conditions shown in the table below. Retention time (R.T.) represents the time at which mass spectral peaks appear in LC-MS measurements.

Powder X-ray diffraction measurement (powder XRD) was performed using various conditions shown in the table below.

Differential scanning calorimetry (DSC) was performed using various conditions shown in the table below.

The following abbreviations may also be used herein.
The following abbreviations are used in the NMR data of Reference Examples and Examples.
Me: methyl DMF: N,N-dimethylformamide THF: tetrahydrofuran tert-: tertiary CDCl ₃ : heavy chloroform DMSO-d ₆ : heavy dimethyl sulfoxide

The proton nuclear magnetic resonance spectrum was measured using a JEOL FT-NMR spectrometer (300 MHz or 400 MHz). The chemical shift values are given in terms of δ values (ppm). Symbols used in NMR are: s for singlet, d for doublet, dd for double doublet, dt for double triplet, t for triplet, q for quartet, m for multiplet. Lines, br broad, brs broad singlet, and J denote the coupling constant.

参考例１の化合物（２０．０ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（０．５ ｍＬ）に、Ｄ－乳酸（６．１８ ｍｇ）、トリエチルアミン（２０．８ ｍｇ）とヘキサフルオロリン酸 ２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－1－イル）－１，１，３，３－テトラメチルイソウロニウム（３３．８ ｍｇ）を加えた。室温で１６時間攪拌後、反応混合物に水（４．０ ｍＬ）を加え、クロロホルム（１０ ｍＬ×２回）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。濃縮残渣を高速液体クロマトグラフィー（カラム；ＳＥＭＩＰＲＥＰＡＲＡＴＩＶＥ Ｃ－１８ ｃｏｌｕｍｎ，分離条件；アセトニトリル／トリフルオロ酢酸：水／トリフルオロ酢酸）で分離精製し、ＭＰ－Ｃａｒｂｏｎａｔｅ ｒｅｓｉｎで脱塩処理することで、表題化合物（９．７３ ｍｇ）を得た。
LC‐MS：R.T. = 1.433 min ObsMS = 364 [M+1] Example 1
(2R)-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

N,N-dimethylformamide solution (0.5 mL) of the compound of Reference Example 1 (20.0 mg), D-lactic acid (6.18 mg), triethylamine (20.8 mg) and hexafluorophosphoric acid 2 -(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium (33.8 mg) was added. After stirring at room temperature for 16 hours, water (4.0 mL) was added to the reaction mixture, extracted with chloroform (10 mL×2 times), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by high-performance liquid chromatography (column: SEMIPREPARATIVE C-18 column, separation conditions: acetonitrile/trifluoroacetic acid: water/trifluoroacetic acid), and desalted with MP-Carbonate resin to obtain the title compound. (9.73 mg) was obtained.
LC-MS: RT = 1.433 min ObsMS = 364 [M+1]

参考例２の化合物（５０．０ ｍｇ）のジクロロメタン懸濁液（１．０ ｍＬ）に、トリエチルアミン（０．０７７ ｍＬ）、３０％ ３－ヒドロキシプロピオン酸水溶液（０．０４６ ｍＬ）とヘキサフルオロリン酸 ２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－1－イル）－１，１，３，３－テトラメチルイソウロニウム（６７．９ ｍｇ）を加えた。室温で２時間攪拌後、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、表題化合物（４３．２ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.89-7.86 (1H, m), 7.37-7.30 (1H, m), 7.29-7.24 (1H, m), 7.11-7.04 (1H, m), 4.44-4.27 (1H, m), 3.87-3.77 (2H, m), 3.72-3.57 (1H, m), 3.51-3.42 (1H, m), 3.42-3.27 (3H, m), 3.17-2.96 (2H, m), 2.59-2.47 (4H, m), 2.36-2.17 (4H, m), 2.05-1.89 (2H, m), 1.18-1.05 (3H, m). Example 2
N-ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide

To a dichloromethane suspension (1.0 mL) of the compound of Reference Example 2 (50.0 mg), triethylamine (0.077 mL), 30% 3-hydroxypropionic acid aqueous solution (0.046 mL) and hexafluorophosphorus Acid 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium (67.9 mg) was added. After stirring at room temperature for 2 hours, the reaction mixture was separated and purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (43.2 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.89-7.86 (1H, m), 7.37-7.30 (1H, m), 7.29-7.24 (1H, m), 7.11-7.04 (1H, m), 4.44 -4.27 (1H, m), 3.87-3.77 (2H, m), 3.72-3.57 (1H, m), 3.51-3.42 (1H, m), 3.42-3.27 (3H, m), 3.17-2.96 (2H, m), 2.59-2.47 (4H, m), 2.36-2.17 (4H, m), 2.05-1.89 (2H, m), 1.18-1.05 (3H, m).

参考例２の化合物（５０．０ ｍｇ）のジクロロメタン懸濁液（１．０ ｍＬ）に、トリエチルアミン（０．０７７ ｍＬ）、Ｄ－乳酸（１４．９ ｍｇ）とヘキサフルオロリン酸 ２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－1－イル）－１，１，３，３－テトラメチルイソウロニウム（６７．９ ｍｇ）を加えた。室温で４時間攪拌後、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、表題化合物（１３．９ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.93 (1H, s), 7.42-7.28 (2H, m), 7.18-7.08 (1H, m), 4.50-4.20 (2H, m), 3.80-3.62 (1H, m), 3.59-2.88 (4H, m), 2.68-2.53 (1H, m), 2.44-2.20 (3H, m), 2.11-1.94 (1H, m), 1.67-1.44 (5H, m), 1.37-1.10 (6H, m). Example 3
(2R)-N-ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

In a dichloromethane suspension (1.0 mL) of the compound of Reference Example 2 (50.0 mg), triethylamine (0.077 mL), D-lactic acid (14.9 mg) and hexafluorophosphate 2-(1H -benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium (67.9 mg) was added. After stirring at room temperature for 4 hours, the reaction mixture was separated and purified by silica gel column chromatography (chloroform/methanol) to give the title compound (13.9 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.93 (1H, s), 7.42-7.28 (2H, m), 7.18-7.08 (1H, m), 4.50-4.20 (2H, m), 3.80-3.62 (1H, m), 3.59-2.88 (4H, m), 2.68-2.53 (1H, m), 2.44-2.20 (3H, m), 2.11-1.94 (1H, m), 1.67-1.44 (5H, m) , 1.37-1.10 (6H, m).

Examples 4-15
According to the method described in Example 3, the compounds of Examples 4 to 15 were obtained from the corresponding compounds of Reference Examples.

参考例１の化合物（４００ ｍｇ）のテトラヒドロフラン懸濁液（１．１ ｍＬ）に、トリエチルアミン（０．７６３ ｍＬ）、Ｌ－乳酸（０．０９８ ｍＬ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（０．５０１ ｍｇ）を加えた。室温で４時間攪拌後、反応混合物にメタノール（６．０ ｍＬ）、２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（３．０ ｍＬ）と水（１．０ ｍＬ）を加え、さらに室温で１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（３０ｍＬ×２回）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（２７９ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.72-7.56 (1H, m), 7.17 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (1H, td, J = 8.8, 1.8 Hz), 4.48-4.32 (1H, m), 3.75-3.59 (1H, m), 3.52-2.86 (7H, m), 2.58-2.44 (2H, m), 2.32-2.11 (2H, m), 2.09-1.87 (4H, m), 1.32-1.25 (3H, m), 1.17 (2H, t, J = 7.0 Hz), 1.09 (1H, t, J = 7.0 Hz). Example 16
(2S)-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

In a tetrahydrofuran suspension (1.1 mL) of the compound of Reference Example 1 (400 mg), triethylamine (0.763 mL), L-lactic acid (0.098 mL) and hexafluorophosphate O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (0.501 mg) was added. After stirring at room temperature for 4 hours, methanol (6.0 mL), 2 mol/L aqueous sodium hydroxide solution (3.0 mL) and water (1.0 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. . After that, water (30 mL) was added to the reaction mixture, extracted with chloroform (30 mL×2 times), 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 (279 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.72-7.56 (1H, m), 7.17 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (1H, td, J = 8.8, 1.8 Hz), 4.48-4.32 (1H, m), 3.75-3.59 (1H, m), 3.52-2.86 (7H, m), 2.58-2.44 (2H, m), 2.32-2.11 (2H, m), 2.09-1.87 (4H , m), 1.32-1.25 (3H, m), 1.17 (2H, t, J = 7.0 Hz), 1.09 (1H, t, J = 7.0 Hz).

参考例１の化合物（３．９７ ｇ）のアセトニトリル懸濁液（５０ ｍＬ）に、トリエチルアミン（６．０８ ｍＬ）、３－ヒドロキシプロピオン酸（４．９１ ｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（６．２２ ｇ）を加えた。室温で２時間攪拌後、反応混合物にメタノール（５０ ｍＬ）と炭酸セシウム（１４．２ ｇ）を加え、７０℃で２時間攪拌した。その後、反応混合物をろ過した後、濃縮した。残渣にクロロホルム（５０ ｍＬ）を加え、不溶物をろ別し、ろ液を濃縮した。濃縮残渣をアミノシリカゲルクロマトグラフィー（ヘキサン/酢酸エチルおよびクロロホルム／メタノール）で精製後、さらに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（２．９７ ｇ）を得た。
¹H-NMR (400 MHz, CD₃OD) δ: 7.93-7.84 (1H, m), 7.42-7.33 (1H, m), 7.20-7.12 (1H, m), 3.88-3.79 (2H, m), 3.62-3.37 (4H, m), 3.23-3.04 (4H, m), 2.69-2.54 (4H, m), 2.42-2.26 (2H, m), 2.15-1.95 (4H, m), 1.29-1.07 (3H, m).
粉末ＸＲＤ（°, 2θ±0.2）
8.32, 9.72, 13.30, 13.62, 13.83, 14.24, 16.77, 17.81, 19.89, 19.95, 21.58, 22.02, 24.03, 26.77, 26.84（これらのうち、特徴的な１０個のピークは 8.32, 9.72, 13.83, 14.24, 16.77, 19.89, 19.95, 21.58, 22.02, 24.03、更に特徴的な４個のピークは 8.32, 9.72, 13.83, 16.77であった。）
ＤＳＣ
Enthalpy (normalized): 71.71 J/g
Onset x: 67.55℃ Example 17
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide

An acetonitrile suspension (50 mL) of the compound of Reference Example 1 (3.97 g) was added with triethylamine (6.08 mL), 3-hydroxypropionic acid (4.91 g) and hexafluorophosphoric acid O-(7 -Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (6.22 g) was added. After stirring at room temperature for 2 hours, methanol (50 mL) and cesium carbonate (14.2 g) were added to the reaction mixture, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was then filtered and then concentrated. Chloroform (50 mL) was added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated. The concentrated residue was purified by amino silica gel chromatography (hexane/ethyl acetate and chloroform/methanol) and further separated and purified by silica gel column chromatography (chloroform/methanol) to give the title compound (2.97 g).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.93-7.84 (1H, m), 7.42-7.33 (1H, m), 7.20-7.12 (1H, m), 3.88-3.79 (2H, m), 3.62-3.37 (4H, m), 3.23-3.04 (4H, m), 2.69-2.54 (4H, m), 2.42-2.26 (2H, m), 2.15-1.95 (4H, m), 1.29-1.07 (3H , m).
Powder XRD (°, 2θ±0.2)
8.32, 9.72, 13.30, 13.62, 13.83, 14.24, 16.77, 17.81, 19.89, 19.95, 21.58, 22.02, 24.03, 26.77, 26.84 16.77, 19.89, 19.95, 21.58, 22.02, 24.03, and four characteristic peaks were 8.32, 9.72, 13.83, 16.77.)
DSC
Enthalpy (normalized): 71.71 J/g
Onset x: 67.55℃

参考例１の化合物（７０．０ ｍｇ）のテトラヒドロフラン懸濁液（１．９ ｍＬ）に、トリエチルアミン（０．１３４ ｍＬ）、２－ヒドロキシ－３－メトキシプロピオン酸（２７．７ ｍｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（８８．０ ｍｇ）を加えた。室温で３時間攪拌後、反応混合物を濃縮後、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（５１．７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.78-7.62 (1H, m), 7.24-7.19 (1H, m), 7.03 (1H, td, J = 8.9, 2.2 Hz), 4.58-4.47 (1H, m), 3.82-2.89 (13H, m), 2.64-2.48 (2H, m), 2.39-1.96 (6H, m), 1.26-1.08 (3H, m). Example 18
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxy-3-methoxypropanamide

To a tetrahydrofuran suspension (1.9 mL) of the compound of Reference Example 1 (70.0 mg), triethylamine (0.134 mL), 2-hydroxy-3-methoxypropionic acid (27.7 mg) and hexafluoro O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium phosphate (88.0 mg) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (51.7 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.78-7.62 (1H, m), 7.24-7.19 (1H, m), 7.03 (1H, td, J = 8.9, 2.2 Hz), 4.58-4.47 (1H , m), 3.82-2.89 (13H, m), 2.64-2.48 (2H, m), 2.39-1.96 (6H, m), 1.26-1.08 (3H, m).

参考例６の化合物（４００ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（４．０ ｍＬ）にジイソプロピルエチルアミン（０．５７７ ｍＬ）、ＤＬ－乳酸（０．０８２ ｍＬ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（６２８ ｍｇ）を加えた。室温で１時間攪拌後、反応混合物に２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（３．０ ｍＬ）を加え、さらに室温で１時間攪拌した。その後、反応混合物に水（１０ ｍＬ）を加え、クロロホルム（５．０ ｍＬ×３回）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（２１７ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 10.01-9.79 (1H, m), 7.74-7.63 (1H, m), 7.06 (1H, dd, J = 9.1, 1.8 Hz), 6.88 (1H, t, J = 7.9 Hz), 4.52-4.37 (1H, m), 3.88-3.74 (2H, m), 3.74-3.59 (2H, m), 3.58-3.14 (3H, m), 3.11-2.93 (3H, m), 2.65-2.49 (2H, m), 2.36-1.95 (5H, m), 1.38-1.30 (3H, m), 1.26-1.10 (3H, m). Example 19
N-ethyl-N-{2-[4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

Diisopropylethylamine (0.577 mL), DL-lactic acid (0.082 mL) and hexafluorophosphate O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (628 mg) was added. After stirring at room temperature for 1 hour, 2 mol/L aqueous sodium hydroxide solution (3.0 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. After that, water (10 mL) was added to the reaction mixture, extracted with chloroform (5.0 mL×3 times), 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 (217 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.01-9.79 (1H, m), 7.74-7.63 (1H, m), 7.06 (1H, dd, J = 9.1, 1.8 Hz), 6.88 (1H, t , J = 7.9 Hz), 4.52-4.37 (1H, m), 3.88-3.74 (2H, m), 3.74-3.59 (2H, m), 3.58-3.14 (3H, m), 3.11-2.93 (3H, m ), 2.65-2.49 (2H, m), 2.36-1.95 (5H, m), 1.38-1.30 (3H, m), 1.26-1.10 (3H, m).

参考例７の化合物（３０．０ ｍｇ）のテトラヒドロフラン懸濁液（０．８３ ｍＬ）に、トリエチルアミン（０．０５７５ ｍＬ）、Ｌ－乳酸（８．９５ ｍｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（３７．８ ｍｇ）を加えた。室温で２時間攪拌後、反応混合物にメタノール（０．８ ｍＬ）と２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（０．４ ｍＬ）を加え、さらに、室温で３０分間攪拌した。反応混合物を濃縮後、クロロホルム（１０ ｍＬ）を加え、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（２４．３ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.01 (1H, s), 7.45 (1H, dd, J = 8.5, 5.5 Hz), 6.97 (1H, dd, J = 9.8, 2.4 Hz), 6.87 (1H, s), 6.82-6.77 (1H, m), 4.47-4.32 (1H, m), 3.77-2.87 (6H, m), 2.79-2.68 (1H, m), 2.60-2.44 (2H, m), 2.30-2.13 (2H, m), 2.06-1.67 (4H, m), 1.33-1.25 (3H, m), 1.22-1.06 (3H, m). Example 20
(2S)-N-ethyl-N-{2-[4-(6-fluoro-1H-indol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

In a tetrahydrofuran suspension (0.83 mL) of the compound of Reference Example 7 (30.0 mg), triethylamine (0.0575 mL), L-lactic acid (8.95 mg) and hexafluorophosphate O-(7 -Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (37.8 mg) was added. After stirring at room temperature for 2 hours, methanol (0.8 mL) and 2 mol/L aqueous sodium hydroxide solution (0.4 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. After concentrating the reaction mixture, chloroform (10 mL) was added, 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 (24.3 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.01 (1H, s), 7.45 (1H, dd, J = 8.5, 5.5 Hz), 6.97 (1H, dd, J = 9.8, 2.4 Hz), 6.87 ( 1H, s), 6.82-6.77 (1H, m), 4.47-4.32 (1H, m), 3.77-2.87 (6H, m), 2.79-2.68 (1H, m), 2.60-2.44 (2H, m), 2.30-2.13 (2H, m), 2.06-1.67 (4H, m), 1.33-1.25 (3H, m), 1.22-1.06 (3H, m).

参考例２の化合物（４００ ｍｇ）のテトラヒドロフラン懸濁液（４．０ ｍＬ）に、トリエチルアミン（０．７６８ ｍＬ）、Ｌ－乳酸（１６１ ｍｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（７８６ ｍｇ）を加えた。室温で３時間攪拌後、反応混合物に１５％水酸化ナトリウム水溶液（４．０ ｍＬ）を加え、さらに室温で１時間攪拌した。その後、反応混合物がｐＨ ７になるまで濃塩酸を加え、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（２６９ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.88 (1H, s), 7.38-7.24 (2H, m), 7.12-7.04 (1H, m), 4.48-4.29 (2H, m), 3.77-3.56 (2H, m), 3.50-2.93 (5H, m), 2.72-2.48 (2H, m), 2.38-2.18 (3H, m), 2.12-1.88 (2H, m), 1.32-1.25 (3H, m), 1.23-1.06 (3H, m). Example 21
(2S)-N-ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

In a tetrahydrofuran suspension (4.0 mL) of the compound of Reference Example 2 (400 mg), triethylamine (0.768 mL), L-lactic acid (161 mg) and hexafluorophosphate O-(7-azabenzotriazole -1-yl)-N,N,N',N'-tetramethyluronium (786 mg) was added. After stirring at room temperature for 3 hours, 15% aqueous sodium hydroxide solution (4.0 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. Concentrated hydrochloric acid was then added until the reaction mixture reached pH 7 and was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform/methanol) to give the title compound (269 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.88 (1H, s), 7.38-7.24 (2H, m), 7.12-7.04 (1H, m), 4.48-4.29 (2H, m), 3.77-3.56 (2H, m), 3.50-2.93 (5H, m), 2.72-2.48 (2H, m), 2.38-2.18 (3H, m), 2.12-1.88 (2H, m), 1.32-1.25 (3H, m) , 1.23-1.06 (3H, m).

参考例８の化合物（３００ ｍｇ）のテトラヒドロフラン懸濁液（８．７ ｍＬ）に、トリエチルアミン（０．６０６ ｍＬ）、ＤＬ－乳酸（９４．０ ｍｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（３９８ ｍｇ）を加えた。室温で３時間攪拌後、反応混合物にメタノール（６．０ ｍＬ）と２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（３．０ ｍＬ）を加え、さらに室温で１時間攪拌した。その後、反応混合物を濃縮後、残渣にクロロホルム（３０ ｍＬ）を加え、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（２５８ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.93-7.85 (1H, m), 7.57 (1H, d, J = 7.9 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.12 (1H, t, J = 7.3 Hz), 7.03 (1H, t, J = 7.0 Hz), 6.91 (1H, s), 4.47-4.33 (1H, m), 3.80-3.08 (4H, m), 3.05-2.87 (2H, m), 2.83-2.73 (1H, m), 2.59-2.43 (2H, m), 2.30-2.13 (2H, m), 2.06-1.93 (2H, m), 1.83-1.66 (2H, m), 1.29 (3H, t, J = 6.4 Hz), 1.21-1.06 (3H, m). Example 22
N-ethyl-2-hydroxy-N-{2-[4-(1H-indol-3-yl)piperidin-1-yl]ethyl}propanamide

In a tetrahydrofuran suspension (8.7 mL) of the compound of Reference Example 8 (300 mg), triethylamine (0.606 mL), DL-lactic acid (94.0 mg) and hexafluorophosphate O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (398 mg) was added. After stirring at room temperature for 3 hours, methanol (6.0 mL) and 2 mol/L aqueous sodium hydroxide solution (3.0 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated, chloroform (30 mL) was added to the residue, 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 (258 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.93-7.85 (1H, m), 7.57 (1H, d, J = 7.9 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.12 (1H, t, J = 7.3 Hz), 7.03 (1H, t, J = 7.0 Hz), 6.91 (1H, s), 4.47-4.33 (1H, m), 3.80-3.08 (4H, m), 3.05-2.87 (2H , m), 2.83-2.73 (1H, m), 2.59-2.43 (2H, m), 2.30-2.13 (2H, m), 2.06-1.93 (2H, m), 1.83-1.66 (2H, m), 1.29 (3H, t, J = 6.4 Hz), 1.21-1.06 (3H, m).

参考例８の化合物（３００ ｍｇ）のテトラヒドロフラン懸濁液（８．７ ｍＬ）に、トリエチルアミン（０．６０６ ｍＬ）、Ｌ－乳酸（９４．０ ｍｇ）とヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（３９８ ｍｇ）を加えた。室温で３時間攪拌後、反応混合物にメタノール（６．０ ｍＬ）と２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（３．０ ｍＬ）を加え、さらに室温で１時間攪拌した。その後、反応混合物を濃縮後、残渣にクロロホルム（３０ ｍＬ）を加え、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（２５８ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.06-7.92 (1H, m), 7.61 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.17 (1H, t, J = 7.3 Hz), 7.08 (1H, t, J = 7.6 Hz), 6.99-6.94 (1H, m), 4.51-4.36 (1H, m), 3.82-1.74 (16H, m), 1.34 (3H, t, J = 6.1 Hz), 1.26-1.11 (3H, m). Example 23
(2S)-N-ethyl-2-hydroxy-N-{2-[4-(1H-indol-3-yl)piperidin-1-yl]ethyl}propanamide

To a tetrahydrofuran suspension (8.7 mL) of the compound of Reference Example 8 (300 mg), triethylamine (0.606 mL), L-lactic acid (94.0 mg) and hexafluorophosphate O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (398 mg) was added. After stirring at room temperature for 3 hours, methanol (6.0 mL) and 2 mol/L aqueous sodium hydroxide solution (3.0 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated, chloroform (30 mL) was added to the residue, 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 (258 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.06-7.92 (1H, m), 7.61 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.17 (1H, t, J = 7.3 Hz), 7.08 (1H, t, J = 7.6 Hz), 6.99-6.94 (1H, m), 4.51-4.36 (1H, m), 3.82-1.74 (16H, m), 1.34 (3H , t, J = 6.1 Hz), 1.26-1.11 (3H, m).

Examples 24-50
According to the method described in Example 23, the compounds of Examples 24 to 50 were obtained from the corresponding compounds of Reference Examples.

参考例２３の化合物（６３６ ｍｇ）のテトラヒドロフラン溶液（２０ ｍＬ）に、１０％ 水酸化テトラブチルアンモニウム水溶液（１７．３ ｍ）を加えた。６０℃で２時間攪拌後、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（クロロホルム／メタノール）で分離精製し、表題化合物（３３０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.79 (1H, dd, J = 8.9, 5.2 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.04 (1H, td, J = 8.9, 2.2 Hz), 5.94 (1H, br s), 4.03-3.95 (2H, m), 3.60-3.53 (2H, m), 3.33-3.24 (4H, m), 3.21-3.09 (3H, m), 2.59-2.52 (2H, m), 2.31-2.13 (4H, m), 2.11-2.00 (2H, m), 1.25 (3H, t, J = 7.0 Hz). Example 51
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxyethane-1-sulfonamide

To a tetrahydrofuran solution (20 mL) of the compound of Reference Example 23 (636 mg) was added 10% aqueous tetrabutylammonium hydroxide solution (17.3 m). After stirring at 60°C for 2 hours, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform/methanol) and further separated and purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (330 mg) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.79 (1H, dd, J = 8.9, 5.2 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.04 (1H, td, J = 8.9 , 2.2 Hz), 5.94 (1H, br s), 4.03-3.95 (2H, m), 3.60-3.53 (2H, m), 3.33-3.24 (4H, m), 3.21-3.09 (3H, m), 2.59 -2.52 (2H, m), 2.31-2.13 (4H, m), 2.11-2.00 (2H, m), 1.25 (3H, t, J = 7.0 Hz).

Examples 52-64
According to the method described in Example 51, the compounds of Examples 52 to 64 were obtained from the corresponding compounds of Reference Examples.

３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－２－ヒドロキシプロピオン酸（４０．６ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（２．０ ｍＬ）に、ヘキサフルオロリン酸 Ｏ－（７－アザベンゾトリアゾール－1－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム（７５．０ ｍｇ）を加えた。室温で１時間攪拌後、トリエチルアミン（０．０５３ ｍＬ）と参考例１の化合物（６０．０ ｍｇ）を加えた。室温で３時間攪拌後、反応混合物に水（１０ ｍＬ）を加え、クロロホルム／メタノール（１０ ｍＬ×６回）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）で分離精製した。続いて得られた化合物（５０ ｍｇ）に４ ｍｏｌ／Ｌ 塩酸－酢酸エチル（２．０ ｍＬ）を加え、室温で１時間攪拌後、反応混合物を濃縮した。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）で分離精製し、表題化合物（３７．０ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.77-7.58 (1H, m), 7.20 (1H, d, J = 7.9 Hz), 7.08-6.91 (1H, m), 4.76-4.24 (1H, m), 3.86-2.69 (9H, m), 2.69-2.41 (4H, m), 2.41-1.74 (7H, m), 1.35-0.89 (3H, m). Example 65
3-amino-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

In N,N-dimethylformamide solution (2.0 mL) of 3-((tert-butoxycarbonyl)amino)-2-hydroxypropionic acid (40.6 mg), hexafluorophosphate O-(7-azabenzo Triazol-1-yl)-N,N,N',N'-tetramethyluronium (75.0 mg) was added. After stirring at room temperature for 1 hour, triethylamine (0.053 mL) and the compound of Reference Example 1 (60.0 mg) were added. After stirring at room temperature for 3 hours, water (10 mL) was added to the reaction mixture, extracted with chloroform/methanol (10 mL x 6 times), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform/methanol). Subsequently, 4 mol/L hydrochloric acid-ethyl acetate (2.0 mL) was added to the obtained compound (50 mg), and after stirring at room temperature for 1 hour, the reaction mixture was concentrated. The concentrated residue was separated and purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (37.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.58 (1H, m), 7.20 (1H, d, J = 7.9 Hz), 7.08-6.91 (1H, m), 4.76-4.24 (1H, m ), 3.86-2.69 (9H, m), 2.69-2.41 (4H, m), 2.41-1.74 (7H, m), 1.35-0.89 (3H, m).

Examples 66-70
According to the method described in Example 65, the compounds of Examples 66 to 70 were obtained from the corresponding compounds of Reference Examples.

実施例６５の化合物（２０．０ ｍｇ）のテトラヒドロフラン溶液（２．０ ｍＬ）に無水酢酸（０．００５９８ ｍＬ）を加え、室温で１時間攪拌した。その後、反応混合物に２ ｍｏｌ／Ｌ 水酸化ナトリウム水溶液（０．１ ｍＬ）を加え、さらに室温で１０分間攪拌した。反応混合物を濃縮後、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（１０．１ ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.77-7.55 (1H, m), 7.19-7.14 (1H, m), 7.05-6.97 (1H, m), 6.19-6.01 (1H, m), 4.49-4.34 (1H, m), 4.03-3.47 (4H, m), 3.47-2.84 (6H, m), 2.72-2.48 (2H, m), 2.43-2.19 (2H, m), 2.16-1.97 (4H, m), 1.96-1.90 (3H, m), 1.24-1.06 (3H, m). Example 71
3-acetamido-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide

Acetic anhydride (0.00598 mL) was added to a tetrahydrofuran solution (2.0 mL) of the compound of Example 65 (20.0 mg), and the mixture was stirred at room temperature for 1 hour. After that, 2 mol/L aqueous sodium hydroxide solution (0.1 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 10 minutes. After concentrating the reaction mixture, it was separated and purified by amino silica gel column chromatography (chloroform/methanol) to obtain the title compound (10.1 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.55 (1H, m), 7.19-7.14 (1H, m), 7.05-6.97 (1H, m), 6.19-6.01 (1H, m), 4.49 -4.34 (1H, m), 4.03-3.47 (4H, m), 3.47-2.84 (6H, m), 2.72-2.48 (2H, m), 2.43-2.19 (2H, m), 2.16-1.97 (4H, m), 1.96-1.90 (3H, m), 1.24-1.06 (3H, m).

Examples 72-74
According to the method described in Example 71, the compounds of Examples 72 to 74 were obtained from the corresponding compounds of Reference Examples.

実施例６６の化合物（１０．０ ｍｇ）のメタノール溶液（０．５ ｍＬ）に、３７％ホルムアルデヒド水溶液（０．００２ ｍＬ）、シアノホウ素化水素ナトリウム（１．０９ ｍｇ）と酢酸（０．００３ ｍＬ）を加え、室温で１６時間攪拌した。その後、反応混合物に水（１０ ｍＬ）を加え、クロロホルム（１０ ｍＬ×２回）で抽出し、濃縮した。濃縮残渣を高速液体クロマトグラフィー（カラム；ｓｅｍｉｐｒｅｐａｒａｔｉｖｅ Ｃ－１８ ｃｏｌｕｍｎ，分離条件；アセトニトリル/トリフルオロ酢酸：水／トリフルオロ酢酸）で分離精製し、ＭＰ－Ｃａｒｂｏｎａｔｅ ｒｅｓｉｎで脱塩処理することで、表題化合物（６．８８ ｍｇ）を得た。
LC‐MS：R.T. = 1.083 min ObsMS = 419 [M+1] Example 75
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-4-hydroxy-1-methylpyrrolidine-3-carboxamide

To a methanol solution (0.5 mL) of the compound of Example 66 (10.0 mg), 37% formaldehyde aqueous solution (0.002 mL), sodium cyanoborohydride (1.09 mg) and acetic acid (0.003 mL) was added and stirred at room temperature for 16 hours. After that, water (10 mL) was added to the reaction mixture, extracted with chloroform (10 mL×2 times), and concentrated. The concentrated residue was separated and purified by high-performance liquid chromatography (column: semipreparative C-18 column, separation conditions: acetonitrile/trifluoroacetic acid: water/trifluoroacetic acid), and desalted with MP-Carbonate resin to obtain the title compound. (6.88 mg) was obtained.
LC-MS: RT = 1.083 min ObsMS = 419 [M+1]

実施例７５と同様の手法により、実施例６７の化合物から表題化合物を得た。
LC‐MS：R.T. = 1.092 min ObsMS = 433 [M+1] Example 76
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-4-hydroxy-1-methylpiperidine-3-carboxamide

The title compound was obtained from the compound of Example 67 in a manner similar to that of Example 75.
LC-MS: RT = 1.092 min ObsMS = 433 [M+1]

Example 77
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide orotate in Example 17 Orotic acid (14.4 mg) was added to a methanol solution (0.4 mL) of the obtained compound (30 mg), and the mixture was stirred at 60°C for 1 hour. Ethyl acetate (2.0 mL) was then added to the reaction mixture. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration to obtain the title compound (27.3 mg).
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 11.02 (1H, s), 9.94 (1H, brs), 8.03 (1H, dd, J = 8.8, 5.2 Hz), 7.74-7.68 (1H, m ), 7.35-7.27 (1H, m), 5.79 (1H, d, J = 1.8 Hz), 4.53 (1H, brs), 3.65 (2H, t, J = 6.7 Hz), 3.62-3.49 (3H, m) , 3.48-3.19 (6H, m), 3.18-2.62 (4H, m), 2.28-2.13 (2H, m), 2.13-1.91 (2H, m), 1.12 (2H, t, J = 7.0 Hz), 1.02 (1H, t, J = 7.0Hz).
Powder XRD (°, 2θ ± 0.2)
4.87, 7.24, 15.27, 15.75, 16.02, 16.39, 16.73, 17.62, 19.51, 20.04, 21.24, 22.05, 22.34, 24.23, 24.80. 16.02, 17.62, 19.51, 20.04, 21.24, 22.05, and four characteristic peaks were 4.87, 19.51, 20.04, 21.24.)
DSC
Enthalpy (normalized): 62.81 J/g
Onset x: 157.09℃

Example 78
Form of N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide hydrobromide A.
10-20% HBr-EtOH (14.1 g) was added dropwise to an acetonitrile solution (77 mL) of the compound (6.03 g) obtained in Example 17, and after stirring at room temperature for 1 hour, a solid precipitated. confirmed. The mixture was stirred at 80° C. and stirred for 1 hour after confirming that the precipitated solid was completely dissolved. Then, it was gradually cooled and stirred at room temperature for 12 hours. The precipitated solid was collected by filtration, washed with acetonitrile (10 mL), and dried to obtain a white solid (7.0 g). A mixture of the obtained white solid (7.0 g) and tetrahydrofuran (15 mL) was stirred at 80° C. for 3.5 hours. After that, the mixture was gradually cooled and stirred at room temperature for 12 hours, and the solid was collected by filtration, washed with tetrahydrofuran (10 mL) and dried to obtain the title compound (6.20 g).
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 9.48 (0.2H, brs), 9.19 (0.8H, brs), 8.11-7.99 (1H, m), 7.78-7.70 (1H, m), 7.40 -7.30 (1H, m), 4.53 (1H, brs), 3.78-3.56 (6H, m), 3.55-3.09 (8H, m), 2.40-2.18 (3H, m), 2.15-1.97 (2H, m) , 1.19-0.97 (3H, m).
Powder XRD (°, 2θ ± 0.2)
4.48, 8.98, 12.40, 13.63, 15.23, 16.35, 17.07, 17.88, 18.06, 21.19, 23.13, 23.83, 24.48, 25.22, 25.98. 17.88, 21.19, 23.13, 24.48, 25.22, 25.98, and four characteristic peaks were 12.40, 15.23, 17.07, 21.19.)
DSC
Enthalpy (normalized): 82.83 J/g
Onset x: 163.64℃

Example 79
Form of N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide hydrobromide B.
10-20% HBr-EtOH (0.2 mL) was added dropwise to an acetonitrile solution (2.0 mL) of the compound (100 mg) obtained in Example 17. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration to obtain the title compound (67.0 mg).
Powder XRD (°, 2θ ± 0.2)
7.25, 7.65, 9.90, 11.17, 12.48, 15.34, 15.71, 22.36, 23.36, 23.74, 24.62, 25.05, 25.18, 25.26, 29.36. 15.71, 23.36, 24.62, 25.05, 25.18, 25.26, and four characteristic peaks were 7.25, 7.65, 9.90, 15.34.)
DSC
Enthalpy (normalized): 86.51 J/g
Onset x: 164.04℃

Example 80
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide tosylate in Example 17 An acetone solution (150 mL) of p-toluenesulfonic acid monohydrate (41.9 g) was added to an acetone solution (200 mL) of the obtained compound (66.7 g). After the mixture was stirred at room temperature for 2 hours, the precipitated solid was collected by filtration, washed with acetone (60 mL) and dried to give a white solid (78.8 g). A mixture of the obtained white solid (78.8 g), acetone (608 mL) and water (33.4 mL) was stirred at 70°C, and after confirming that the white solid was completely dissolved, it was gradually cooled to room temperature. and stirred for 12 hours. After stirring at 0°C for 1 hour, the resulting solid was collected by filtration, washed with a 5% water-acetone mixed solvent (70 mL) cooled to 0°C, and dried to give the title compound (69.4 g). got
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 9.39-9.00 (1H, m), 8.08-7.99 (1H, m), 7.77-7.71 (1H, m), 7.46 (2H, d, J = 7.9 Hz), 7.39-7.30 (1H, m), 7.10 (2H, d, J = 7.9 Hz), 4.53 (1H, brs), 3.76-3.56 (6H, m), 3.54-3.11 (8H, m), 2.38-2.17 (6H, m), 2.12-1.96 (2H, m), 1.16-0.98 (3H, m).
Powder XRD (°, 2θ ± 0.2)
6.87, 7.03, 9.64, 13.74, 15.19, 15.37, 15.68, 16.22, 19.82, 21.60, 21.67, 22.10, 23.15, 23.88, 27.67. 15.68, 16.22, 21.60, 21.67, 23.15, 23.88, and four characteristic peaks were 7.03, 9.64, 15.19, 15.68.)
DSC
Enthalpy (normalized): 99.47 J/g
Onset x: 162.26℃

６－フルオロ－３－（４－ピペリジニル）－１，２－ベンゾイソキサゾール（５．７８ ｇ）のクロロホルム溶液（１３１ ｍＬ）に、ｔｅｒｔ－ブチルエチル（２－オキソエチル）カーバメイト（４．９１ ｇ）とトリアセトキシ水素化ホウ素ナトリウム（１１．１ ｇ）を加え、室温で５時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液（１００ ｍＬ）を加え、クロロホルム（１００ ｍＬ×２回）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）で分離精製した。得られた生成物のクロロホルム溶液（１３１ ｍＬ）に４ ｍｏｌ／Ｌ 塩酸－酢酸エチル（６０ ｍＬ）を加え、室温で２時間攪拌した。析出した固体をろ取し、酢酸エチル（２０ ｍＬ×２回）で洗浄後、乾燥し、表題化合物（６．２４ ｇ）を得た。
¹H-NMR (400 MHz, DMSO-D₆) δ: 9.31 (2H, brs), 8.18 (1H, dd, J = 8.5, 5.5 Hz), 7.74 (1H, dd, J = 8.9, 2.1 Hz), 7.35 (1H, ddd, J = 9.0, 9.0, 2.2 Hz), 3.81-3.72 (2H, m), 3.55-3.46 (5H, m), 3.28-3.15 (2H, m), 3.08-2.97 (2H, m), 2.43-2.23 (4H, m), 1.25 (3H, t, J = 7.3 Hz). Reference example 1
N-ethyl-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine dihydrochloride

To a chloroform solution (131 mL) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.78 g) was added tert-butyl ethyl (2-oxoethyl)carbamate (4.91 g). and sodium triacetoxyborohydride (11.1 g) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL×2 times), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform/methanol). 4 mol/L hydrochloric acid-ethyl acetate (60 mL) was added to a chloroform solution (131 mL) of the obtained product, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with ethyl acetate (20 mL×2 times) and dried to give the title compound (6.24 g).
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 9.31 (2H, brs), 8.18 (1H, dd, J = 8.5, 5.5 Hz), 7.74 (1H, dd, J = 8.9, 2.1 Hz), 7.35 (1H, ddd, J = 9.0, 9.0, 2.2 Hz), 3.81-3.72 (2H, m), 3.55-3.46 (5H, m), 3.28-3.15 (2H, m), 3.08-2.97 (2H, m ), 2.43-2.23 (4H, m), 1.25 (3H, t, J = 7.3 Hz).

Reference examples 2 to 13
According to the method described in Reference Example 1, the compounds of Reference Examples 2 to 13 were obtained from the corresponding compounds or reagents of Reference Examples.

ａ）ｔｅｒｔ－ブチル ４－［メトキシ（メチル）カルバモイル］ピペリジン－１－カルボキシレート（化合物ＩＮ－１－１）の製造
１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボキシリックアシッド（５．００ ｇ）、Ｎ，Ｏ－ジメチルヒドロキシアミン塩酸塩（３．１９ ｇ）、Ｎ１－（（エチルイミノ）メチレン）－Ｎ３，Ｎ３－ジメチルプロパン－１，３－ジアミン塩酸塩（５．０２ ｇ）、トリエチルアミン（４．４１ ｇ）とＮ，Ｎ－ジメチルホルムアミド（１００ ｍＬ）の混合物を室温で１．５時間攪拌した。その後、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。合わせた有機層を飽和塩化アンモニウム水溶液で２回、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過して濃縮し、表題化合物（４．５２ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 4.03-4.24 (2H, m), 3.72 (3H, s), 3.19 (3H, s), 2.70-2.86 (3H, m), 1.63-1.76 (4H, m), 1.46 (9H, s). Reference example 14
6-fluoro-5-methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride

a) Preparation 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-dimethylpropane-1,3-diamine hydrochloride (5.02 g), triethylamine ( 4.41 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1.5 hours. After that, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed twice with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.52 g). .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.03-4.24 (2H, m), 3.72 (3H, s), 3.19 (3H, s), 2.70-2.86 (3H, m), 1.63-1.76 (4H , m), 1.46 (9H, s).

b) Preparation of tert-butyl 4-(2,4-difluoro-5-methylbenzoyl)piperidine-1-carboxylate (compound IN-1-2) 1-bromo-2,4-difluoro-5-methylbenzene ( 2.28 g) in tetrahydrofuran solution (36 mL) at −78° C., 1.63 mol/L n-butyllithium/hexane (7.43 mL) was added dropwise over 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. After that, saturated aqueous ammonium chloride solution was added to the reaction mixture, and 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 H-NMR (400 MHz, CDCl ₃ ) δ: 7.17-7.25 (1H, m), 6.80-6.87 (1H, m), 1.83-1.92 (2H, m), 1.59-1.69 (2H, m), 1.45 (9H, s).

c) Preparation of tert-butyl 4-(6-fluoro-5-methyl-1,2-benzoxazol-3-yl)piperidine-1-carboxylate (Compound IN-1-3) Compound IN-1-2 ( 731 mg), hydroxylamine hydrochloride (599 mg), sodium acetate (707 mg) and ethanol (10 mL) was stirred at 60° C. for 4 hours. After that, water was added to the reaction mixture, and 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 obtained 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. Thereafter, 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 H-NMR (400 MHz, CDCl ₃ ) δ: 7.47 (1H, d, J = 7.1 Hz), 7.21 (1H, d, J = 9.0 Hz), 4.11-4.36 (2H, m), 3.16-3.26 ( 1H, m), 2.89-3.03 (2H, m), 2.38 (3H, d, J = 1.7 Hz), 2.01-2.10 (2H, m), 1.87-1.99 (2H, m).

d) Preparation of 6-fluoro-5-methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride (Reference Example 14) Dichloromethane solution of compound IN-1-3 (131 mg) 4 mol/L hydrochloric acid/ethyl acetate (1.0 mL) was added to (1.0 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give the title compound (114 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.30 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.06 (1H, d, J = 9.1 Hz), 4.12-4.04 (2H, m), 3.09-3.01 (1H, m), 2.84-2.75 (2H, m), 2.22 (3H, d, J = 1.8 Hz), 1.93-1.86 (2H, m), 1.84-1.71 (2H, m) .

参考例１４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: 7.48-7.43 (2H, m), 7.38-7.34 (1H, m), 4.29-4.20 (2H, m), 3.28-3.18 (1H, m), 3.02-2.92 (2H, m), 2.48 (3H, s), 2.11-2.03 (2H, m), 2.03-1.90 (2H, m). Reference example 15
5-methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride

The title compound was obtained from 1-fluoro-2-iodo-4-methylbenzene in the same manner as in Reference Example 14.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.48-7.43 (2H, m), 7.38-7.34 (1H, m), 4.29-4.20 (2H, m), 3.28-3.18 (1H, m), 3.02 -2.92 (2H, m), 2.48 (3H, s), 2.11-2.03 (2H, m), 2.03-1.90 (2H, m).

２－（４－（６－フルオロベンゾ［ｄ］イソキサゾール－３－イル）ピペリジン－１－イル）エタン－１－アミン（５０．０ ｍｇ）のクロロホルム溶液（２．０ｍＬ）に、シクロプロパンカルボアルデヒド（１６．０ ｍｇ）を加え、室温で３０分間攪拌した。その後、反応混合物に水素化トリアセトキシホウ素ナトリウム（６０．４ ｍｇ）を加えた。室温で１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回）で抽出し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮し表題化合物（２６．０ ｍｇ）を得た。
LC‐MS：R.T. = 1.250 min ObsMS = 318 [M+1] Reference example 16
N-(Cyclopropylmethyl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine

2-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethan-1-amine (50.0 mg) in chloroform solution (2.0 mL), cyclopropanecarbaldehyde (16.0 mg) was added and stirred at room temperature for 30 minutes. After that, sodium triacetoxyborohydride (60.4 mg) was added to the reaction mixture. After stirring at room temperature for 1 hour, saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, extracted with chloroform (30 mL x 2 times), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (26 .0 mg) was obtained.
LC-MS: RT = 1.250 min ObsMS = 318 [M+1]

参考例１６と同様の手法により、アセトンから表題化合物を得た。
LC‐MS：R.T. = 1.176 min ObsMS = 306 [M+1] Reference example 17
N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-2-amine

The title compound was obtained from acetone in the same manner as in Reference Example 16.
LC-MS: RT = 1.176 min ObsMS = 306 [M+1]

５５％水素化ナトリウム（７．９２ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド懸濁液（２．０ ｍＬ）に、参考例２０の化合物（６０．０ ｍｇ）を加え、室温で３０分間攪拌後、反応混合物に、２－ヨードアセトニトリル（４１．３ ｍｇ）を加えた。室温で１時間攪拌後、反応混合物に、水（３０ ｍＬ）を加え、クロロホルム（３０ ｍＬ×２回）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。濃縮残渣に４ ｍｏｌ／Ｌ 塩酸／酢酸エチル（３．０ ｍＬ）を加え、室温で１時間攪拌後、反応混合物を濃縮した。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）で分離精製し、表題化合物（２５．０ ｍｇ）を得た。
LC‐MS：R.T. = 0.530 min ObsMS = 303 [M+1] Reference example 18
({2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}amino)acetonitrile

The compound of Reference Example 20 (60.0 mg) was added to N,N-dimethylformamide suspension (2.0 mL) of 55% sodium hydride (7.92 mg) and stirred at room temperature for 30 minutes. 2-Iodoacetonitrile (41.3 mg) was added to the reaction mixture. After stirring at room temperature for 1 hour, water (30 mL) was added to the reaction mixture, extracted with chloroform (30 mL×2 times), dried over anhydrous sodium sulfate, filtered and concentrated. 4 mol/L hydrochloric acid/ethyl acetate (3.0 mL) was added to the concentrated residue, and after stirring at room temperature for 1 hour, the reaction mixture was concentrated. The concentrated residue was separated and purified by amino silica gel column chromatography (hexane/ethyl acetate) to give the title compound (25.0 mg).
LC-MS: RT = 0.530 min ObsMS = 303 [M+1]

参考例１８と同様の手法により、参考例２１の化合物から表題化合物を得た。 Reference example 19
N-ethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propan-1-amine dihydrochloride

The title compound was obtained from the compound of Reference Example 21 in the same manner as in Reference Example 18.

６－フルオロ－3－（ピペリジン－4－イル）ベンゾ［ｄ］イソキサゾール（２．８９ ｇ）のクロロホルム溶液（６０ ｍＬ）に、ｔｅｒｔ－ブチル（２－オキソエチル）カーバメイト（２．３０ ｇ）を加え、室温で３０分間攪拌した。水素化トリアセトキシホウ素ナトリウム（３．３４ ｇ）を加え、室温で３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（１００ ｍＬ）を加え、クロロホルム（１００ ｍＬ×２回）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（３．９８ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.67 (1H, dd, J = 8.8, 5.2 Hz), 7.24-7.20 (1H, m), 7.04 (1H, ddd, J = 8.8, 8.8, 2.0 Hz), 5.02 (1H, s), 3.29-3.20 (2H, m), 3.10-2.98 (3H, m), 2.53-2.46 (2H, m), 2.22-2.13 (2H, m), 2.09-2.00 (4H, m), 1.45 (9H, s). Reference example 20
tert-butyl {2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}carbamate

To a chloroform solution (60 mL) of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.89 g) was added tert-butyl(2-oxoethyl)carbamate (2.30 g). , and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.34 g) was added, and after stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction mixture, extracted with chloroform (100 mL x 2 times), and dried. After drying with sodium sulfate, it was filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform/methanol) to give the title compound (3.98 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.67 (1H, dd, J = 8.8, 5.2 Hz), 7.24-7.20 (1H, m), 7.04 (1H, ddd, J = 8.8, 8.8, 2.0 Hz ), 5.02 (1H, s), 3.29-3.20 (2H, m), 3.10-2.98 (3H, m), 2.53-2.46 (2H, m), 2.22-2.13 (2H, m), 2.09-2.00 (4H , m), 1.45 (9H, s).

６－フルオロ－3－（ピペリジン－4－イル）ベンゾ［ｄ］イソキサゾール（２．００ ｇ）のアセトニトリル溶液（５０ ｍＬ）に、水（１２．５ ｍＬ）、ｔｅｒｔ－ブチル（３－ブロモプロピル）カーバメイト（２．５９ ｇ）と炭酸カリウム（３．７６ ｇ）を加えた。６０℃で３．５時間攪拌後、反応混合物に水（２００ ｍＬ）を加え、酢酸エチル（２００ ｍＬ×２回）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（３．４６ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.67 (1H, dd, J = 8.8, 5.2 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.02 (1H, ddd, J = 8.8, 8.8, 2.2 Hz), 5.50 (1H, s), 3.23-3.17 (2H, m), 3.12-3.00 (3H, m), 2.46 (2H, t, J = 6.7 Hz), 2.16-1.99 (6H, m), 1.72-1.64 (2H, m), 1.43 (9H, s). Reference example 21
tert-butyl {3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propyl}carbamate

6-Fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.00 g) in acetonitrile solution (50 mL), water (12.5 mL), tert-butyl (3-bromopropyl) Carbamate (2.59 g) and potassium carbonate (3.76 g) were added. After stirring at 60° C. for 3.5 hours, water (200 mL) was added to the reaction mixture, extracted with ethyl acetate (200 mL×2), 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 (3.46 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.67 (1H, dd, J = 8.8, 5.2 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.02 (1H, ddd, J = 8.8 , 8.8, 2.2 Hz), 5.50 (1H, s), 3.23-3.17 (2H, m), 3.12-3.00 (3H, m), 2.46 (2H, t, J = 6.7 Hz), 2.16-1.99 (6H, m), 1.72-1.64 (2H, m), 1.43 (9H, s).

ａ）３－［１－（２－クロロエチル）ピペリジン－４－イル］－６－フルオロ－１，２－ベンゾイソオキサゾール（化合物ＩＮ－２－１）の製造
６－フルオロ－3－（ピペリジン－4－イル）ベンゾ［ｄ］イソキサゾール（３．００ ｇ）のテトラヒドロフラン溶液（２５ ｍＬ）に、水（６．３ ｍＬ）、水酸化カリウム（１．６８ ｇ）と１－ブロモ－２－クロロエタン（５．６５ ｍＬ）を加え、室温で２４時間攪拌した。反応混合物に水（１５ ｍＬ）を加え、クロロホルム（１０ ｍＬ×３回）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（酢酸エチル／メタノール）で分離精製し、表題化合物（１．９４ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.70 (1H, dd, J = 8.5, 5.3 Hz), 7.25 (1H, dd, J = 8.9, 2.5 Hz), 7.06 (1H, ddd, J = 8.8, 8.8, 2.1 Hz), 3.64 (2H, t, J = 6.9 Hz), 3.01-3.15 (3H, m), 2.81 (2H, t, J = 6.9 Hz), 2.24-2.39 (2H, m), 2.02-2.18 (4H, m). Reference example 22
N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-1-amine

a) Preparation of 3-[1-(2-chloroethyl)piperidin-4-yl]-6-fluoro-1,2-benzisoxazole (compound IN-2-1) 6-fluoro-3-(piperidine-4 -yl)benzo[d]isoxazole (3.00 g) in tetrahydrofuran (25 mL), water (6.3 mL), potassium hydroxide (1.68 g) and 1-bromo-2-chloroethane (5 .65 mL) was added and stirred at room temperature for 24 hours. Water (15 mL) was added to the reaction mixture, extracted with chloroform (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.94 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.70 (1H, dd, J = 8.5, 5.3 Hz), 7.25 (1H, dd, J = 8.9, 2.5 Hz), 7.06 (1H, ddd, J = 8.8 , 8.8, 2.1 Hz), 3.64 (2H, t, J = 6.9 Hz), 3.01-3.15 (3H, m), 2.81 (2H, t, J = 6.9 Hz), 2.24-2.39 (2H, m), 2.02 -2.18 (4H, m).

b) Preparation of N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-1-amine (Reference Example 22) Compound IN- 2-1 (80.0 mg) in acetonitrile solution (1.4 mL), n-propylamine (0.0349 mL), potassium carbonate (117 mg) and potassium iodide (9.39 mg) were added, Stirred at 90° C. for 4 hours. After filtering the reaction mixture, it was concentrated, and the concentrated residue was separated and purified by amino silica gel column chromatography (chloroform/methanol) to obtain the title compound (50.9 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (1H, dd, J = 8.8, 5.2 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.03 (1H, ddd, J = 8.8 , 8.8, 2.2 Hz), 3.10-2.99 (3H, m), 2.72 (2H, t, J = 6.1 Hz), 2.58 (2H, t, J = 7.0 Hz), 2.53 (2H, t, J = 6.4 Hz ), 2.21-1.99 (6H, m), 1.56-1.46 (2H, m), 0.91 (3H, t, J = 7.3 Hz).

参考例１の化合物（１．００ ｇ）のジクロロメタン溶液（４０ ｍＬ）に、トリエチルアミン（２．３９ ｍＬ）と２－クロロエタンスルホニルクロライド（０．４３３ ｍＬ）を加え、室温で４時間攪拌した。反応混合物を濃縮後、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（０．６７０ ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (1H, dd, J = 8.5, 4.9 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.04 (1H, ddd, J = 8.9, 8.9, 2.2 Hz), 6.54 (1H, dd, J = 16.5, 9.8 Hz), 6.20 (1H, d, J = 16.5 Hz), 5.89 (1H, d, J = 9.8 Hz), 3.31 (2H, t, J = 7.0 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.11-3.00 (3H, m), 2.61 (2H, t, J = 6.7 Hz), 2.32-2.17 (2H, m), 2.10-1.97 (4H, m), 1.20 (3H, t, J = 7.3 Hz). Reference example 23
N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}ethenesulfonamide

Triethylamine (2.39 mL) and 2-chloroethanesulfonyl chloride (0.433 mL) were added to a dichloromethane solution (40 mL) of the compound of Reference Example 1 (1.00 g), and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture, the concentrated residue was separated and purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (0.670 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.65 (1H, dd, J = 8.5, 4.9 Hz), 7.22 (1H, dd, J = 8.5, 2.4 Hz), 7.04 (1H, ddd, J = 8.9 , 8.9, 2.2 Hz), 6.54 (1H, dd, J = 16.5, 9.8 Hz), 6.20 (1H, d, J = 16.5 Hz), 5.89 (1H, d, J = 9.8 Hz), 3.31 (2H, t , J = 7.0 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.11-3.00 (3H, m), 2.61 (2H, t, J = 6.7 Hz), 2.32-2.17 (2H, m), 2.10 -1.97 (4H, m), 1.20 (3H, t, J = 7.3 Hz).

Reference examples 24-36
According to the method described in Reference Example 23, the compounds of Reference Examples 24 to 36 were obtained from the corresponding compounds of Reference Example.

参考例１８および参考例２１と同様の手法により、３－（ピペリジン－４－イル）ベンゾ［ｄ］イソキサゾールから表題化合物を得た。 Reference example 37
3-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]-N-ethylpropan-1-amine dihydrochloride

The title compound was obtained from 3-(piperidin-4-yl)benzo[d]isoxazole in the same manner as in Reference Examples 18 and 21.

参考例１８および参考例２１と同様の手法により、６－フルオロ－３－（ピペラジン－１－イル）ベンゾ［ｄ］イソキサゾール 一塩酸塩から表題化合物を得た。 Reference example 38
N-ethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazin-1-yl]propan-1-amine dihydrochloride

By the same method as in Reference Examples 18 and 21, the title compound was obtained from 6-fluoro-3-(piperazin-1-yl)benzo[d]isoxazole monohydrochloride.

Test Example 1: Evaluation of human 5-HT _2A receptor, human 5-HT ₇ receptor, and human D ₂ receptor binding activity of the compounds of the present invention to human 5-HT _2A receptor and human 5- Binding affinities for _HT7 receptor and human D2 receptor _were measured by the following method.
CHO cell membrane fractions expressing human 5-HT _2A receptor, human 5-HT ₇ receptor, and human D ₂ receptor were purchased from PerkinElmer. In binding assays, test compound dissolved in dimethylsulfoxide (DMSO), various receptor membrane preparations diluted in buffer, and [3H]Ketanserin for 5- _HT2A receptors and 5- _HT7 receptors [3H]SB- ₂₆₉₉₇₀ for D2 receptor and [3H]Spiperone (all manufactured by PerkinElmer) were mixed and incubated at room temperature for 60 minutes. Non-specific binding to receptors was determined by competitive binding tests in the presence of 10 μmol/L 8-OH-DPAT, 10 μmol/L Mianserin, and 10 μmol/L Spiperone, respectively. After measuring the radioactivity bound to the receptor using a liquid scintillation counter (manufactured by PerkinElmer), the 50% inhibitory concentration was calculated, and the Ki value was evaluated from the dissociation constant calculated from the saturation binding test and the substrate concentration. , was used as the binding affinity. The results are shown in the table below.

Test Example 2: Evaluation of antagonist activity against human 5-HT _2A receptor and human 5-HT ₇ receptor Transient expression of each receptor of aequorin and Gα16 protein in CHO-K1 cells (Chinese hamster ovary) After overnight culture at 37° C. in a CO ₂ incubator, the cells were seeded in 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 luminescence intensity were measured with an FDSS/μCELL drug discovery screening support system (manufactured by Hamamatsu Photonics). Regarding the antagonist activity, the inhibitory activity of each compound was calculated based on the luminescence level of the well added with 10 μmol/L endogenous ligand as 100%. The results are shown in the table below.

Test Example 3-1 Human Liver Microsomal Metabolic Stability Test The human liver microsomal 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 a test substance were mixed in 25 mmol/L phosphate buffer (pH 7.4) so as to have 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
After 30 minutes, the residual rate of the test substance in the sample was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated from the following formula.
Human liver microsomal metabolic stability (mL/min/mg protein) = -LN (residual rate)/30/0.1
The results are shown in the table below.

Test Example 3-2: Human Liver Microsomal Metabolic Stability Test In order to more accurately evaluate the human liver microsomal metabolic stability, the human liver microsomal metabolic stability of the compound of the present invention was measured at an appropriate human liver microsomal concentration by the following method. Evaluated by Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and a test substance were mixed in 25 mmol/L phosphate buffer (pH 7.4) so as to have the following concentrations, and incubated at 37° C. for 60 minutes.
・Human liver microsomes: 0.5 or 1.0 mg/mL
・NAPDH: 3.2mmol/L
・ Test substance: 0.1 μmol / L
After 30 or 60 minutes, the residual rate of the test substance in the sample was measured by LC-MS, and the human liver microsomal metabolic stability was calculated from the following formula.
Human liver microsome metabolic stability (mL/min/mg protein)=-LN (residual rate)/reaction time/human liver microsome concentration The results are shown in the table below.

Test Example 4 Human Half-Life Prediction Test The elimination half-life of the compound of the present invention in humans was predicted by the following method.
A 0.01 mol/L aqueous solution of hydrochloric acid was intravenously administered to rats, and blood samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration. was taken. Plasma was obtained from the collected blood, the drug concentration in plasma was measured by LC-MS, and the rat distribution volume was calculated from this concentration transition.
Human and rat serum unbound fractions of the compounds of the present invention were determined using equilibrium dialysis.
The half-life in humans was calculated by applying the following formula using the rat distribution volume, the unbound fraction in human and rat serum, and the results of human liver microsomal metabolic stability obtained in Test Example 3-2.
・Human distribution volume = rat distribution volume × human serum unbound fraction / rat serum unbound fraction ・Human liver clearance =
(Human hepatic blood flow x Fraction of unbound form in human serum x 56.7 x Human liver microsomal metabolic stability)
/(human hepatic blood flow + unbound form fraction in human serum x 56.7 x human liver myrosome 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 5: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the compound of the present invention was evaluated using auto patch clamp using CHO cells in which hERG channels involved in human rapidly activated delayed rectifier potassium current (I _Kr ) were forcibly expressed. It was measured by the whole-cell patch-clamp method using the system.
(Preparation of cell suspension)
hERG-CHO cells purchased from ChanTest were cultured at 37° C. in a CO ₂ incubator and detached from the flask using trypsin just prior to hERG current measurement to prepare a cell suspension.
(Solution preparation)
Extracellular fluid and intracellular fluid used for measurement were prepared as follows.
Extracellular fluid: ₂ mmol/L CaCl2, 1 mmol/L MgCl2, 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: A test substance solution was prepared by dissolving the test substance in DMSO so as to be 2 mmol/L or 20 mmol/L. Further, the test substance solution was diluted 200-fold with the extracellular fluid, and serially diluted with the extracellular fluid to prepare and apply the test substance solution at each concentration required for calculating the hERG inhibition IC ₅₀ value.
(Current value measurement and data analysis)
A cell suspension, an extracellular solution, an intracellular solution, and a measurement plate were placed in an auto patch clamp system, and hERG current was measured by the whole-cell patch clamp method. The voltage protocol consisted of a holding potential of −80 mV, a depolarizing pulse of −50 mV to +20 mV for 5 seconds, followed by a repolarizing pulse of −50 mV for 5 seconds and returning to the holding potential. Each pulse interval was 15 seconds. Analysis software for Qube (manufactured by Sophion Sophion) was used for data analysis. Four concentrations of each test substance were applied in increments, and the mean value of the maximum peak tail current obtained from the last three stimulations of each applied concentration was used as evaluation data. Also, the IC ₅₀ value was calculated from the current inhibition rate at each concentration of each test substance relative to the pre-application value using the Hill equation using the software.
The results are shown in the table below.

Test Example 6: Fear Conditioning Test Male SD rats were used. A 0.01 mol/L hydrochloric acid solution was used as a solvent for the preparation of the administration solution of the test compound.
The fear conditioning test was performed using Image J FZ2 for Contextual and Cued Fear Conditioning Test manufactured by Ohara Medical Sangyo Co., Ltd. as follows.
The animal was placed in a chamber attached to the Image J FZ2 for Contextual and Cued Fear Conditioning Test described above, and 0.5 mA electrical stimulation was applied 7 times for 10 seconds. Thereafter, the rat was gently removed from the chamber, the compound administration solution (solvent or test compound solution) was administered subcutaneously the next day, and the animal was placed in the chamber after 30 minutes. The rate of freezing reaction time up to 300 seconds after being placed in the chamber was used as the test result.
Analysis of the test results was performed as follows.
Parametric Dunnett's multiple comparison (significance level: 5% on both sides) was performed between the test compound-administered group and the vehicle-administered group. When the test compound-administered group showed significant suppression of the freezing reaction time compared to the solvent-administered group, it was judged to have anxiolytic effects.
The results of the above tests with the compound of Example 17 are shown in FIG.

Test Example 7 Measurement of Rat Cerebral Glutamic Acid Release A cannula was placed in the prefrontal cortex of Wistar male rats, and after a recovery period of one week or longer, the experiment was performed.
A 5 mM glutamate solution and a 100 mM ascorbic acid solution were used for biosensor calibration. Glutamate release was measured using a calibrated biosensor. Measurement was started 12 hours or more after inserting the biosensor into the guide cannula. After administration of the test substance, measurements were made for 2 hours or longer.
Based on the average amount of glutamic acid released 30 minutes before administration, the curve area for 2 hours after administration was calculated, and the data of the solvent-administered group and the data of the compound-administered group were compared.
The average values of each group were compared using a parametric Dunnett-type multiple comparison test, and when the test substance-administered group had significantly higher values than the solvent-administered group, it was judged that there was a glutamic acid release promoting effect (significance level of both sides 5%).
The results of the above tests with the compound of Example 17 are shown in FIG.

Test Example 8: Evaluation of binding activity to side effect-related receptors The binding affinity of the compounds of the present invention to side effect-related receptors (eg, adrenergic α1A receptor) can be measured by the following method.
A binding evaluation test is performed as follows using a CHO cell membrane fraction in which a human-type target receptor is expressed. A test compound dissolved in dimethylsulfoxide (DMSO), various receptor membrane preparations diluted with buffer, and [3H]-labeled ligands with strong binding activity to each target receptor were mixed and incubated at room temperature. , quickly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) and filtered under reduced pressure. Radioactivity remaining on the filter is measured using a liquid scintillation counter (manufactured by PerkinElmer). The binding inhibition rate is calculated by the following formula. A control compound having strong binding activity to the target receptor is used in place of the test substance to calculate the amount of non-specific binding to the receptor membrane sample.

Inhibitory rate of binding to target receptor (%) = 100 - 100 x {(amount of [ ³ H]-labeled ligand binding in the presence of test substance)} - ([ ³ H]-labeled ligand in the presence of 10 µmol/L control compound Binding amount)}/{([ ³ H]-labeled ligand binding amount in the absence of test substance)}-([ ³ H]-labeled ligand binding amount in the presence of 10 μmol/L control compound)}

Test Example 9: Evaluation of penetration into the brain (rat brain penetration test)
In this test, the intracerebral penetration of the compound of the present invention can be evaluated by the following method. The compound of the present invention was administered subcutaneously in a physiological saline solution or orally in a methylcellulose suspension solution to SD or WKY rats aged 7 weeks, and administered 0.5 hour, 1 hour or 2 hours after administration. Plasma and brain were collected at 12:00 and the plasma and brain drug concentrations were measured by LC-MS.
Serum and brain protein binding rates of the compounds of the present invention were determined using the equilibrium dialysis method.
Kp, uu, brain (brain/plasma unbound drug concentration ratio) was calculated by applying the plasma and brain compound concentrations and the plasma and brain protein binding ratios obtained from the above test to the following formula. 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 9 are shown in the table below.

Test Example 10: Evaluation of hepatotoxicity risk (dansylated glutathione (dGSH) trapping assay)
By the following method, the compound of the present invention was metabolized by liver microsomes, and reactive metabolites reacting with dansylated glutathione (dGSH) were detected and quantified from the produced metabolites. The metabolic reaction was measured using a screening robot (manufactured by Tecan), and the metabolite-dGSH conjugate concentration 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. A microsome (dGSH(+)) solution was prepared by adding 1.14 mL of a dGSH solution (20 mmol/L) to 6.48 mL of the microsome solution. A cofactor solution was prepared by dissolving 80.9 mg of NADPH in 30 mL of pure water. A reaction stop solution 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 of the mixture was dispensed into 6 wells of a 96-well plate. The above 6 wells were divided into 3 groups of 2 wells each, which were designated as "reacted group", "unreacted group" and "dGSH-unadded group". A microsome (dGSH(+)) solution was added to the “reacted group” and the “unreacted group”, and 50 μL of microsomes (dGSH(−)) was added to the “dGSH non-added group”. 50 μL of the cofactor solution was added to the “reacted group” and the “dGSH-unadded 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 reaction stopping solution. Pure water was added to the “reacted group” and “dGSH-unadded group”, and 50 μL of cofactor solution was added to the “unreacted group”, the plate was cooled at −20° C. for 1 hour, and then centrifuged (4000 rpm, 10 minutes). went. The supernatant was collected on another plate and subjected to analysis.

(analysis)
Metabolite-dGSH conjugate concentrations were measured under the following conditions using a fluorescence detection UPLC system (manufactured by Waters).
Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1×10 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 varies depending on the composition of the organic solvent, the composition of the organic solvent at the time of elution was corrected.

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

Since the compounds of the present invention exhibit antagonistic activity against serotonin 5-HT _2A receptors and serotonin 5-HT ₇ receptors, they are useful as therapeutic agents for neuropsychiatric disorders.

Claims (22)

Formula (1):

[In the formula,
Z represents a nitrogen atom or -CR ^A -,
Y represents carbonyl or sulfonyl,
m represents 1, 2, 3, or 4;
n represents 0, 1, 2, or 3;
However, when Y is sulfonyl, n is not 0,
R ^A represents a hydrogen atom, hydroxy, C _1-6 alkyl, or C _1-6 alkoxy;
R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, hydroxy, halogen, or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogens;
^Each of R ^2a , R ^2b , R ^2c and R ^2d is ^{independently} a hydrogen atom, a halogen, or a C _1-6 alkyl (wherein the alkyl is a halogen , hydroxy, C _3-8 cycloalkyl and C _1-6 alkoxy, optionally substituted with the same or different 1 to 5 substituents), wherein R ^2a and When R ^2b , or R ^2c and R ^2d attached to the same carbon are each independently the above C _1-6 alkyl, together with the carbon atom to which they are attached, a 3- to 6-membered saturated carbon may form a ring,
R ³ is C _1-6 alkyl, wherein the alkyl is 1 to 5 identical or different substituents selected from the group consisting of halogen, hydroxy, cyano, C _3-8 cycloalkyl and C _1-6 alkoxy; may be substituted with),
R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is halogen, hydroxy, cyano, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkyl esters, and 1 or 2 identical or different C _1-6 alkyls, which may be substituted with oxo optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of optionally substituted amino), C _2-6 alkynyl, or amino (wherein said amino is optionally substituted with 1 or 2 identical or different C _1-6 alkyl), wherein any two of R ^4a , R ^4b , R ^4c and R ^4d are each independently In the case of the above C _1-6 alkyl, when the C _1-6 alkyl has a substituent together with the carbon atoms to which they are bonded, the substituent may also be included as a ring-constituting element, may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring,
provided that when Y is sulfonyl and n is 1, either one of R ^4c or R ^4d is a hydrogen atom, and when Y is sulfonyl and n is 2 or 3, R ^4c bonded to the carbon atom adjacent to Y or either one of R ^4d is a hydrogen atom,
Ring Q is the following formula (2a), (2b), (2c), (2d), (2e) or (2f):

{In the formula,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy (the alkyl and the alkoxy are each independently optionally substituted by the same or different 1 to 3 halogens), or amino optionally substituted by the same or different 1 or 2 C _1-6 alkyl,
R ⁶ is a hydrogen atom, C _1-6 alkyl, or C _3-8 cycloalkyl (the alkyl and the cycloalkyl may each independently be substituted with 1 to 3 halogen atoms which are the same or different); ) represents a group represented by]] or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof. R ^1a , R ^1b , R ^1c and R ^1d are hydrogen atoms;
A pharmaceutical composition according to claim 1 . R ^2a , R ^2b , R ^2c and R ^2d are hydrogen atoms;
3. The pharmaceutical composition according to claim 1 or claim 2. m is 1;
4. The pharmaceutical composition according to any one of claims 1-3. R ³ is C _1-6 alkyl;
5. The pharmaceutical composition according to any one of claims 1-4. Z is -CR ^A -,
6. The pharmaceutical composition according to any one of claims 1-5. R ^A is a hydrogen atom,
7. The pharmaceutical composition according to any one of claims 1-6. R ^5a , R ^5b , R ^5c , and R ^5d are each independently a hydrogen atom, halogen, or C _1-6 alkyl;
8. The pharmaceutical composition according to any one of claims 1-7. R ^5a , R ^5c and R ^5d are hydrogen atoms;
9. The pharmaceutical composition according to any one of claims 1-8. R ^5b is a hydrogen atom, halogen, or C _1-6 alkyl;
10. The pharmaceutical composition according to any one of claims 1-9. R ⁶ is a hydrogen atom,
11. The pharmaceutical composition according to any one of claims 1-10. R ^4a , R ^4b , R ^4c and R ^{4d are} each ^{independently} hydrogen atom, halogen, or C _1-6 alkyl (wherein said alkyl is halogen , hydroxy, and optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of C _1-6 alkoxy,
12. The pharmaceutical composition according to any one of claims 1-11. n is 0 or 1;
13. The pharmaceutical composition according to any one of claims 1-12. Y is carbonyl;
14. The pharmaceutical composition according to any one of claims 1-13. Y is sulfonyl,
14. The pharmaceutical composition according to any one of claims 1-13. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is a compound of any of the following formulas or a pharmaceutically acceptable salt thereof: .

A therapeutic agent for psychiatric disorders or central nervous system disorders, comprising the pharmaceutical composition according to any one of claims 1 to 16. Psychiatric or central nervous system disorder is schizophrenia, bipolar disorder, sleep disorder, autism spectrum disorder, major depression, treatment-resistant depression, neurological symptoms or dementia associated with Alzheimer's disease or Parkinson's disease 18. The therapeutic agent of claim 17. 17. Use of the pharmaceutical composition according to any one of claims 1 to 16 for the manufacture of a therapeutic agent for psychiatric disorders or central nervous system disorders. 17. A pharmaceutical composition according to any one of claims 1 to 16 for use in the treatment of psychiatric disorders or central nervous system disorders. The pharmaceutical composition according to any one of claims 1 to 16, a therapeutic drug for developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, an antipsychotic drug and a therapeutic drug for schizophrenia, and a treatment for bipolar disorder Drugs, antidepressants, anti-anxiety drugs, drugs for obsessive-compulsive disorder, drugs for stress disorders such as post-traumatic stress disorder, drugs for mood disorders, drugs for eating disorders, insomnia/narcolepsy/sleep apnea syndrome・Drugs for sleep disorders such as circadian rhythm disorders, drugs for sexual dysfunction, drugs for drug dependence, drugs for dementia such as Alzheimer's disease, drugs for behavioral and psychological symptoms associated with dementia, drugs for improving brain metabolism and circulation, A psychiatric drug containing in combination at least one drug selected from the group consisting of drugs for improving movement disorders such as Parkinson's disease, analgesics, antiepileptic drugs, anticonvulsants, migraine therapeutic drugs, anesthetics, and central stimulants A therapeutic agent for a disease or central nervous system disorder. Drugs for developmental disorders such as autism spectrum disorder and attention-deficit hyperactivity disorder, antipsychotics and drugs for schizophrenia, drugs for bipolar disorder, antidepressants, anti-anxiety drugs, drugs for obsessive-compulsive disorder, post-traumatic drugs Drugs for stress disorders such as stress disorders, drugs for mood disorders, drugs for eating disorders, drugs for sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome, and circadian rhythm disorders, drugs for sexual dysfunction, drug dependence Therapeutic drugs, drugs for treating dementia such as Alzheimer's disease, drugs for behavioral and psychological symptoms associated with dementia, drugs for improving brain metabolism and circulation, drugs for improving movement disorders such as Parkinson's disease, analgesics, antiepileptic drugs, anticonvulsants, 17. Any of claims 1 to 16 for treating psychiatric disorders or central nervous system disorders in combination with at least one drug selected from the group consisting of migraine drugs, anesthetics, and central stimulants. A therapeutic agent comprising the pharmaceutical composition according to any one of items.

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