Aliphatic acid amide derivatives

Abstract

The present invention relates: to a compound represented by formula (1), the compound having antagonist activity against serotonin 5-HT2A receptors and serotonin 5-HT7 receptors; or a pharmaceutically acceptable salt of the compound. (In the formula, Z is a nitrogen atom or the like; Y is carbonyl and the like; m and n are 1 and the like; R1a through R1d, R2a through R2d, and R4a through R4d are a hydrogen atom and the like; R3 is an alkyl and the like; and Q is a specific bicyclic group.)

Description

[Technical field]

[0001] The present invention relates to serotonin 5-HT 2A The present invention relates to an aliphatic acid amide derivative or a pharma- ceutical acceptable salt thereof having antagonist activity against the serotonin 5-HT7 receptor and the serotonin 5-HT7 receptor, and a therapeutic agent for treating psychoneurotic disorders comprising said derivative as an active ingredient. [Background technology]

[0002] Serotonin (5-hydroxytryptamine) (hereinafter referred to as "5-HT"), known as one of the major neurotransmitters in the central nervous system, is known to be involved in various brain functions including emotional responses and cognitive functions.

[0003] 5-HT, one of the subtypes of 5-HT receptors 2A The receptor is a Gq / 11 protein-coupled receptor, and is highly expressed in the cerebral cortex, hippocampus, and raphe nuclei. 2A Drugs that have antagonist activity against the 5-HT receptor include the antidepressants mianserin and mirtazapine. 2A It has antagonist activity against the receptor and is used as a therapeutic drug for schizophrenia, bipolar disorder, major depression, autism spectrum disorder, and the like (Non-Patent Documents 1 and 2).

[0004] The 5-HT7 receptor is a Gs protein-coupled receptor, and is widely expressed in the hypothalamus, thalamus, hippocampus, and raphe nucleus (Non-Patent Document 9). Drugs that have antagonistic activity against the 5-HT7 receptor include lurasidone, which is used as a treatment for schizophrenia and bipolar disorder, and vortioxetine, which is used to treat major depression, but there is no commercially available drug that selectively exhibits antagonistic activity against the 5-HT7 receptor. Lurasidone is used as a treatment for schizophrenia and bipolar disorder, and vortioxetine is used as a treatment 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 in some animal models shows antidepressant, anxiolytic, and cognitive function improving effects (Non-Patent Documents 6 and 7). It is also known that 5-HT7 receptor-deficient mice show antidepressant effects (Non-Patent Document 8).

[0005] As mentioned above, 5-HT 2A Although antagonists to the 5-HT7 receptor and 5-HT6 receptor have been shown to be useful in treating various psychiatric and neurological disorders, 2A There have been no reports of drugs that selectively and potently exhibit antagonist activity against the 5-HT7 receptor and the 5-HT8 receptor. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] P. Seeman, Can. J. Psychiatry.4:27-38, 2002 [Non-Patent Document 2] CJ Schmidt, Life Science.56(25):2209-2222, 1995 [Non-Patent Document 3] L. Citrome, J. Clinical Practice.65(2):189-210, 2011 [Non-Patent Document 4] YS. Woo, Neuropsychiatric Disease and Treatment.9:1521-1529, 2013 [Non-Patent Document 5] C. Sanchez, Pharmacology & Therapeutics.145:43-57, 2015 [Non-Patent Document 6] Bonaventure P, J Pharmacol Exp Ther. 321:690-8, 2007 [Non-Patent Document 7] Horisawa T, Behavioral Brain Research. 220:83-90, 2011 [Non-Patent Document 8] M. Guscott, Neuropharmacology. 48:492-502, 2005 [Non-Patent Document 9] T. W. Lovenberg, Neuron. 11:449-458, 1993. Summary of the Invention [Problem to be solved by the invention]

[0007] The subject of the present invention is the synthesis of serotonin 5-HT 2A The present invention aims to provide a novel compound which has antagonist activity against both the 5-HT7 receptor and the 5-HT8 receptor and is useful as a therapeutic agent for psychiatric and neurological disorders. [Means for solving the problem]

[0008] As a result of intensive research to achieve the above object, the present inventors have found that the compound represented by the following formula (1) or a pharma- ceutical acceptable salt thereof (hereinafter, sometimes referred to as the "compound of the present invention") acts as an inhibitor of serotonin 5-HT 2A The present inventors have found that the compound has antagonist activity against both the 5-HT7 receptor and the 5-HT7 receptor, and have thus completed the present invention.

[0009] That is, the present invention is as follows. [1] Formula (1): [ka] [In the formula, Z is a nitrogen atom or -CR A - represents 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 is a hydrogen atom, hydroxyl, C 1-6 Alkyl, or C 1-6 represents alkoxy, R 1a , R 1b , R 1c and R 1d each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, or a C group which may be substituted with 1 to 3 identical or different halogen atoms; 1-6 represents an alkyl group, R 2a , R 2b , R 2c and R 2d are each independently R 2c and R 2d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 3-8 Cycloalkyl and C 1-6 alkoxy), wherein R 2a and R 2b , or R attached to the same carbon 2c and R 2d However, each of them is independently 1-6 When they are alkyl, they may be joined together with the carbon atom to which they are attached to form a 3- to 6-membered saturated carbocyclic ring; R 3 is C 1-6 Alkyl (the alkyl is halogen, hydroxy, cyano, C3-8 Cycloalkyl and C 1-6 alkoxy), R 4a , R 4b , R 4c and R 4d are each independently R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, cyano, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 wherein R 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, when Y is sulfonyl and n is 1, R 4c or R 4d When Y is sulfonyl and n is 2 or 3, R bonded to the carbon atom adjacent to Y is a hydrogen atom. 4c or R 4d is a hydrogen atom, Ring Q is represented by the following formula (2a), (2b), (2c), (2d), (2e) or (2f): [ka] {In the formula, R 5a , R 5b , R 5c , and R 5d are each independently a hydrogen atom, a halogen atom, a cyano, or C 1-6 Alkyl, C 1-6 Alkoxy (the alkyl and the alkoxy may each be independently substituted with the same or different 1 to 3 halogens), or the same or different 1 or 2 C 1-6 represents an amino group optionally substituted with alkyl; R 6 is a hydrogen atom, C 1-6 Alkyl, or C 3-8 cycloalkyl (the alkyl and the cycloalkyl may each be independently substituted with 1 to 3 identical or different halogens)}, or a pharma- ceutically acceptable salt thereof.

[0010] [2] R 1a , R 1b , R 1c and R 1d is a hydrogen atom, The compound according to item [1] or a pharma- ceutically acceptable salt thereof.

[0011] [3] R 2a , R 2b , R 2c and R 2d is a hydrogen atom, The compound according to item [1] or [2] or a pharma- ceutically acceptable salt thereof.

[0012] [4] m is 1; The compound according to any one of items [1] to [3] or a pharma- ceutically acceptable salt thereof.

[0013] [5] R 3 But, C 1-6 is alkyl, The compound according to any one of items [1] to [4] or a pharma- ceutically acceptable salt thereof.

[0014] [6] Z is -CR A - is, The compound according to any one of items [1] to [5] or a pharma- ceutically acceptable salt thereof.

[0015] [7] R A is a hydrogen atom, The compound according to any one of items [1] to [6] or a pharma- ceutically acceptable salt thereof.

[0016] [8] R 5a , R 5b , R 5c , and R 5d are each independently a hydrogen atom, a halogen, or C 1-6 is alkyl, The compound according to any one of items [1] to [7] or a pharma- ceutically acceptable salt thereof.

[0017] [9] R 5a , R 5c and R 5d is a hydrogen atom, The compound according to any one of items [1] to [8] or a pharma- ceutically acceptable salt thereof.

[0018]

[10] R 5b is a hydrogen atom, halogen, or C 1-6 is alkyl, The compound according to any one of items [1] to [9] or a pharma- ceutically acceptable salt thereof.

[0019]

[11] R 6 is a hydrogen atom, The compound according to any one of items [1] to

[10] or a pharma- ceutically acceptable salt thereof.

[0020]

[12] R 4a , R 4b , R 4cand R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (wherein the alkyl is selected from halogen, hydroxy, and C 1-6 alkoxy, each of which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of The compound according to any one of items [1] to

[11] or a pharma- ceutically acceptable salt thereof.

[0021]

[13] n is 0 or 1; The compound according to any one of items [1] to

[12] or a pharma- ceutically acceptable salt thereof.

[0022]

[14] Y is carbonyl. The compound according to any one of items [1] to

[13] or a pharma- ceutically acceptable salt thereof.

[0023]

[15] Y is sulfonyl. The compound according to any one of items [1] to

[13] or a pharma- ceutically acceptable salt thereof.

[0024]

[16] The compound according to item [1], which is represented by any one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka]

[0025]

[17] A pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof according to any one of [1] to

[16] as an active ingredient.

[0026]

[18] A therapeutic agent for a psychiatric disorder or a central nervous system disorder, comprising the compound according to any one of [1] to

[16] or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0027]

[19] The therapeutic agent according to item

[18] , wherein the psychiatric disorder or central nervous system disease is schizophrenia, bipolar disorder, sleep disorder, autism spectrum disorder, major depression, treatment-resistant depression, or a neurological symptom or dementia associated with Alzheimer's disease or Parkinson's disease.

[0028]

[20] A method for treating a psychiatric disorder or a central nervous system disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of [1] to

[16] or a pharma- ceutically acceptable salt thereof.

[0029]

[21] Use of the compound according to any one of [1] to

[16] or a pharma- ceutically acceptable salt thereof for the manufacture of a therapeutic agent for a psychiatric disorder or a central nervous system disorder.

[0030]

[22] The compound according to any one of [1] to

[16] or a pharma- ceutically acceptable salt thereof for use in the treatment of a psychiatric disorder or a central nervous system disorder.

[0031]

[23] A therapeutic agent for a mental disorder or a central nervous system disorder, comprising in combination the compound according to any one of [1] to

[16] or a pharma- ceutically acceptable salt thereof, and at least one drug selected from the group consisting of therapeutic agents for developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, antipsychotics and therapeutic agents for schizophrenia, therapeutic agents for bipolar disorder, antidepressants, anti-anxiety drugs, therapeutic agents for obsessive-compulsive disorder, therapeutic agents for stress disorders such as post-traumatic stress disorder, therapeutic agents for mood disorders, therapeutic agents for eating disorders, therapeutic agents for sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome, and circadian rhythm disorders, therapeutic agents for sexual dysfunction, therapeutic agents for drug dependence, therapeutic agents for dementia such as Alzheimer's disease, therapeutic agents for behavioral and psychological symptoms associated with dementia, agents for improving cerebral metabolism and circulation, agents for improving movement disorders such as Parkinson's disease, analgesics, antiepileptics, anticonvulsants, therapeutic agents for migraine, anesthetics, and central stimulants.

[0032]

[24] A therapeutic agent for treating a mental disorder or a central nervous system disorder, comprising as an active ingredient the compound according to any one of [1] to

[16] or a pharmacologic acceptable salt thereof, in combination with at least one drug selected from the group consisting of therapeutic drugs for developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, antipsychotic drugs and therapeutic drugs for schizophrenia, therapeutic drugs for bipolar disorder, antidepressants, anti-anxiety drugs, therapeutic drugs for obsessive-compulsive disorder, therapeutic drugs for stress disorders such as post-traumatic stress disorder, therapeutic drugs for mood disorders, therapeutic drugs for eating disorders, therapeutic drugs for sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome, and circadian rhythm disorders, therapeutic drugs for sexual dysfunction, therapeutic drugs for drug addiction, therapeutic drugs for dementia such as Alzheimer's disease, therapeutic drugs for behavioral and psychological symptoms associated with dementia, drugs for improving cerebral metabolism and circulation, drugs for improving movement disorders such as Parkinson's disease, analgesics, antiepileptic drugs, anticonvulsants, therapeutic drugs for migraine, anesthetics, and central stimulants.

[0033]

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

[0034] The compound of the present invention is a 5-HT 2A The compound of the present invention has antagonist activity against the 5-HT7 receptor and the 5-HT7 receptor. Therefore, the compound of the present invention is useful as a therapeutic agent for neuropsychiatric disorders and central nervous system disorders. [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 shows the results of a fear conditioning test (Test Example 6) of the compound of Example 17. [Diagram 2] FIG. 1 shows the results of measuring the amount of glutamic acid released in rat brain by the compound of Example 17 (Test Example 7). [Diagram 3] 1 shows a powder XRD measurement chart of the compound of Example 78. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The present invention will be described in more detail below. In the present specification, the number of carbon atoms in the definition of "substituent" is, for example, "C 1-6 " etc. Specifically, "C 1-6 The term "alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms.

[0037] "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, a fluorine atom or a chlorine atom is used.

[0038] "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 As "alkyl", preferably "C 1-4 alkyl" and more preferably "C 1-3 "C alkyl" is one example. 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 Specific examples of "alkyl" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. 1-6 Specific examples of "alkyl" include the above-mentioned "C 1-4 In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like are included. In the present invention, "alkyl is substituted with oxo" means that any carbon atom constituting the alkyl is in the form of a keto form (C=O).

[0039] "C 3-8"Cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, including those having a partially unsaturated bond and those having a bridged structure. 3-8 Cycloalkyl" is preferably "C 3-6 "Cycloalkyl" is one example. 3-6 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-8 Specific examples of "cycloalkyl" include the above-mentioned "C 3-6 In addition to the specific examples of "cycloalkyl", cycloheptyl, cyclooctyl, etc. are included.

[0040] "C 1-6 Alkoxy means "C 1-6 "C 1-6 The "C alkyl" portion is 1-6 "C" is synonymous with "alkyl". 1-6 The "alkoxy" is preferably "C 1-4 Alkoxy" is preferred, and "C 1-3 "Alkoxy" is one example. 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-4 Specific examples of "alkoxy" include the above-mentioned "C 1-3 In addition to the specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. 1-6 Specific examples of "alkoxy" include the above-mentioned "C 1-4 In addition to the specific examples of "alkoxy", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like.

[0041] "C 1-6An "alkyl ester" is an ester (-COOR') in which the R' moiety is one of the above "C 1-6 "C" means an ester that is "alkyl". 1-6 As the "alkyl ester", preferably "C 1-4 More preferably, "C 1-3 "C alkyl esters" are examples. 1-3 Specific examples of "alkyl ester" include, for example, methyl ester, ethyl ester, propyl ester, 1-methylethyl ester, etc. 1-4 Specific examples of the "alkyl ester" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl esters," butyl esters, 1,1-dimethylethyl esters, 1-methylpropyl esters, 2-methylpropyl esters, etc. are also included. 1-6 Specific examples of the "alkyl ester" include the above-mentioned "C 1-4 In addition to the specific examples of "alkyl ester," examples include 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, and hexyl ester.

[0042] "C 2-6 "Alkynyl" means a straight or branched unsaturated hydrocarbon group containing a triple bond and having 2 to 6 carbon atoms. 2-6 As the alkynyl, preferably "C 2-4 alkynyl" is preferred, and "C 2-3 "Alkynyl" is one example. 2-3 Specific examples of "alkynyl" include, for example, ethynyl and propynyl. 2-4 Specific examples of alkynyl include the above-mentioned "C 2-3 In addition to the specific examples of alkynyl, butynyl is also included. 2-6 Specific examples of alkynyl include the above-mentioned "C 2-4In addition to the specific examples of "alkynyl", pentynyl, hexynyl, etc. are included.

[0043] The term "3- to 6-membered saturated carbocyclic ring" refers to a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, including those having a partial unsaturated bond and those having a bridged structure. The "3- to 6-membered saturated carbocyclic ring" is preferably a "5- or 6-membered monocyclic saturated carbocyclic ring". Specific examples of the "5- or 6-membered monocyclic saturated carbocyclic ring" include, for example, 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 and cyclobutane.

[0044] The term "4-6-membered saturated heterocyclic group" refers to a saturated ring composed of 4 to 6 atoms, including 1 or 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, in addition to carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. The "4-6-membered saturated heterocyclic group" is preferably 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, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyltetrahydropyranyl, and the like. Examples of the "4- to 6-membered saturated heterocycle" include, in addition to the specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group", oxetanyl, azetidinyl, and the like.

[0045] In the compound represented by formula (1), Z, Y, m, n, and R A , R 1a , R 1b , R 1c , R 1d , R 2a , R2b , R 2c , R 2d , R 3 , R 4a , R 4b , R 4c , R 4d , Q, R 5a , R 5b , R 5c , R 5d , and R 6 The preferred ones are as follows, but the technical scope of the present invention is not limited to the range of the compounds listed below.

[0046] One embodiment of Z is -CR A Another embodiment of Z is a nitrogen atom.

[0047] One embodiment of Y is carbonyl, and another embodiment of Y is sulfonyl.

[0048] A preferred embodiment of m is 1 or 2. A more preferred embodiment is 1.

[0049] Preferred embodiments of n include 0, 1, or 2. More preferred embodiments include 0 or 1. Particularly preferred embodiments include 1.

[0050] R A Preferred embodiments of the formula include a hydrogen atom, a hydroxyl group, or C 1-6 In a more preferred embodiment, the alkyl group is a hydrogen atom or C 1-3 In a more preferred embodiment, it is a hydrogen atom, an ethyl atom, or a methyl atom. In a most preferred embodiment, it is a hydrogen atom.

[0051] R 1a , R 1b , R 1c , and R 1d In a preferred embodiment, each independently represents a hydrogen atom, a hydroxyl, a halogen, or C 1-6In a more preferred embodiment, the alkyl group is a hydrogen atom, a halogen atom, or C 1-3 In a more preferred embodiment, the alkyl group is a hydrogen atom, a fluorine atom, a chlorine atom, an ethyl atom, or a methyl atom. In a particularly preferred embodiment, the alkyl group is a hydrogen atom, a fluorine atom, or a methyl atom. In a most preferred embodiment, the alkyl group is a hydrogen atom.

[0052] R 2a , R 2b , R 2c , and R 2d In a preferred embodiment, each independently represents a hydrogen atom, a halogen, or C 1-6 In a more preferred embodiment, the alkyl group is a hydrogen atom, a halogen atom, or C 1-3 In a more preferred embodiment, the alkyl group is a hydrogen atom, a fluorine atom, a chlorine atom, an ethyl atom, or a methyl atom. In a particularly preferred embodiment, the alkyl group is a hydrogen atom, a fluorine atom, or a methyl atom. In a most preferred embodiment, the alkyl group is a hydrogen atom.

[0053] R 3 A preferred embodiment of the above is C 1-6 In a more preferred embodiment, the alkyl group is C 1-3 In a more preferred embodiment, it is ethyl or methyl. In a particularly preferred embodiment, it is ethyl.

[0054] R 4a , R 4b , R 4c , and R 4d In a preferred embodiment, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl, C 2-6 Alkynyl, or the same or different 1 or 2 C 1-6 In a more preferred embodiment, the amino group is a hydrogen atom, a halogen atom, or a C 1-6 Alkyl or 1 or 2 identical or different C 1-6In a more preferred embodiment, the amino group is a hydrogen atom, a halogen atom, or a C 1-6 In a particularly preferred embodiment, the alkyl group is a hydrogen atom or C 1-6 In a particularly preferred embodiment, the aryl group is a hydrogen atom, a methyl group, or a methoxymethyl group. In a most preferred embodiment, the aryl group is a hydrogen atom.

[0055] Preferred embodiments of Q include (2a), (2c), (2d), (2e) or (2f). More preferred embodiments include (2a), (2d) or (2e). Particularly preferred embodiment is (2a).

[0056] R 5a , R 5b , R 5c , and R 5d In a preferred embodiment, each of the groups is independently a hydrogen atom, a halogen atom, a cyano, or C 1-6 Alkyl, C 1-6 Alkoxy or the same or different 1 or 2 C 1-6 In a more preferred embodiment, the amino group is a hydrogen atom, a halogen atom, a cyano, or a C 1-6 Alkyl, or C 1-6 In a more preferred embodiment, the alkyl group is a hydrogen atom, a fluorine atom, or a chlorine atom. In a particularly preferred embodiment, the alkyl group is a hydrogen atom or a fluorine atom.

[0057] R 6 Preferred embodiments of the formula include a hydrogen atom, C 1-6 Alkyl, or C 3-8 In a more preferred embodiment, the alkyl group is a hydrogen atom or C 1-6 In a more preferred embodiment, the alkyl group is a hydrogen atom or C 1-3 In a particularly preferred embodiment, the alkyl group is a hydrogen atom.

[0058] One embodiment of the compound represented by formula (1) is the following (A). (A) Z is a nitrogen atom or -CR A - and 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 is alkyl, R 1a , R 1b , R 1c and R 1d are each independently a hydrogen atom or C 1-6 is alkyl, R 2a , R 2b , R 2c and R 2d However, each independently, R 2c and R 2d When there are multiple, each independently represents a hydrogen atom or C 1-6 is alkyl, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, when Y is sulfonyl and n is 1, R 4c or R 4d When Y is sulfonyl and n is 2 or 3, R bonded to the carbon atom adjacent to Y is a hydrogen atom. 4c or R 4d is a hydrogen atom, Ring Q is represented by the following formula (2a), (2b), (2c), (2d), (2e) or (2f): [ka] {In the formula, R 5a , R 5b , R 5c , and R 5d are each independently a hydrogen atom, a halogen, or C 1-6 is alkyl, R 6 is a hydrogen atom or C 1-6 The compound or a pharma- ceutically acceptable salt thereof, wherein the compound is a group represented by the formula:

[0059] An embodiment of the compound represented by formula (1) is the following (B). (B) Z is a nitrogen atom or -CR A - and Y is carbonyl; m is 1 or 2; n is 0, 1, 2, or 3; R A is a hydrogen atom or C1-6 is alkyl, R 1a , R 1b , R 1c and R 1d are each independently a hydrogen atom or C 1-6 is alkyl, R 2a , R 2b , R 2c and R 2d However, each independently, R 2c and R 2d When there are multiple, each independently represents a hydrogen atom or C 1-6 is alkyl, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. Ring Q is represented by the following formula (2a), (2b), (2c), (2d), (2e) or (2f): [ka] {In the formula, R 5a , R 5b , R 5c , and R 5d are each independently a hydrogen atom, a halogen, or C 1-6 is alkyl, R 6 is a hydrogen atom or C 1-6 The compound or a pharma- ceutically acceptable salt thereof, wherein the compound is a group represented by the formula:

[0060] An embodiment of the compound represented by formula (1) is the following (C). (C) Z is a nitrogen atom or -CR A - and Y is sulfonyl; m is 1 or 2; n is 1, 2, or 3; R A is a hydrogen atom or C 1-6 is alkyl, R 1a , R 1b , R 1c and R 1d are each independently a hydrogen atom or C 1-6 is alkyl, R 2a , R 2b , R 2c and R 2d However, each independently, R 2c and R 2d When there are multiple, each independently represents a hydrogen atom or C 1-6 is alkyl, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4dHowever, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, if n is 1, R 4c or R 4d When n is 2 or 3, R bonded to the carbon atom adjacent to Y is a hydrogen atom. 4c or R 4d is a hydrogen atom, Ring Q is represented by the following formula (2a), (2b), (2c), (2d), (2e) or (2f): [ka] {In the formula, R 5a , R 5b , R 5c , and R 5d are each independently a hydrogen atom, a halogen, or C 1-6 is alkyl, R 6 is a hydrogen atom or C1-6 The compound or a pharma- ceutically acceptable salt thereof, wherein the compound is a group represented by the formula:

[0061] An embodiment of the compound represented by formula (1) is the following (D). (D) Z is -CR A - and Y is carbonyl; m is 1, n is 0 or 1; R A is a hydrogen atom, R 1a , R 1b , R 1c and R 1d is a hydrogen atom, R 2a , R 2b , R 2c and R 2d is a hydrogen atom, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4dAny two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. The compound or a pharma- ceutically acceptable salt thereof, wherein ring Q is (2a):

[0062] An embodiment of the compound represented by formula (1) is the following (E). (E) Z is -CR A - and Y is carbonyl; m is 1, n is 0 or 1; R A 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 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. The compound or a pharma- ceutically acceptable salt thereof, wherein ring Q is (2d).

[0063] An embodiment of the compound represented by formula (1) is the following (F). (F) Z is -CR A - and Y is carbonyl; m is 1, n is 0 or 1; R A is a hydrogen atom, R 1a , R 1b , R 1c and R 1d is a hydrogen atom, R 2a , R 2b , R 2c and R 2d is a hydrogen atom, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4dWhen there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. A compound or a pharma- ceutically acceptable salt thereof, wherein ring Q is represented by (2e).

[0064] An embodiment of the compound represented by formula (1) is the following (G). (G) Z is -CR A - and Y is sulfonyl; m is 1, n is 1, R A is a hydrogen atom, R 1a , R 1b , R 1c and R 1d is a hydrogen atom, R 2a , R 2b , R 2c and R 2d is a hydrogen atom, R 3 But, C1-6 is alkyl, R 4a , R 4b , R 4c and R 4d are each independently R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, R 4c or R 4d is a hydrogen atom, The compound or a pharma- ceutically acceptable salt thereof, wherein ring Q is (2a):

[0065] An embodiment of the compound represented by formula (1) is the following (H). (H) Z is -CR A - and Y is sulfonyl; m is 1, n is 1, R A is a hydrogen atom, R 1a , R 1b , R 1c and R 1d is a hydrogen atom, R 2a , R 2b , R 2c and R 2d is a hydrogen atom, R 3 But, C 1-6 is alkyl, R 4a , R 4b , R 4c and R 4d However, each independently, R 4c and R 4d When there are multiple, each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl (the alkyl is halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Alkyl esters and one or two identical or different C 1-6 alkyl (the alkyl may be substituted by oxo); C 2-6 Alkynyl, or amino (the amino is selected from the group consisting of 1 or 2 identical or different C 1-6 substituted with alkyl, 4a , R 4b , R 4c and R 4d Any two of the above C 1-6 When they are alkyl, together with the carbon atom to which they are attached, the C 1-6 When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, R 4c or R 4d is a hydrogen atom, The compound or a pharma- ceutically acceptable salt thereof, wherein ring Q is (2e).

[0066] The compound represented by formula (1) may have at least one asymmetric carbon atom. Therefore, the compound of the present invention includes not only the racemic form of the compound represented by formula (1) but also the optically active form of these compounds. When the compound represented by formula (1) has two or more asymmetric carbon atoms, stereoisomerism may occur. Therefore, the compound of the present invention also includes the stereoisomers of these compounds and their mixtures.

[0067] In addition, any one or more of the compounds represented by formula (1) 1 H 2 Deuterium converters converted to H(D) are also included in the compound represented by formula (1).

[0068] The compound represented by formula (1) and its pharma- ceutically acceptable salts may exist in the form of a hydrate and / or a solvate, and therefore these hydrates or solvates such as ethanol solvates are also included in the compounds of the present invention. Furthermore, the compounds of the present invention also include all crystal forms.

[0069] When the compound represented by formula (1) has an acidic group, examples of pharma- ceutically acceptable salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; and organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.

[0070] When the compound represented by formula (1) has a basic group, examples of the acid salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and organic acid salts such as acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, and orotate.

[0071] The production methods of the compounds of the present invention will be explained below with reference to examples, but the present invention is not limited to these.

[0072] Manufacturing method The compound of the present invention can be synthesized by a combination of the following production method and a known synthesis method. The compounds in the reaction schemes may each form a salt, and examples of such salts include the same salts as those of the compound represented by formula (1). Note that these reactions are merely illustrative, and the compounds of the present invention may be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

[0073] In each of the production methods described below, even if the use of a protecting group is not specifically indicated, when a functional group that requires protection is present, the functional group may be protected as necessary, and the target compound may be obtained by deprotecting the functional group after completion of the reaction or after a series of reactions.

[0074] As the protecting group, a typical protecting group described in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) can be used. More specifically, as the protecting group for an amino group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. can be mentioned. Furthermore, as the protecting group for a hydroxy group, for example, trialkylsilyl, acetyl, benzyl, etc. can be mentioned.

[0075] Introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) or a method analogous thereto.

[0076] 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. [ka] [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 are as defined above in [1].

[0077] 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 carried out in the presence of a suitable base. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, condensing agent used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

[0078] Specific examples of condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldiimidazole (CDI), benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). If necessary, additives such as N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt) and the like may be added.

[0079] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0080] 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 dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

[0081] 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. [ka] [In the formula, 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 represents 0, 1, 2, or 3.

[0082] Compound (8) can be produced by reductive amination of compound (6), an aldehyde represented by formula (7), and a suitable reducing agent in a suitable inert solvent. The reaction may be carried out in the presence of a suitable base or acid, if necessary. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reducing agent used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0083] Specific examples of the reducing agent include complex hydrogen compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, and sodium cyanoborohydride; borane complexes (such as borane-dimethylsulfide complex or borane-tetrahydrofuran complex); and the like.

[0084] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0085] Specific examples of the acid include organic acids such as acetic acid, trifluoroacetic acid, and methanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid.

[0086] Specific examples of inert solvents include water; acetonitrile; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; alcohol solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone; and mixed solvents thereof.

[0087] 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 of -20°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as reaction temperature, acid used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

[0088] Specific examples of the acid include organic acids such as trifluoroacetic acid; and inorganic acids such as hydrochloric acid and sulfuric acid.

[0089] 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, 1,4-dioxane, and 1,2-dimethoxyethane; 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.

[0090] Manufacturing method 3 The compound represented by formula (8) can be produced, for example, by the method shown below. [ka] [In the formula, Z, m, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R2c , R 2d , R 3 and ring Q are as defined in [1] above, and LG represents a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, a substituted sulfonyl group (e.g., a methanesulfonyl group, a p-toluenesulfonyl group, etc.)).

[0091] 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 be carried out in the presence of a suitable base, and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range of 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.

[0092] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0093] Specific examples of phase transfer catalysts include tetrabutylammonium hydrogen sulfate.

[0094] 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 dimethyl sulfoxide; and mixed solvents thereof.

[0095] 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 be carried out in the presence of a suitable base, and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range of 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.

[0096] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0097] Specific examples of phase transfer catalysts include tetrabutylammonium hydrogen sulfate.

[0098] 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 dimethyl sulfoxide; and mixed solvents thereof.

[0099] 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 be carried out in the presence of a suitable base, and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range of 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.

[0100] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0101] Specific examples of phase transfer catalysts include tetrabutylammonium hydrogen sulfate.

[0102] 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 dimethyl sulfoxide; and mixed solvents thereof.

[0103] 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. [ka] [In the formula, 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 as defined above in [1].

[0104] Compound (14) can be prepared by reacting compound (4) with a sulfonyl chloride represented by formula (13) in a suitable inert solvent. The reaction may be carried out in the presence of a suitable base. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the raw materials used, the solvent, and other conditions, but is usually 10 minutes to 48 hours.

[0105] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0106] 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 dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

[0107] 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 is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.

[0108] Examples of inert solvents include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0109] 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. [ka] [In the formula, R 5a , R 5b , R 5c , and R 5d is the same as defined in [1] above, and A represents an iodine atom, a bromine atom, or a chlorine atom.

[0110] Compound (15) can be produced by reacting 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid with N,O-dimethylhydroxyamine or its hydrochloride in the presence of a suitable condensing agent in a suitable inert solvent. The reaction may be carried out in the presence of a suitable base. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0111] Compound (15) can also be produced by reacting N,O-dimethylhydroxyamine or a salt thereof with an acid halide or an acid anhydride derived from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in the presence of a suitable base in a suitable inert solvent. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0112] Specific examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate salt (BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldiimidazole (CDI), benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate salt (HBTU), etc. If necessary, the reaction can be carried out by adding an additive such as N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc.

[0113] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0114] 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 dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

[0115] Compound (17) can be produced by reacting compound (15) with a lithiated product generated by treating compound (16) with an organolithium such as n-butyllithium in a suitable inert solvent. The reaction temperature is usually within the range of about -78°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the reagents, raw materials, and solvent used, but is usually 10 minutes to 48 hours.

[0116] Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and mixed solvents thereof.

[0117] Compound (18) can be produced by reacting compound (17) with hydroxylamine or a salt thereof, if necessary, in the presence of a suitable base. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

[0118] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; and sodium acetate.

[0119] Specific examples of the solvent 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.

[0120] Compound (19) can be produced by treating compound (18) with a suitable base in a suitable inert solvent. The reaction temperature is usually from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

[0121] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0122] 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 dimethyl sulfoxide; and mixed solvents thereof.

[0123] 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 of -20°C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as reaction temperature, acid used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

[0124] 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, 1,4-dioxane, and 1,2-dimethoxyethane; 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.

[0125] Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0126] By appropriately combining the above-mentioned production methods, the compound of the present invention having the desired substituent at the desired position can be obtained. The intermediates and products in the above-mentioned production methods can be isolated and purified by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, etc. In addition, the intermediates can be used in the next reaction without any particular purification.

[0127] In the above-mentioned production methods, the starting compounds or intermediates may exist in the form of a salt, for example, a hydrochloride, depending on the reaction conditions, etc., but they can be used as they are or in a free form. When the starting compounds or intermediates are obtained in the form of a salt and it is desired to use or obtain the starting compounds or intermediates in a free form, they can be converted to the free form by dissolving or suspending them in an appropriate solvent and neutralizing them with a base, for example, an aqueous solution of sodium hydrogen carbonate, or the like.

[0128] Among the compounds represented by formula (1) or pharma- ceutically acceptable salts thereof, some may exist in the form of isomers such as tautomers, positional isomers, geometric isomers or optical isomers, and all possible isomers including these and mixtures of said isomers in any ratio are included in the present invention.

[0129] In addition, optical isomers can be separated in an appropriate step of the above-mentioned production method by carrying out a known separation step such as a method using an optically active column, a fractional crystallization method, etc. Also, optically active substances can be used as starting materials.

[0130] When it is desired to obtain a salt of the compound represented by formula (1), if a salt of the compound represented by formula (1) is obtained, it can be purified as it is. Alternatively, if the compound represented by formula (1) is obtained in a free form, the compound represented by formula (1) can be dissolved or suspended in a suitable solvent and an acid or base can be added to form a salt.

[0131] The compound of the present invention is a 5-HT 2A The compound of the present invention has both antagonist activity against the 5-HT7 receptor and antagonist activity against the 5-HT7 receptor, and has a mechanism of action different from that of existing drugs for treating psychiatric disorders, so that it can provide a new option for pharmacological treatment in various psychiatric disorders. That is, the compound of the present invention is effective in treating psychiatric disorders. The compound of the present invention is also effective in treating central nervous system disorders.

[0132] Examples of psychiatric disorders or central nervous system disorders for which efficacy is expected include F00-F09: organic mental disorders, including symptomatic, F10-F19: mental and behavioral disorders due to psychoactive substance use, F20-F29: schizophrenia, schizophrenia-type disorders, and delusional disorders, F30-F39: mood [affective] disorders, F40-F48: neurotic disorders, stress-related disorders, and somatoform disorders, F51: nonorganic sleep disorders, F52: sexual dysfunction, not due to organic disorder or disease, F84: pervasive developmental disorders, F90-F98: behavioral and emotional disorders usually occurring in childhood and adolescence, G20-G26: extrapyramidal disorders and abnormal movements, G30-G32: other degenerative disorders of the nervous system, and G47: sleep disorders, in the International Classification of Diseases, 10th edition (ICD-10). F00-F09: Organic (including symptomatic) mental disorders include, for example, mental disorders associated with diseases such as Alzheimer's disease, vascular dementia, dementia with Lewy bodies, Parkinson's disease dementia, brain injury, and other mental disorders due to brain dysfunction and physical illness. F10-F19: Mental and behavioral disorders due to psychoactive substance use include delirium tremens, psychotic disorders, and amnesic syndromes due to the use of various substances. F20-F29: Schizophrenia, schizophreniform disorder and delusional disorder include paranoid schizophrenia, simple schizophrenia, delusional disorder, etc. F30-F39: Mood [affective] disorders include, for example, manic episodes, bipolar disorder, and depressive episodes. F40-F48: Neurotic disorders, stress-related disorders and somatoform disorders include, for example, phobic anxiety disorder, obsessive-compulsive disorder, somatoform disorder, etc. F51: Non-organic sleep disorders include, for example, non-organic insomnia, sleepwalking, and nightmares. F52: Sexual dysfunction, not due to organic disorder or disease, includes, for example, lack of or loss of sexual desire, unspecified sexual dysfunction. F84: Pervasive developmental disorders include, for example, autism, mental retardation, and hypermobility disorder associated with stereotyped movements. F90-F98: Hyperactivity Disorder Behavioral and emotional disorders usually occurring during childhood and adolescence include, for example, hyperactivity disorder, conduct disorder and mixed conduct and 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 lobar degeneration, dementia with Lewy bodies, and senile brain degeneration. G47: Sleep disorders include, for example, disorders of initiating and maintaining sleep [insomnia], disorders of the sleep-wake schedule, narcolepsy and cataplexy. The compound of the present invention is useful for treating or preventing the recurrence of various symptoms (psychotic symptoms, sleep disorders, depressive symptoms, anxiety symptoms, cognitive dysfunction, etc.) associated with these diseases.

[0133] Serotonin (5-hydroxytryptamine: 5-HT), known as one of the major neurotransmitters in the central nervous system, is known to be involved in various brain functions including emotional responses and cognitive functions. 5-HT, one of the subtypes of 5-HT receptors, 2A The receptor is highly expressed in the cerebral cortex, hippocampus, and raphe nuclei. 5-HT is also expressed in the prefrontal cortex. 2A It is known that the 5-HT receptor positively regulates the dopamine neural pathway in the ventral tegmental area (Non-Patent Document 2). 2A It is believed that blocking the receptor has a suppressive effect on psychotic symptoms.

[0134] In addition, 5-HT7 receptors are widely expressed in the hypofloor, thalamus, hippocampus, raphe nucleus, etc., and are involved in the regulation of mammalian circadian rhythms (Non-Patent Document 9). Disruption of circadian rhythms has been found to be related to many CNS disorders, including depression, seasonal affective disorder, sleep disorders, shift work syndrome, and jet lag. In addition, drugs that have antagonistic activity against 5-HT7 receptors include lurasidone, which is used as a treatment for schizophrenia and bipolar disorder, and vortioxetine, which is used to treat major depression, but there are no drugs that selectively exhibit antagonistic activity against 5-HT7 receptors.

[0135] It is also known that antagonizing the 5-HT7 receptor has antidepressant, anti-anxiety and cognitive function improving effects in some animal models (Non-patent Documents 6 and 7).

[0136] From the above pharmacological viewpoint, 5-HT 2A It is expected that by inhibiting the 5-HT7 receptor at the same time as inhibiting the 5-HT receptor, it will be useful in treating various neuropsychiatric disorders such as depression, sleep disorders, and psychotic symptoms. 2A There have been no reports of drugs that selectively and potently exhibit antagonist activity against the 5-HT7 receptor and the 5-HT8 receptor.

[0137] The compound of the present invention is a 5-HT 2A It has strong binding affinity to the 5-HT receptor and the 5-HT7 receptor (Test Example 1), 2A In a preferred embodiment of the present invention, the compound has antagonist activity against the 5-HT receptor and the 5-HT7 receptor. 2A The binding affinity of 5-HT to the 5-HT7 receptor and 5-HT8 receptor is more than 100 times stronger than that of the D2 receptor, so 5-HT is released at blood concentrations that do not cause side effects such as extrapyramidal symptoms and hyperprolactinemia, which are thought to be due to D2 antagonism. 2A It can exert pharmacological actions based on its receptor antagonistic properties and 5-HT7 receptor antagonistic properties.

[0138] In addition, in a preferred embodiment of the compound of the present invention, the hERG channel inhibitory concentration, which is an index of the onset of arrhythmia due to QT prolongation, is different from the concentration at which the expected pharmacological action is expressed (Test Example 5), and therefore, it is expected that the compound will have a small effect on the cardiovascular system.

[0139] The elimination half-life (T1 / 2) of a drug is a factor that determines the number of times it needs to be taken to maintain its effect. Multiple dosings per day due to a short T1 / 2 can lead to forgetting to take the drug or leaving it untreated, which is thought to be an obstacle to proper drug treatment. In addition, there are concerns that an increase in the number of doses will increase the incidence of side effects, or that tolerability will decrease due to restrictions on high-dose administration. From the above perspective, achieving a long T1 / 2 will lead to the creation of long-acting drugs with fewer of the above concerns, which is expected to reduce the burden on patients taking 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 therefore the compound is expected to have a long-lasting efficacy in the human body, improve the medication adherence of patients undergoing drug therapy, and show high tolerability when administered.

[0140] The compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. When administered parenterally, it can be administered in the form of a topical agent, an injection, a transdermal agent, a nasal agent, etc. Examples of oral or rectal agents include capsules, tablets, pills, powders, cachets, suppositories, liquids, etc. Examples of injection agents include sterile solutions or suspensions, etc. Examples of topical agents include creams, ointments, lotions, transdermal agents (normal patches, matrix agents), etc.

[0141] The above dosage forms are prepared in a conventional manner with pharma- ceutically acceptable excipients and additives, such as carriers, binders, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. Examples of pharma- ceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cacao butter, etc. Capsules can be prepared by placing the compound of the present invention together with a pharma- ceutically acceptable carrier. The compound of the present invention can be mixed with a pharma- ceutically acceptable excipient or placed in a capsule without an excipient. Cachets can also be prepared in a similar manner.

[0142] Injectable liquids include solutions, suspensions, emulsions, etc. Examples of such liquids include aqueous solutions, water-propylene glycol solutions, etc. Liquids can also be prepared in the form of polyethylene glycol and / or propylene glycol solutions, which may contain water. Liquids suitable for oral administration can be prepared by adding the compound of the present invention to water and adding colorants, flavorings, stabilizers, sweeteners, solubilizers, thickeners, etc. as necessary. Liquids suitable for oral administration can also be prepared by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of thickeners include pharma- ceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or known suspending agents.

[0143] The dosage varies depending on the individual compound, the patient's disease, age, weight, sex, symptoms, administration route, etc., but the compound of the present invention is usually administered to an adult (body weight 50 kg) at 0.1 to 1000 mg / day, preferably 1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.

[0144] The compound of the present invention can be used in combination with other drugs in order to enhance its effect and / or reduce side effects. For example, it can be used in combination with anxiolytics such as selective serotonin reuptake inhibitors. Hereinafter, drugs that can be used in combination with the compound of the present invention are abbreviated as "combined drugs."

[0145] Specific examples of concomitant medications include 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, 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 for drug addiction, drugs for dementia such as Alzheimer's disease, drugs for behavioral and psychological symptoms associated with dementia, drugs to improve cerebral metabolism and circulation, drugs to improve movement disorders such as Parkinson's disease, analgesics, antiepileptics, anticonvulsants, drugs for migraine, anesthetics, and central stimulants.

[0146] 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. The compound of the present invention and the concomitant drug may be combined. The dose of the concomitant drug may be appropriately selected based on the dose used in clinical practice. The compounding ratio of the compound of the present invention to the concomitant drug may be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per part by weight of the compound of the present invention. In addition, for the purpose of suppressing side effects, the compound of the present invention may be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing drugs, and anticonvulsants. EXAMPLES

[0147] The present invention will be described in more detail below with reference examples, examples and test examples, 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 to simplify the description, but these abbreviations have the same meaning as described above. The compound was identified by proton nuclear magnetic resonance absorption spectroscopy ( 1H-NMR, LC-MS, etc. were used. In the amino chromatography in the Reference Examples and Examples, an amino column manufactured by Yamazen Corporation was used. LC-MS was performed under the various conditions shown in the table below. The retention time (RT) indicates the time at which a mass spectrum peak appears in the LC-MS measurement. [Table 1]

[0148] Powder X-ray diffraction measurements (powder XRD) were performed under the various conditions shown in the table below. [Table 2]

[0149] Differential scanning calorimetry (DSC) was carried out using various conditions as shown in the table below. [Table 3]

[0150] The following abbreviations may be used herein: The following abbreviations are used in the NMR data of the Reference Examples and Examples. Me: Methyl DMF: N,N-dimethylformamide THF: tetrahydrofuran tert-: tertiary CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide

[0151] Proton nuclear magnetic resonance spectra were measured using a JEOL FT-NMR measuring device (300 MHz or 400 MHz). Chemical shift values ​​are listed in 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, br for broad, brs for broad singlet, and J for coupling constant.

[0152] Example 1 (2R)-N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] To a solution (0.5 mL) of the compound of Reference Example 1 (20.0 mg) in N,N-dimethylformamide, D-lactic acid (6.18 mg), triethylamine (20.8 mg) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (33.8 mg) were added. After stirring at room temperature for 16 hours, water (4.0 mL) was added to the reaction mixture, which was extracted with chloroform (10 mL x 2), 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). LC‐MS:RT = 1.433 min ObsMS = 364 [M+1]

[0153] Example 2 N-Ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide [ka] To a dichloromethane suspension (1.0 mL) of the compound of Reference Example 2 (50.0 mg), triethylamine (0.077 mL), 30% aqueous 3-hydroxypropionic acid solution (0.046 mL), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (67.9 mg) were 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, 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, 2.05-1.89 (2H, m), 1.18-1.05 (3H, m).

[0154] Example 3 (2R)-N-Ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] Triethylamine (0.077 mL), D-lactic acid (14.9 mg) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (67.9 mg) were added to a dichloromethane suspension (1.0 mL) of the compound of Reference Example 2 (50.0 mg). After stirring at room temperature for 4 hours, the reaction mixture was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (13.9 mg). 1 H-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).

[0155] Examples 4 to 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. [Table 4] TIFF0007662534000019.tif176155

[0156] Example 16 (2S)-N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] Triethylamine (0.763 mL), L-lactic acid (0.098 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.501 mg) were added to the compound of Reference Example 1 (400 mg) in tetrahydrofuran suspension (1.1 mL). 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. Then, water (30 mL) was added to the reaction mixture, which was extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (279 mg). 1 H-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).

[0157] Example 17 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide [ka] To a suspension (50 mL) of the compound of Reference Example 1 (3.97 g) in acetonitrile, triethylamine (6.08 mL), 3-hydroxypropionic acid (4.91 g) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.22 g) were 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 concentrated. Chloroform (50 mL) was added to the residue, 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 then further separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (2.97 g). 1 H-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). 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 (Of these, the ten characteristic peaks were 8.32, 9.72, 13.83, 14.24, 16.77, 19.89, 19.95, 21.58, 22.02, 24.03, and the four more characteristic peaks were 8.32, 9.72, 13.83, and 16.77.) DSC Enthalpy (normalized): 71.71 J / g Onset x: 67.55℃

[0158] Example 18 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxy-3-methoxypropanamide [ka] Triethylamine (0.134 mL), 2-hydroxy-3-methoxypropionic acid (27.7 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (88.0 mg) were added to a tetrahydrofuran suspension (1.9 mL) of the compound of Reference Example 1 (70.0 mg). 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, 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).

[0159] Example 19 N-Ethyl-N-{2-[4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] Diisopropylethylamine (0.577 mL), DL-lactic acid (0.082 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (628 mg) were added to the compound of Reference Example 6 (400 mg) in N,N-dimethylformamide (4.0 mL). 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 further stirred at room temperature for 1 hour. Then, water (10 mL) was added to the reaction mixture, extracted with chloroform (5.0 mL x 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 obtain the title compound (217 mg). 1 H-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).

[0160] Example 20 (2S)-N-Ethyl-N-{2-[4-(6-fluoro-1H-indol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] Triethylamine (0.0575 mL), L-lactic acid (8.95 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37.8 mg) were added to a suspension (0.83 mL) of the compound of Reference Example 7 (30.0 mg). 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, which was then stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and then 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 obtain the title compound (24.3 mg). 1 H-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).

[0161] Example 21 (2S)-N-Ethyl-N-{2-[4-(5-fluoro-1H-indazol-1-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] To a suspension (4.0 mL) of the compound of Reference Example 2 (400 mg) in tetrahydrofuran, triethylamine (0.768 mL), L-lactic acid (161 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (786 mg) were added. After stirring at room temperature for 3 hours, 15% aqueous sodium hydroxide solution (4.0 mL) was added to the reaction mixture, which was then stirred at room temperature for an additional 1 hour. Thereafter, concentrated hydrochloric acid was added until the reaction mixture reached pH 7, and the mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (269 mg). 1 H-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).

[0162] Example 22 N-Ethyl-2-hydroxy-N-{2-[4-(1H-indol-3-yl)piperidin-1-yl]ethyl}propanamide [ka] To a suspension (8.7 mL) of the compound of Reference Example 8 (300 mg) in tetrahydrofuran, triethylamine (0.606 mL), DL-lactic acid (94.0 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (398 mg) were 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. After that, the reaction mixture was concentrated, and chloroform (30 mL) was added to the residue, which was dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (258 mg). 1 H-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).

[0163] Example 23 (2S)-N-Ethyl-2-hydroxy-N-{2-[4-(1H-indol-3-yl)piperidin-1-yl]ethyl}propanamide [ka] To a suspension (8.7 mL) of the compound of Reference Example 8 (300 mg) in tetrahydrofuran, triethylamine (0.606 mL), L-lactic acid (94.0 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (398 mg) were 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. After that, the reaction mixture was concentrated, and chloroform (30 mL) was added to the residue, which was dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (258 mg). 1 H-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).

[0164] Examples 24 to 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. [Table 5] TIFF0007662534000029.tif219157 TIFF0007662534000030.tif212156 TIFF0007662534000031.tif227157 TIFF0007662534000032.tif69153

[0165] Example 51 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxyethane-1-sulfonamide [ka] A 10% aqueous solution of tetrabutylammonium hydroxide (17.3 mL) was added to a solution (20 mL) of the compound (636 mg) of Reference Example 23 in tetrahydrofuran. 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 then further separated and purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (330 mg). 1 H-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).

[0166] Examples 52 to 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. [Table 6] TIFF0007662534000035.tif217153 TIFF0007662534000036.tif84155

[0167] Example 65 3-Amino-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] To a solution (2.0 mL) of 3-((tert-butoxycarbonyl)amino)-2-hydroxypropionic acid (40.6 mg) in N,N-dimethylformamide, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (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, which was 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). Next, 4 mol / L hydrochloric acid-ethyl acetate (2.0 mL) was added to the obtained compound (50 mg), and the mixture was stirred at room temperature for 1 hour, after which the reaction mixture was concentrated. The concentrated residue was separated and purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (37.0 mg). 1 H-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).

[0168] Examples 66 to 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. [Table 7]

[0169] Example 71 3-Acetamido-N-ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-hydroxypropanamide [ka] Acetic anhydride (0.00598 mL) was added to a solution (2.0 mL) of the compound of Example 65 (20.0 mg) in tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Then, 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. The reaction mixture was concentrated, and then purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (10.1 mg). 1 H-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).

[0170] Examples 72 to 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. [Table 8]

[0171] Example 75 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-4-hydroxy-1-methylpyrrolidine-3-carboxamide [ka] 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) were added, and the mixture was stirred at room temperature for 16 hours. Then, water (10 mL) was added to the reaction mixture, which was extracted with chloroform (10 mL x 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). LC‐MS:RT = 1.083 min ObsMS = 419 [M+1]

[0172] Example 76 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-4-hydroxy-1-methylpiperidine-3-carboxamide [ka] The title compound was obtained from the compound of Example 67 by the same method as in Example 75. LC‐MS:RT = 1.092 min ObsMS = 433 [M+1]

[0173] Example 77 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide orotate Orotic acid (14.4 mg) was added to a methanol solution (0.4 mL) of the compound obtained in Example 17 (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 filtered to obtain the title compound (27.3 mg). 1 H-NMR (400 MHz, DMSO-D6) 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 = 7.0 Hz). 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 (Of these, the ten characteristic peaks were 4.87, 7.24, 15.27, 15.75, 16.02, 17.62, 19.51, 20.04, 21.24, 22.05, and the four more characteristic peaks were 4.87, 19.51, 20.04, 21.24.) DSC Enthalpy (normalized): 62.81 J / g Onset x: 157.09℃

[0174] Example 78 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide hydrobromide Form 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 the mixture was stirred at room temperature for 1 hour, after which precipitation of a solid was confirmed. The mixture was stirred at 80°C, and after confirming that the precipitated solid was completely dissolved, the mixture was stirred for 1 hour. Then, the mixture was gradually cooled and stirred at room temperature for 12 hours. The precipitated solid was collected by filtration, washed with acetonitrile (10 mL), and then 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. Then, 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 then dried to obtain the title compound (6.20 g). 1 H-NMR (400 MHz, DMSO-D6) 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 (Of these, the ten characteristic peaks were 4.48, 12.40, 15.23, 17.07, 17.88, 21.19, 23.13, 24.48, 25.22, 25.98, and the four more characteristic peaks were 12.40, 15.23, 17.07, 21.19.) DSC Enthalpy (normalized): 82.83 J / g Onset x: 163.64℃

[0175] Example 79 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide hydrobromide Form B To a solution (2.0 mL) of the compound (100 mg) obtained in Example 17 in acetonitrile, 10-20% HBr-EtOH (0.2 mL) was added dropwise. 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 (Of these, the ten characteristic peaks were 7.25, 7.65, 9.90, 15.34, 15.71, 23.36, 24.62, 25.05, 25.18, 25.26, and the four more characteristic peaks were 7.25, 7.65, 9.90, 15.34.) DSC Enthalpy (normalized): 86.51 J / g Onset x: 164.04℃

[0176] Example 80 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-hydroxypropanamide tosylate A solution of p-toluenesulfonic acid monohydrate (41.9 g) in acetone (150 mL) was added to a solution of the compound (66.7 g) obtained in Example 17 in acetone (200 mL). The mixture was stirred at room temperature for 2 hours, and the precipitated solid was collected by filtration, washed with acetone (60 mL), and then dried to obtain 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 and stirred at room temperature for 12 hours. After stirring at 0° C. for 1 hour, the obtained solid was collected by filtration, washed with a 5% water-acetone mixed solvent (70 mL) cooled to 0° C., and dried to obtain the title compound (69.4 g). 1 H-NMR (400 MHz, DMSO-D6) 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 (Of these, the ten characteristic peaks were 7.03, 9.64, 15.19, 15.37, 15.68, 16.22, 21.60, 21.67, 23.15, 23.88, and the four more characteristic peaks were 7.03, 9.64, 15.19, 15.68.) DSC Enthalpy (normalized): 99.47 J / g Onset x: 162.26℃

[0177] Reference example 1 N-Ethyl-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine dihydrochloride [ka] To a chloroform solution (131 mL) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.78 g), tert-butylethyl(2-oxoethyl)carbamate (4.91 g) and sodium triacetoxyborohydride (11.1 g) were added and stirred at room temperature for 5 hours. A saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture, which was extracted with chloroform (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol). To a chloroform solution (131 mL) of the obtained product, 4 mol / L hydrochloric acid-ethyl acetate (60 mL) was added and stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with ethyl acetate (20 mL x 2), and then dried to obtain the title compound (6.24 g). 1 H-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).

[0178] Reference examples 2~13 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. [Table 9] TIFF0007662534000045.tif143154

[0179] Reference example 14 6-Fluoro-5-methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride [ka] a) Preparation of tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (compound IN-1-1) A mixture of 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. Then, a 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 a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and saturated saline, then dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.52 g). 1 H-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).

[0180] 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) was added dropwise with 1.63 mol / L n-butyllithium / hexane (7.43 mL) at -78°C for 3 minutes. After stirring at -78°C for 1 hour, compound IN-1-1 (1.50 g) was added and stirred at -78°C for 2.5 hours. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, 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 obtain the title compound (2.01 g). 1 H-NMR (400 MHz, CDCl3) 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).

[0181] c) Preparation of tert-butyl 4-(6-fluoro-5-methyl-1,2-benzoxazol-3-yl)piperidine-1-carboxylate (compound IN-1-3) A mixture of 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. Then, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated saline, 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. Then, the reaction mixture was filtered, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (90.8 mg). 1H-NMR (400 MHz, CDCl3) 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).

[0182] d) Preparation of 6-fluoro-5-methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride (Reference Example 14) To a solution of compound IN-1-3 (131 mg) in dichloromethane (1.0 mL), 4 mol / L hydrochloric acid / ethyl acetate (1.0 mL) was added and 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, CDCl3) 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).

[0183] Reference example 15 5-Methyl-3-(piperidin-4-yl)-1,2-benzisoxazole monohydrochloride [ka] The title compound was obtained from 1-fluoro-2-iodo-4-methylbenzene by a method similar to that in Reference Example 14. 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).

[0184] Reference example 16 N-(cyclopropylmethyl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine [ka] Cyclopropanecarbaldehyde (16.0 mg) was added to a chloroform solution (2.0 mL) of 2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethan-1-amine (50.0 mg) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (60.4 mg) was then added to the reaction mixture. After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium bicarbonate (30 mL) was added to the reaction mixture, which was extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (26.0 mg). LC‐MS:RT = 1.250 min ObsMS = 318 [M+1]

[0185] Reference example 17 N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-2-amine [ka] The title compound was obtained from acetone by a method similar to that of Reference Example 16. LC‐MS:RT = 1.176 min ObsMS = 306 [M+1]

[0186] Reference example 18 ({2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}amino)acetonitrile [ka] The compound of Reference Example 20 (60.0 mg) was added to a suspension (2.0 mL) of 55% sodium hydride (7.92 mg) in N,N-dimethylformamide, and the mixture was 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, which was extracted with chloroform (30 mL x 2), 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 the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The concentrated residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (25.0 mg). LC‐MS:RT = 0.530 min ObsMS = 303 [M+1]

[0187] Reference example 19 N-Ethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propan-1-amine dihydrochloride [ka] The title compound was obtained from the compound of Reference Example 21 by the same method as in Reference Example 18.

[0188] Reference example 20 tert-Butyl {2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}carbamate [ka] 6-Fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.89 g) in chloroform (60 mL) was added with tert-butyl(2-oxoethyl)carbamate (2.30 g) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.34 g) was added and stirred at room temperature for 3 hours, after which a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture, which was extracted with chloroform (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3.98 g). 1 H-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).

[0189] Reference example 21 tert-Butyl {3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]propyl}carbamate [ka] To a solution (50 mL) of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2.00 g) in acetonitrile, 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, which was then extracted with ethyl acetate (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3.46 g). 1 H-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).

[0190] Reference example 22 N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-1-amine [ka] a) Preparation of 3-[1-(2-chloroethyl)piperidin-4-yl]-6-fluoro-1,2-benzisoxazole (compound IN-2-1) To a solution (25 mL) of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (3.00 g) in tetrahydrofuran, water (6.3 mL), potassium hydroxide (1.68 g) and 1-bromo-2-chloroethane (5.65 mL) were added and stirred at room temperature for 24 hours. Water (15 mL) was added to the reaction mixture, which was then extracted with chloroform (10 mL x 3 times), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (1.94 g). 1 H-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).

[0191] b) Preparation of N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}propan-1-amine (Reference Example 22) To a solution (1.4 mL) of compound IN-2-1 (80.0 mg), n-propylamine (0.0349 mL), potassium carbonate (117 mg) and potassium iodide (9.39 mg) were added and stirred at 90° C. for 4 hours. The reaction mixture was filtered and then 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). 1H-NMR (400 MHz, CDCl3) 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).

[0192] Reference example 23 N-Ethyl-N-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}ethenesulfonamide [ka] To a solution (40 mL) of the compound (1.00 g) of Reference Example 1 in dichloromethane, triethylamine (2.39 mL) and 2-chloroethanesulfonyl chloride (0.433 mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.670 g). 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).

[0193] 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 Examples. [Table 10] TIFF0007662534000057.tif207154 TIFF0007662534000058.tif216152

[0194] Reference example 37 3-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]-N-ethylpropan-1-amine dihydrochloride [ka] The title compound was obtained from 3-(piperidin-4-yl)benzo[d]isoxazole by a method similar to that of Reference Example 18 and Reference Example 21.

[0195] Reference example 38 N-Ethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazin-1-yl]propan-1-amine dihydrochloride [ka] The title compound was obtained from 6-fluoro-3-(piperazin-1-yl)benzo[d]isoxazole monohydrochloride by a method similar to that of Reference Example 18 and Reference Example 21.

[0196] Test Example 1: Human 5-HT 2A Receptor, human 5-HT 7 receptor, and human type D 2 Receptor binding activity evaluation The compound of the present invention is human 5-HT 2A The binding affinity to the human 5-HT7 receptor and the human D2 receptor was measured by the following method. Human 5-HT 2A The CHO cell membrane fraction expressing the 5-HT7 receptor, human 5-HT7 receptor, and human D2 receptor was purchased from PerkinElmer. In the binding evaluation test, the test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted in buffer, and 5-HT 2A [3H]Ketanserin was mixed for the receptor, [3H]SB-269970 for the 5-HT7 receptor, and [3H]Spiperone for the D2 receptor (all manufactured by PerkinElmer) and incubated at room temperature for 60 minutes. Non-specific binding to the receptor was determined by competitive binding tests in the presence of 10μmol / L 8-OH-DPAT, 10μmol / L Mianserin, and 10μmol / 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, and used as the binding affinity. The results are shown in the table below. [Table 11] TIFF0007662534000062.tif234153

[0197] Test Example 2: Human 5-HT 2A Receptor, human 5-HT 7 Evaluation of antagonist activity against receptors Aequorin, Gα16 protein, and each receptor were transiently expressed in CHO-K1 cells (Chinese hamster ovary) and cultured overnight at 37℃ in a CO2 incubator, then seeded on a 384-well plate and left to stand at room temperature for more than 2 hours. Various compounds dissolved in DMSO were added, and the change in luminescence intensity was measured using the FDSS / μCELL Drug Discovery Screening Support System (Hamamatsu Photonics). For antagonist activity, the luminescence intensity of the well to which 10μmol / L endogenous ligand was added was set as 100%, and the inhibitory activity of each compound was calculated. The results are shown in the table below. [Table 12] TIFF0007662534000064.tif234153

[0198] Test Example 3-1: Human liver microsome metabolic stability test The metabolic stability of the compound of the present invention in human liver microsomes was evaluated by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and test substances were mixed in 25 mmol / L phosphate buffer (pH 7.4) to the following concentrations, and incubated at 37° C. for 30 minutes. Human liver microsomes: 0.1mg / mL NAPDH: 3.2mmol / L, Test substance: 0.1 μmol / L The remaining rate of the test substance in the sample after 30 minutes was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated using the following formula. Human liver microsome metabolic stability (mL / min / mg protein) = -LN (residual rate) / 30 / 0.1 The results are shown in the table below. [Table 13]

[0199] Test Example 3-2: Human liver microsome metabolic stability test In order to evaluate the metabolic stability of human liver microsomes more accurately, the metabolic stability of the compound of the present invention in human liver microsomes was evaluated at an appropriate concentration of human liver microsomes by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and test substances were mixed in 25 mmol / L phosphate buffer (pH 7.4) to 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 The remaining rate of the test substance in the sample after 30 or 60 minutes was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated using 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. [Table 14]

[0200] 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. The compound of the present invention was administered intravenously to rats in a 0.01 mol / L aqueous hydrochloric acid solution, and blood samples were collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration. Plasma was obtained from the collected blood, and the drug concentration in the plasma was measured by LC-MS. The rat distribution volume was calculated from the concentration change. The unbound fraction of the compound of the present invention in human and rat serum was measured by equilibrium dialysis. The half-life in humans was calculated by applying the following formula to the rat distribution volume, the unbound fraction in human and rat serum, and the results of the metabolic stability in human liver microsomes obtained in Test Example 3-2. Human distribution volume = Rat distribution volume × unbound fraction in human serum / unbound fraction in rat serum Human hepatic clearance = (Human hepatic blood flow rate × unbound fraction in human serum × 56.7 × metabolic stability of human liver microsomes) / (human hepatic blood flow rate + unbound fraction in human serum × 56.7 × metabolic stability of human hepatic myrosomes) Human half-life = 0.693 × human distribution volume / human hepatic clearance The results are shown in the table below. [Table 15]

[0201] Test Example 5: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the compounds of the present invention was evaluated using human rapidly activating delayed rectifier potassium current (I Kr We used CHO cells overexpressing the hERG channel involved in vascular endothelial cell death (VEGF) and performed whole-cell patch clamp measurements using an autopatch clamp system. (Preparation of cell suspension) hERG-CHO cells purchased from ChanTest were cultured at 37° C. in a CO 2 incubator, and immediately before measuring the hERG current, the cells were detached from the flask using trypsin to prepare a cell suspension. (solution preparation) The extracellular and intracellular fluids used in the measurements were prepared as follows. Extracellular fluid: 2mmol / L CaCl2, 1mmol / L MgCl2, 10mmol / L HEPES, 4mmol / L KCl, 145mmol / L NaCl, 10mmol / L Glucose Intracellular fluid: 10mmol / L HEPES, 10mmol / L EGTA, 20mmol / L KCl, 130mmol / L KF Test substance solution: The test substance was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test substance solution. The test substance solution was further diluted 200-fold with extracellular fluid, and the solution was serially diluted with extracellular fluid to obtain the hERG inhibition IC 50 Test substance solutions of the respective concentrations required for value calculation were prepared and applied. (Current measurement and data analysis) The cell suspension, extracellular solution, intracellular solution, and measurement plate were placed in an auto patch clamp system, and hERG current measurements were performed using the whole-cell patch clamp method. The voltage protocol was a holding potential of -80 mV, a depolarizing pulse was applied from -50 mV to +20 mV for 5 seconds, a repolarizing pulse was applied at -50 mV for 5 seconds, and the potential was returned to the holding potential. The interval between each pulse was 15 seconds. Data were analyzed using Qube analysis software (Sophion Sophion). Four concentrations of each test substance were applied incrementally, and the average value of the maximum outward current (Peak tail current) obtained in the final three stimulations of each applied concentration was used as the evaluation data. In addition, the IC was calculated using the Hill equation using the software from the current inhibition rate at each concentration of each test substance relative to the value before application. 50 The value was calculated. The results are shown in the table below. [Table 16] TIFF0007662534000069.tif193161

[0202] Test Example 6: Fear conditioning test Male SD rats were used. The test compound was dissolved in 0.01 mol / L hydrochloric acid as a solvent to prepare an administration solution. The fear conditioning test was performed as follows using Image J FZ2 for Contextual and cued fear conditioning test manufactured by Obara Medical Industry Co., Ltd. The animals were placed in the chamber attached to the Image J FZ2 for Contextual and cued fear conditioning test described above, and 0.5 mA electrical stimulation was given seven times for 10 seconds. After that, the rats were gently removed from the chamber, and the compound administration solution (solvent or test compound solution) was subcutaneously administered the next day, and the animals were placed in the chamber 30 minutes later. The percentage of freezing reaction time from being placed in the chamber until 300 seconds later was used as the test result. The analysis of the test results was carried out as follows. A parametric Dunnett's multiple comparison (significance level: two-sided 5%) was performed between the test compound administration group and the vehicle administration group. If the test compound administration group showed a significant inhibition of the freezing reaction time compared to the vehicle administration group, it was judged to have an anxiolytic effect. The results of the above test using the compound of Example 17 are shown in FIG.

[0203] Test Example 7: Measurement of glutamic acid release in rat brain A cannula was placed in the prefrontal cortex of male Wistar rats, and they were allowed to recover for at least one week before the experiment. A 5 mM glutamic acid solution and a 100 mM ascorbic acid solution were used to calibrate the biosensor. The calibrated biosensor was used to measure the release of glutamic acid. Measurements were started 12 hours or more after the biosensor was inserted into the guide cannula. Measurements were continued for 2 hours or more after administration of the test substance. The area under the curve for 2 hours after administration was calculated based on the average amount of glutamate released during 30 minutes before administration, and the data for the vehicle-administered group and the compound-administered group were compared. The average values ​​of each group were compared using a parametric Dunnett's multiple comparison test, and if the test substance-treated group had a significantly higher value than the vehicle-treated group, it was determined that the test substance had an effect of promoting glutamate release (significance level of 5% on both sides). The results of the above test using the compound of Example 17 are shown in FIG.

[0204] Test Example 8: Evaluation of binding activity to side effect-related receptors The binding affinity of the compound of the present invention to a side effect-related receptor (for example, adrenergic α1A receptor) can be measured by the following method. Using CHO cell membrane fractions expressing human target receptors, binding evaluation tests are performed as follows. Test compounds dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and [3H]-labeled ligands with strong binding activity to each target receptor are mixed and incubated at room temperature, and then quickly added to a glass fiber filter plate (Multiscreen FB, Millipore) and filtered under reduced pressure. The radioactivity remaining on the filter is measured using a liquid scintillation counter (PerkinElmer). The binding inhibition rate is calculated according to the following formula. To calculate the amount of non-specific binding to the receptor membrane specimens, a control compound with strong binding activity to the target receptor is used instead of the test substance.

[0205] Binding inhibition rate to target receptor (%) = 100-100 x {(in the presence of test substance) 3 H] labeled ligand binding amount)}-(10 μmol / L in the presence of control compound [ 3 H] labeled ligand binding amount} / {(in the absence of test substance [ 3 H] labeled ligand binding amount)}-(10 μmol / L in the presence of control compound [ 3 H] labeled ligand binding amount)

[0206] Test Example 9: Evaluation of brain transferability (rat brain transferability test) In this test, the brain penetration of the compound of the present invention can be evaluated by the following method: The compound of the present invention was subcutaneously administered in a physiological saline solution or orally administered in a methylcellulose suspension solution to 7-week-old SD or WKY rats, and plasma and brain samples were collected 0.5, 1, or 2 hours after administration, and the drug concentrations in the plasma and brain were measured by LC-MS. The serum and brain protein binding rates of the compounds of the present invention were measured using an equilibrium dialysis method. The plasma and brain compound concentrations and plasma and brain protein binding rates obtained from the above tests can be applied to the following formula to calculate Kp,uu,brain (brain / plasma unbound drug concentration ratio). Kp,uu,brain = (brain compound concentration x (100 - brain protein binding rate (%)) / 100) / (plasma compound concentration x (100 - plasma protein binding rate (%)) / 100)

[0207] The results of Test Example 9 are shown in the table below. [Table 17]

[0208] Test Example 10: Assessment of hepatotoxicity risk (dansylated glutathione (dGSH) trapping assay) The compound of the present invention was metabolized in liver microsomes, and reactive metabolites that react with dansylated glutathione (dGSH) were detected and quantified from the generated metabolites by the following method. The metabolic reaction was performed using a screening robot (manufactured by Tecan), and the concentration of metabolite-dGSH conjugates was measured using a fluorescence detection UPLC system (manufactured by Waters).

[0209] (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 microsome (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 microsome solution. A microsome (dGSH(+)) solution was prepared by adding 1.14 mL of dGSH solution (20 mmol / L) to 6.48 mL of 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.

[0210] (reaction) 12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL was dispensed into 6 wells of a 96-well plate. The 6 wells were divided into 3 groups of 2 wells each, which were designated as the "reaction group", the "unreaction group", and the "dGSH-free group". 50 μL of microsome (dGSH(+)) solution was added to the "reaction group" and the "unreaction group", and 50 μL of microsome (dGSH(-)) was added to the "dGSH-free group". 50 μL of cofactor solution was added to the "reaction group" and the "dGSH-free group", and 50 μL of pure water was added to the "unreaction group". After incubation at 37°C for 60 minutes, the reaction was stopped by adding 450 μL of reaction stop solution to each well. Pure water was added to the "reaction group" and the "dGSH-free group", and 50 μL of cofactor solution was added to the "unreaction group". The plate was cooled to -20°C for 1 hour, and then centrifuged (4000 rpm, 10 minutes). The supernatant was collected on a separate plate and subjected to analysis.

[0211] (analysis) The metabolite-dGSH conjugate concentrations were measured using a fluorescence detection UPLC system (Waters) under the following conditions. Column: Waters ACQUITY UPLC BEHC18 1.7μm 2.1 × 10 mm Elution solvent: A, 0.2% formic acid in water; 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 organic solvent composition, correction was performed based on the organic solvent composition at the time of elution.

[0212] The results of Test Example 10 are shown in the table below. [Table 18] [Industrial Applicability]

[0213] The compound of the present invention inhibits serotonin 5-HT 2ASince it exhibits antagonist activity against the serotonin 5-HT7 receptor and the serotonin 5-HT7 receptor, it is useful as a therapeutic agent for psychiatric and neurological disorders.

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, Z is a nitrogen atom or -CR Ａ - represents Y represents carbonyl or sulfonyl; m represents 1, 2, 3, or 4; n represents 0, 1, 2, or 3; With the proviso that when Y is sulfonyl, n is not 0, R Ａ is a hydrogen atom, hydroxy, C １－６ Alkyl, or C １－６ represents alkoxy, R １ａ , R １ｂ , R １ｃ and R １ｄ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, or a C group optionally substituted with 1 to 3 identical or different halogen atoms; １－６ represents an alkyl group, R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are each independently R ２ｃ and R ２ｄ When there are a plurality of, each independently represents a hydrogen atom, a halogen, or C １－６ Alkyl (the alkyl is selected from halogen, hydroxy, C ３－８ Cycloalkyl and C １－６ alkoxy), wherein R ２ａ and R ２ｂ or R bonded to the same carbon ２ｃ and R ２ｄ are each independently the above C １－６ when they are alkyl, they may together with the carbon atom to which they are attached form a 3- to 6-membered saturated carbocyclic ring; R ３ is C １－６ Alkyl (the alkyl is halogen, hydroxy, cyano, C ３－８ Cycloalkyl and C １－６ alkoxy), which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are each independently R ４ｃ and R ４ｄ When there are multiple, each independently represents a hydrogen atom, a halogen, or C. １－６ Alkyl (the alkyl is halogen, hydroxy, cyano, C ３－８ Cycloalkyl, C １－６ Alkoxy, C １－６ Alkyl esters and one or two identical or different C １－６ and amino optionally substituted with alkyl (which may be substituted with oxo), C ２－６ Alkynyl, or amino (the amino is the same or different 1 or 2 C １－６ substituted with alkyl, wherein R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ Any two of the above are independently selected from the group consisting of C １－６ When they are alkyl, together with the carbon atom to which they are attached, the C １－６ When the alkyl group has a substituent, the substituent may also be included as a constituent element of the ring, and the ring may form a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring. However, when Y is sulfonyl and n is 1, R ４ｃ Or R ４ｄ When Y is sulfonyl and n is 2 or 3, R bonded to the carbon atom adjacent to Y is a hydrogen atom. ４ｃ Or R ４ｄ is a hydrogen atom, Ring Q is represented by the following formula (2a), (2b), (2c), (2d), (2e) or (2f): 【Chemistry 2】 {During the ceremony, R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ are each independently a hydrogen atom, a halogen atom, a cyano, １－６ Alkyl, C １－６ Alkoxy (the alkyl and the alkoxy may each be independently substituted with the same or different 1 to 3 halogens), or the same or different 1 or 2 C １－６ represents an amino group which may be substituted by alkyl; R ６ is a hydrogen atom, C １－６ Alkyl, or C ３－８ cycloalkyl (the alkyl and the cycloalkyl may each be independently substituted with 1 to 3 identical or different halogens)}, or a pharma- ceutically acceptable salt thereof.

2. R １ａ , R １ｂ , R １ｃ and R １ｄ is a hydrogen atom, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ is a hydrogen atom, 3. A compound according to claim 1 or claim 2, or a pharma- ceutically acceptable salt thereof.

4. m is 1; 4. A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. R ３ But, C １－６ is alkyl, 5. A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

6. Z is -CR Ａ - is, 6. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. R Ａ is a hydrogen atom, 7. A compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ are each independently a hydrogen atom, a halogen, or C １－６ is alkyl, 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof.

9. R ５ａ , R ５ｃ and R ５ｄ is a hydrogen atom, 9. A compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof.

10. R ５ｂ is a hydrogen atom, a halogen atom, or C １－６ is alkyl, 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

11. R ６ is a hydrogen atom, 11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof.

12. R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ Each independently represents R ４ｃ and R ４ｄ When there are a plurality of, each independently represents a hydrogen atom, a halogen, or C １－６ Alkyl (wherein the alkyl is selected from halogen, hydroxy, and C １－６ alkoxy, each of which may be substituted with 1 to 5 identical or different substituents selected from the group consisting of 12. A compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof.

13. n is 0 or 1; 13. A compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof.

14. Y is carbonyl; 14. A compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

15. Y is sulfonyl; 14. A compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

16. The compound according to claim 1, which is represented by any one of the following formulas, or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】

17. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】

18. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 5】

19. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 6】

20. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】

21. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 8】

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