Cyclic lactam derivatives

Abstract

To provide a medicament for treating neuropsychiatric diseases that has both antagonist activity for serotonin 5-HT2A receptor and agonist activity for serotonin 5-HT1A receptor.SOLUTION: The present invention provides a compound of formula (1). (V: CRARB. n: 1, 2. Z: N, C or the like. t: 1-3. bond (a): single bond or double bond. RA, RB: H, C1-6 alkyl or the like. R1a-R1d: H, halogen or the like. Q1: condensed heterocyclic ring containing substituted / unsubstituted 5 or 6 membered aromatic heterocyclic ring. Q2: substituted / unsubstituted benzo-1,2-oxazole or benzo-1,2-thiazole).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a condensed lactam derivative having antagonist activity against serotonin 5-HT 2A receptors and agonist activity against serotonin 5-HT 1A receptors, or a pharmaceutically acceptable salt thereof, and a therapeutic agent for psychoneurological diseases containing the derivative as an active ingredient.

Background Art

[0002] Serotonin (5-hydroxytryptamine) (hereinafter sometimes 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 1A receptors are Gi / o protein-coupled receptors and are expressed in the cerebral cortex, hippocampus, raphe nucleus, amygdala, etc. Compounds having agonist activity against 5-HT 1A receptors include, for example, tandospirone, buspirone, etc. Tandospirone is used as a therapeutic agent for depression in neurosis, fear, and physical symptoms in psychosomatic diseases (autonomic neuropathy, essential hypertension, peptic ulcer), as well as depression, anxiety, restlessness, and sleep disorders. Buspirone is used as a therapeutic agent for generalized anxiety disorder (Non-Patent Document 1).

[0004] 5-HT 2A receptors are Gq / 11 protein-coupled receptors and are highly expressed in the cerebral cortex, hippocampus, raphe nucleus, etc. Agents having antagonist activity against 5-HT 2A receptors include the antidepressants mianserine and mirtazapine. In addition, all atypical antipsychotics have antagonist activity against 5-HT 2A receptors and are used as therapeutic agents for schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, etc. (Non-Patent Document 2, Non-Patent Document 3).

[0005] As described above, 5-HT 1A agonists for receptors and 5-HT 2A antagonists for receptors have each been shown to be useful alone in psychoneurological diseases. However, there are no reported examples of agents that simultaneously and potently exhibit agonist activity for selective 5-HT 1A receptors and antagonist activity for 5-HT 2A receptors.

Prior Art Documents

Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a novel compound having both antagonist activity for serotonin 5-HT 2A receptors and agonist activity for serotonin 5-HT 1A receptors and being useful as a therapeutic agent for psychoneurological diseases.

Means for Solving the Problems

[0008] As a result of intensive studies to achieve the above object, the present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present invention") has serotonin 5-HT 2AAntagonist activity against a receptor and serotonin 5-HT 1A It has been found to have agonist activity against a receptor, and thus the present invention has been completed.

[0009] That is, the present invention is as follows. [Item 1] Formula (1): [Chemical formula] [In the formula, V represents CR A R B ; n represents 1 or 2; Z represents a nitrogen atom, a carbon atom or -CR J -; t represents 1, 2 or 3; The bond (a) including a dashed line represents a single bond or a double bond; R A and R B are each independently, and when there are a plurality of R A or R B they are each independently a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or C 3-10 cycloalkyl (the alkyl, the alkoxy and the cycloalkyl may each independently be substituted with the same or different 1 to 3 halogen atoms); R 1a , R 1b , R 1c and R 1d are each independently a hydrogen atom, a halogen or C 1-6 alkyl which may be substituted with the same or different 1 to 3 halogen atoms; Ring Q 1 is the following formula (2): [Chemical formula] [In the formula, Ring Q 3 represents a 5- or 6-membered aromatic heterocyclic ring which may be substituted; W represents CRC R D represents; m represents 0 or 1; X is -CR E - or -CR F R G - represents; Y is a nitrogen atom or -CR H - represents; The bond (b) including a dashed line represents a group represented by {a single bond or a double bond}; Ring Q 2 is the following formula (3a) or (3b):

Chemical formula

[0010] [Item 2] Ring Q 3 is a 5- or 6-membered aromatic heterocyclic ring which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a hydrogen atom, a halogen, cyano, C 1-6 alkyl, C 3-10 cycloalkyl (the alkyl and the cycloalkyl may each independently be substituted with the same or different 1 to 3 halogens), and C 1-6 alkoxy (the alkoxy may be substituted with the same or different 1 to 3 halogens or a 4- to 8-membered saturated heterocyclic group), the compound or a pharmaceutically acceptable salt thereof according to Item 1.

[0011] [Item 3] When formula (1) is formula (1a):

Chemical formula

[0012] [Item 4] R 1a , R 1b , R 1c and R 1d both being hydrogen atoms, the compound according to any one of Items 1 to 3 or a pharmaceutically acceptable salt thereof.

[0013] [Item 5] R A and R B both being hydrogen atoms, the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.

[0014] [Item 6] n is 2, the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0015] [Item 7] The bond (a) including a dashed line is a single bond, the compound according to any one of Items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0016] [Item 8] Formula (1) is the following formula (1b): [Chemical formula] [wherein Q 1 , Q 2 and Z are as defined above], the compound according to Item 1 or Item 2 or a pharmaceutically acceptable salt thereof.

[0017] [Item 9] Z is a nitrogen atom, the compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0018] [Item 10] Z is -CH-, the compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0019] [Item 11] Y is a nitrogen atom, the compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof.

[0020] [Item 12] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 11, wherein the bond (b) containing a broken line is a single bond and X is -CH2-.

[0021] [Item 13] Ring Q 1 is represented by the following formula (4a), (4b), (4c), (4d), (4e) or (4f): [Chemical formula] [wherein, R 3a and R 3b each independently represents a hydrogen atom, a halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy (the alkyl and the alkoxy may each independently be substituted with the same or different 1 to 3 halogens), or amino which may be substituted with the same or different 1 to 2 C 1-6 alkyl] is the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 12.

[0022] [Item 14] Ring Q 1 is represented by the following formula (5a), (5b), (5c), (5d), (5e), (5f) or (5g): [Chemical formula] [wherein, R 4a represents C 1-6 alkyl or C 1-6 alkoxy, R 4b represents a hydrogen atom or C 1-6 alkyl, R 4c and R 4d each independently represents a hydrogen atom or C 1-6 alkyl, provided that when either R 4c or R 4d is a hydrogen atom, the other represents C 1-6 alkyl, and also, R 4c and R 4dThe compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof, which may form a 3- to 6-membered saturated carbon ring together with the carbon atom to which they are attached.

[0023] [Item 15] Ring Q 2 The compound according to any one of items 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Ring Q is of formula (3a).

[0024] [Item 16] Ring Q 2 The compound according to any one of items 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Ring Q is of formula (3b).

[0025] [Item 17] R 2a , R 2b , R 2c and R 2d The compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof, wherein both R are hydrogen atoms.

[0026] [Item 18] The compound according to item 1 or a pharmaceutically acceptable salt thereof, which is represented by any of the following formulas.

Chemical formula

[0027] [Item 19] A medicament containing the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] [Item 20] A therapeutic agent for mental disorders or central nervous system disorders, containing the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] [Item 21] The therapeutic agent according to Item 20, wherein the mental disorder or central nervous system disorder is an organic mental disorder including symptomatic; mental and behavioral disorders due to use of psychoactive substances; schizophrenia, schizophreniform disorder and delusional disorder; mood [emotion] disorders; neurotic disorders, stress-related disorders and somatic symptom disorders; non-organic sleep disorders; sexual dysfunction, not due to organic disorders or diseases; pervasive developmental disorders; behavioral and emotional disorders usually occurring in childhood and adolescence; extrapyramidal disorders and abnormal movements; other degenerative diseases of the nervous system; or sleep disorders.

[0030] [Item 22] The therapeutic agent according to Item 20, wherein the mental disorder or central nervous system disorder is schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with Lewy body dementia, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or anxiety, excitement or aggression associated with Alzheimer's disease.

[0031] [Item 23] The therapeutic agent according to Item 20, wherein the mental disorder or central nervous system disorder is schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with Lewy body dementia, or anxiety, excitement or aggression associated with Alzheimer's disease.

[0032] [Item 24] A method for treating a mental disorder or central nervous system disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.

[0033] [Item 25] Use of the compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, for manufacturing a therapeutic agent for a mental disorder or central nervous system disorder.

[0034] [Item 26] The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a mental disorder or central nervous system disorder.

[0035] [Item 27] A therapeutic agent for mental disorders or central nervous system disorders, which is a combination of the compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof and at least one agent selected from the group consisting of antidepressants, anxiolytics, antipsychotics, dopamine replacement agents, dopamine receptor agonists, Parkinson's disease therapeutic agents, antiepileptic drugs, anticonvulsants, analgesics, hormonal preparations, migraine therapeutic agents, adrenergic β-receptor antagonists, dementia therapeutic agents, mood disorder therapeutic agents, antiemetics, sleep induction agents, and anticonvulsants.

[0036] [Item 28] A therapeutic agent for treating mental disorders or central nervous system disorders, which contains, as an active ingredient, the compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof, in combination with at least one agent selected from the group consisting of antidepressants, anxiolytics, antipsychotics, dopamine replacement agents, dopamine receptor agonists, Parkinson's disease therapeutic agents, antiepileptic drugs, anticonvulsants, analgesics, hormonal preparations, migraine therapeutic agents, adrenergic β-receptor antagonists, dementia therapeutic agents, mood disorder therapeutic agents, antiemetics, sleep induction agents, and anticonvulsants. [Effect of the Invention]

[0037] The compound of the present invention has antagonist activity against the 5-HT 2A receptor and agonist activity against the 5-HT 1A receptor. Further, in a preferred embodiment, it has excellent metabolic stability, a long elimination half-life (T1 / 2) in humans, and high selectivity with respect to the inhibitory action on other GPCRs such as the dopamine D2 receptor (hereinafter sometimes referred to as the "D2 receptor") and the hERG channel. Therefore, preferred among the compounds of the present invention are useful as therapeutic agents for mental and neurological disorders having long persistence in the human body and high safety. [Brief Description of the Drawings]

[0038]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0039] The present invention will be described in more detail below. In this specification, when expressing the number of carbons in the definition of "substituent", it may be represented as, for example, "C 1-6 ", etc. Specifically, the notation "C 1-6 alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms.

[0040] Examples of "halogen" include fluorine, chlorine, bromine, and iodine.

[0041] "C 1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. As C 1-6 alkyl, preferably "C 1-4 alkyl" is mentioned, and more preferably "C 1-3 alkyl" is mentioned. Specific examples of "C 1-3 alkyl" include, for example, methyl, ethyl, propyl, 1-methylethyl, etc. Specific examples of "C 1-4 alkyl" include, for example, in addition to those mentioned as specific examples of the above "C 1-3 alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. Specific examples of "C 1-6 alkyl" include, for example, in addition to those mentioned as specific examples of the above "C 1-4 alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc.

[0042] "C 3-10"Cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and also includes those having partially unsaturated bonds and those having a cross-linked structure. "C 3-10 As "cycloalkyl", preferably "C 3-7 Cycloalkyl" is mentioned. "C 3-7 Specific examples of "cycloalkyl" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. "C 3-10 Specific examples of "cycloalkyl" include, for example, in addition to those mentioned as specific examples of the above "C 3-7 Cycloalkyl", cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are mentioned.

[0043] "C 1-6 Alkoxy" means "C 1-6 Alkyloxy", and the "C 1-6 Alkyl" part is synonymous with the above "C 1-6 Alkyl". As "C 1-6 Alkoxy", preferably "C 1-4 Alkoxy" is mentioned, and more preferably "C 1-3 Alkoxy" is mentioned. Specific examples of "C 1-3 Alkoxy" include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, etc. Specific examples of "C 1-4 Alkoxy" include, for example, in addition to those mentioned as specific examples of the above "C 1-3 Alkyl", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. Specific examples of "C 1-6 Alkoxy" include, for example, in addition to those mentioned as specific examples of the above "C 1-4 Alkyl", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, etc.

[0044] The term "4- to 8-membered saturated heterocyclic group" means a saturated ring composed of 4 to 8 atoms, including 1 to 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 crosslinked structure. As the "4- to 8-membered saturated heterocyclic group", preferably, it is a "4- to 6-membered monocyclic saturated heterocyclic group", and more preferably, a "5- or 6-membered monocyclic saturated heterocyclic group" can be mentioned. Specific examples of the "5- or 6-membered monocyclic saturated heterocyclic group" include, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl tetrahydropyranyl, etc. Examples of the "4- to 6-membered monocyclic saturated heterocyclic group" include, in addition to those mentioned as specific examples of the above "5- or 6-membered monocyclic saturated heterocycle", oxetanyl, azetidinyl, etc. Examples of the "4- to 8-membered saturated heterocyclic ring" include, in addition to those mentioned as specific examples of the above "4- to 8-membered monocyclic saturated heterocyclic ring", azepinyl, oxepanyl, etc.

[0045] The term "3- to 6-membered saturated carbon ring" means a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. As the "3- to 6-membered saturated carbon ring", preferably, a "5- or 6-membered monocyclic saturated carbon ring" can be mentioned. Specific examples of the "5- or 6-membered monocyclic saturated carbon ring" include, for example, cyclopentane, cyclohexane, etc. Specific examples of the "3- to 6-membered saturated carbon ring" include, in addition to those mentioned as specific examples of the above "5- or 6-membered monocyclic saturated carbon ring", cyclopropane, cyclobutane, etc.

[0046] "The 5- or 6-membered aromatic heterocycle" means a 5- or 6-membered monocyclic aromatic heterocycle containing 1 to 3 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Preferably, pyrrole, imidazole, pyrazole, oxazole, isoxazole, pyridine, and pyrimidine are mentioned. More preferably, pyrrole, pyrazole, and pyridine are mentioned. Specific examples of the "5- or 6-membered aromatic heterocycle" include, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0047] As the "optionally substituted 5- or 6-membered aromatic heterocycle", preferably, (a) halogen, (b) hydroxy, (c) cyano, (d) C selected from the group consisting of halogen and C 1-6 alkoxy, optionally substituted with the same or different 1 to 3 substituents, C 1-6 alkyl, (e) C optionally substituted with the same or different 1 to 3 halogens 1-6 alkoxy, and (f) amino optionally substituted with the same or different 1 to 2 C 1-6 alkyl, from the group consisting of, optionally substituted with the same or different 1 to 5 substituents, a 5- or 6-membered aromatic heterocycle is mentioned. More preferably, C selected from the group consisting of halogen and C 1-6 alkoxy, optionally substituted with the same or different 1 to 3 substituents, C 1-6 alkyl; C optionally substituted with the same or different 1 to 3 halogens 1-6 alkoxy; and a 5- or 6-membered aromatic heterocycle optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen are mentioned. Even more preferably, C optionally substituted with 1 to 4 fluorines1-6 An alkyl or a C which may be substituted with 1 to 4 fluorines 1-6 Examples thereof include a 5- or 6-membered aromatic heterocycle which may be substituted with an alkoxy. Particularly preferably, a C 1-6 alkyl or a C 1-6 Examples thereof include a 5- or 6-membered aromatic heterocycle which may be substituted with an alkoxy.

[0048] Among the compounds of the present invention represented by the formula (1), n, t, Z, bond (a) including a dashed line, R A , R B , R 1a , R 1b , R 1c , R 1d , Q 3 , m, X, Y, bond (b) including a dashed line, Q 2 , R 2a , R 2b , R 2c , R 2d , R C , R D , R E , R F , R G , R H and R J The preferred ones are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.

[0049] Preferably, n is 2.

[0050] One embodiment of Z includes a nitrogen atom. Another embodiment of Z includes -CH-.

[0051] Preferably, t is 2.

[0052] Preferably, the bond (a) including a dashed line is a single bond..

[0053] R A and R B Preferably, they are a hydrogen atom or a C 1-6 alkyl. More preferably, they are a hydrogen atom or a C 1-3Examples of R include alkyl. More preferably, the R is a hydrogen atom, methyl or ethyl. Most preferably, the R is a hydrogen atom.

[0054] R 1a 、R 1b 、R 1c and R 1d are preferably a hydrogen atom or C 1-6 alkyl. More preferably, the R is a hydrogen atom or C 1-3 alkyl. More preferably, the R is a hydrogen atom, methyl or ethyl. Most preferably, the R is a hydrogen atom.

[0055] Q 3 In one embodiment of Q, a 5-membered aromatic heterocyclic ring which may be substituted is included. Q 3 In another embodiment of Q, a 5-membered nitrogen-containing aromatic heterocyclic ring which may be substituted is included. Q 3 In another embodiment of Q, a 5-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of the same or different 1 to 3 halogen atoms or C 1-6 alkyl which may be substituted with alkoxy; C 1-6 alkyl which may be substituted with the same or different 1 to 3 halogen atoms; C 1-6 alkoxy; and halogen is included. Q 3 In another embodiment of Q, a 5-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with the same or different 1 to 2 substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkoxy is included. Q 3 In one embodiment of Q, a 6-membered aromatic heterocyclic ring which may be substituted is included. Q 3 In another embodiment of Q, a 6-membered nitrogen-containing aromatic heterocyclic ring which may be substituted is included. Q 3 In another embodiment of Q, a 6-membered nitrogen-containing aromatic heterocyclic ring which may be substituted with the same or different 1 to 3 halogen atoms or C 1-6 alkyl which may be substituted with alkoxy; C 1-6 alkyl;1-6 Examples of the 6-membered nitrogen-containing aromatic heterocycle include those optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of alkoxy and halogen. Q 3 Another embodiment of Q is C 1-6 alkyl and C 1-6 Examples of the 6-membered nitrogen-containing aromatic heterocycle include those optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of alkoxy.

[0056] One embodiment of m is 0. Another embodiment of m is 1.

[0057] Y is preferably a nitrogen atom.

[0058] The bond (b) including the dashed line is preferably a single bond.

[0059] Q 2 One embodiment of Q is formula (3a). Another embodiment of Q is formula (3b). 2

[0060] R 2a R 2b R 2c and R 2d are preferably a hydrogen atom or C 1-6 alkyl. More preferably, a hydrogen atom or C 1-3 alkyl. Even more preferably, a hydrogen atom, methyl or ethyl. Most preferably, a hydrogen atom.

[0061] R C R D R E R F R G R H and R J are preferably a hydrogen atom or C 1-6 alkyl. More preferably, a hydrogen atom or C 1-3Examples of the alkyl group include. More preferably, a hydrogen atom, methyl or ethyl is included. Most preferably, it is a hydrogen atom.

[0062] One embodiment of the compound of the present invention represented by formula (1) includes the following (A). (A) Formula (1) is formula (1b), Z is -CH-, Ring Q 2 is formula (3a), R 2a 、R 2b 、R 2c and R 2d are both hydrogen atoms, Ring Q 1 is formula (4c) or formula (4f), R 3a and R 3b are each independently a hydrogen atom, C 1-6 alkyl or C 1-6 alkoxy, Compound or a pharmaceutically acceptable salt thereof.

[0063] Another embodiment of the compound of the present invention represented by formula (1) includes the following (B). (B) Formula (1) is formula (1b), Z is a nitrogen atom, Ring Q 2 is formula (3a), R 2a 、R 2b 、R 2c and R 2d are both hydrogen atoms, Ring Q 1 is formula (4a), R 3a and R 3b are each independently a hydrogen atom, C 1-6 alkyl or C 1-6 alkoxy, Compound or a pharmaceutically acceptable salt thereof.

[0064] Another aspect of the compound of the present invention represented by formula (1) includes the following (C). (C) Formula (1) is formula (1b), Z is a nitrogen atom, Ring Q 2 is formula (3b), R 2a , R 2b , R 2c and R 2d are both hydrogen atoms, Ring Q 1 is formula (4a) or formula (4c), R 3a and R 3b are each independently a hydrogen atom, C 1-6 alkyl or C 1-6 alkoxy, The compound or a pharmaceutically acceptable salt thereof.

[0065] The compound represented by formula (1) may exist as a tautomer. Therefore, the compound of the present invention also includes the tautomers of the compound represented by formula (1).

[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 racemates of the compounds represented by formula (1), but also the optically active forms 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 mixtures thereof.

[0067] In addition, any one or two or more of the compounds represented by formula (1) 1 H is 2 The deuterium-converted form converted to H(D) is also included in the compound represented by formula (1).

[0068] The compound represented by formula (1) and its pharmaceutically acceptable salts may exist in the form of hydrates and / or solvates. 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 forms of crystalline forms. As pharmaceutically acceptable salts, when the compound represented by formula (1) has an acidic group, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic metal salts such as zinc salt; and organic base salts such as triethylamine, triethanolamine, tris(hydroxymethyl)aminomethane, and amino acids can be mentioned. When the compound represented by formula (1) has a basic group, for example, 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, and ascorbate can be mentioned.

[0069] Hereinafter, the production method of the compound of the present invention will be described with examples, but the present invention is not limited thereto.

[0070] Manufacturing method The compounds of the present invention are synthesized by combining the production methods shown below and known synthetic methods. The compounds in the reaction formula also include cases where they form salts respectively, and examples of such salts include the same ones as the salts of the compound represented by formula (1). Note that these reactions are merely illustrative, and based on the knowledge of those skilled in organic synthesis, the compounds of the present invention can also be produced by other methods as appropriate.

[0071] In each production method described below, even when the use of a protecting group is not specifically indicated, if there are functional groups that need to be protected, the corresponding functional groups are protected as necessary, and after the reaction is completed or after a series of reactions are carried out, deprotection is performed to obtain the target product.

[0072] As the protecting group, ordinary protecting groups described in the literature (such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999), etc.) can be used. More specifically, examples of the protecting group for amino include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Also, examples of the protection for hydroxy include trialkylsilyl, acetyl, benzyl, etc. The introduction and removal of the protecting group can be carried out by methods commonly used in organic synthetic chemistry (such as the methods described in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999), etc.) or methods analogous thereto.

[0073] Manufacturing method 1 The compound represented by formula (1) is produced, for example, by the method shown below.

Chemical formula

[0074] Compound (5) can be obtained by using a commercially available product or by manufacturing according to a known method, for example, a method described in European Journal of Medicinal Chemistry 2002, 37(9), 721-730, etc.

[0075] Compound (6) can be obtained by using a commercially available product or by manufacturing according to a known method, for example, a method described in European Journal of Medicinal Chemistry 2012, 55, 58-66, etc.

[0076] Compound (1) is produced by reacting compound (5) with compound (6) in a suitable inert solvent in the presence of a suitable base. The reaction may be carried out in the presence of a suitable phase transfer catalyst if necessary. The reaction temperature is usually in the range 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 from 10 minutes to 48 hours.

[0077] 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. Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate. Specific examples of the inert solvent include, for example, 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.

[0078] Manufacturing method 2 Among the compounds represented by formula (1), the compound represented by formula (1c) is produced, for example, by the method shown below.

Chemical formula

[0079] Compound (7) can be produced by using a commercially available product or according to a known method, for example, the method described in Journal of Medicinal Chemistry 1985, 28(6), 761-769, etc.

[0080] Compound (1c) is produced by subjecting compound (7) and an aldehyde represented by formula (8a) or a hemiacetal represented by formula (8b) and a suitable reducing agent to a reductive amination reaction 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 from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reducing agent used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0081] Specific examples of the reducing agent include, for example, complex hydride compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride; borane complexes (such as borane-dimethyl sulfide complex or borane-tetrahydrofuran complex), and the like. Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, 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, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide, and the like. Specific examples of the acid include, for example, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid; inorganic acids such as hydrochloric acid, sulfuric acid, and the like. Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as water, chloroform, dichloromethane; aromatic hydrocarbons such as benzene, toluene; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane; alcohol solvents such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone; and mixed solvents thereof, and the like.

[0082] Manufacturing method 3 The compound represented by formula (5) is produced, for example, by the method shown below.

Chemical formula

[0083] As the compound (9), a commercially available one can be used, or it can be produced according to a known method, for example, the method described in Organic Process Research & Development 2005, 9(6), 774-781, etc.

[0084] As the compound (10), a commercially available one can be used, or it can be produced according to a known method, for example, the method described in Journal of the Chemical Society, Perkin Transactions 1 2001, 10, 1204-1211, etc.

[0085] The compound (5) is produced by reacting the compound (7) 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 from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0086] Specific examples of the base include, for example, 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. Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate. Specific examples of the inert solvent include, for example, 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.

[0087] Compound (5) is produced by converting the hydroxyl group of compound (11) into a halogen or a substituted sulfonyloxy such as p-toluenesulfonyloxy or methanesulfonyloxy by a conventional method in a suitable inert solvent. Specifically, for example, LG 1 When LG in compound (5) is a halogen, compound (5) is produced by reacting compound (11) with carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine in a suitable inert solvent. Also, LG 1The compound (5) where LG is a substituted sulfonyloxy group is produced by reacting compound (11) with, for example, p-toluenesulfonyl chloride or methanesulfonyl chloride, etc., in an inert solvent in the presence of a suitable base. The reaction temperature is usually in the range from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, etc., but is usually from 10 minutes to 48 hours.

[0088] Specific examples of the inert solvent include, for example, halogenated hydrocarbon solvents such as chloroform and dichloromethane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; and mixed solvents thereof, etc. Specific examples of the base include, for example, organic bases such as triethylamine and pyridine; and inorganic bases such as potassium carbonate and sodium hydroxide.

[0089] Also, when LG 1 is a halogen in compound (5), compound (5) where LG 1 is a substituted sulfonyloxy group can also be produced by reacting it with, for example, lithium bromide or lithium chloride, etc., in a suitable inert solvent.

[0090] Compound (11) is produced by reacting compound (7) with an alkylating agent represented by formula (10) in a suitable inert solvent. This reaction may be carried out, if necessary, in the presence of a suitable base and further in the presence of a suitable phase transfer catalyst. The reaction temperature is usually in the range from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, etc., but is usually from 10 minutes to 48 hours.

[0091] Specific examples of the base include, for example, 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. Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate. Specific examples of the inert solvent include, for example, 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.

[0092] Manufacturing method 4 Among the compounds represented by formula (7), the compounds represented by formula (7a) are produced, for example, by the method shown below.

Chemical formula

[0093] For compound (13), a commercially available one can be used, or it can be produced according to a known method, for example, the method described in Chemical Communications 2016, 52(5), 958-961, etc.

[0094] Compound (7a) is produced by treating compound (16) with a suitable acid in a suitable inert solvent. The treatment temperature generally ranges from -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is generally from 10 minutes to 48 hours.

[0095] Specific examples of the inert solvent include, for example, 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 dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0096] Compound (16) is produced by treating compound (15) with a suitable base in a suitable inert solvent. The treatment temperature is generally a temperature in the range from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, but is generally from 10 minutes to 48 hours.

[0097] Specific examples of the base include, for example, 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. Specific examples of the inert solvent include, for example, 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.

[0098] Compound (15) is produced by reacting compound (14) with hydroxylamine or a salt thereof in a suitable inert solvent, optionally in the presence of a suitable base. The treatment temperature is usually a temperature in the range from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0099] Specific examples of the base include, for example, 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. Specific examples of the inert solvent include, for example, 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.

[0100] Compound (14) is produced by reacting a lithiated product generated by treating compound (13) with an organolithium such as n-butyllithium in a suitable inert solvent with compound (12). The treatment temperature is usually a temperature in the range from about -78 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reagents, raw materials, and solvents used, but is usually from 10 minutes to 48 hours.

[0101] Specific examples of the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and mixed solvents thereof.

[0102] Compound (12) is produced by reacting 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid with N,O-dimethylhydroxyamine or its hydrochloride in a suitable inert solvent in the presence of a suitable condensing agent. The reaction may be carried out in the presence of a suitable base if necessary. The reaction temperature is usually in the range from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the condensing agent, raw materials, and solvents used, but is usually from 10 minutes to 48 hours. Compound (12) is also produced by reacting N,O-dimethylhydroxyamine or its salt with an acid halide or acid anhydride etc. derived from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in a suitable inert solvent in the presence of a suitable base. The reaction temperature is usually in the range from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the condensing agent, raw material solvents, etc., but is usually from 10 minutes to 48 hours.

[0103] Specific examples of the condensing agent include, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate salt (BOP), diphenylphosphoryl diamide (DPPA), N,N-carbonyldiimidazole (CDI), benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate salt (HBTU), and the like. If necessary, the reaction can be carried out by adding additives such as N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), and the like. Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, 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, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide, and the like. Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform, dichloromethane; aromatic hydrocarbons such as benzene, toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof, and the like.

[0104] Manufacturing method 5 Among the compounds represented by formula (7), the compound represented by formula (7b) is produced, for example, by the method shown below.

Chemical formula

[0105] For compound (17), a commercially available one can be used, or it can be produced according to a known method, for example, the method described in European Journal of Organic Chemistry 2018, 40, 5520 - 5523, etc.

[0106] Compound (7b) is produced by treating compound (18) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0107] Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 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 dimethyl sulfoxide; and mixed solvents thereof, etc. Specific examples of the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid, etc.

[0108] Compound (18) is produced by reacting compound (17) with a reagent such as phosphoryl halide like phosphoryl chloride, a sulfonylating agent like methanesulfonyl chloride, or bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) in a suitable inert solvent for activation and then reacting with tert-butyl piperazine-1-carboxylate in the presence of a suitable base. The reaction temperature is usually in the range from about -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reagent used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0109] Specific examples of the base include, for example, 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. Specific examples of the inert solvent include, for example, 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; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0110] Manufacturing method 6 Among the compounds represented by formula (7), the compound represented by formula (7c) is produced, for example, by the method shown below.

Chemical formula

[0111] Compound (7c) is produced by treating compound (20) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0112] Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 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 dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0113] Compound (20) is produced by treating compound (19) with sulfuryl chloride in a suitable inert solvent and then reacting with ammonia. The reaction temperature is usually in the range from -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0114] Specific examples of the inert solvent include, for example, 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; and mixed solvents thereof.

[0115] Compound (19) is produced by reacting compound (14) with sodium sulfide in a suitable inert solvent and then treating with a benzyl halide such as benzyl bromide in the presence of a suitable base. Compound (19) can also be produced by reacting compound (14) with benzyl mercaptan in a suitable inert solvent in the presence of a suitable base. The reaction temperature is usually in the range from -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, reagents, raw materials, and solvents used, but is usually from 10 minutes to 48 hours.

[0116] 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. Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0117] Manufacturing method 7 The compound represented by formula (8a) or formula (8b) is produced, for example, by the method shown below.

Chemical formula

[0118] Compound (21) can be prepared by using a commercially available one or according to a known method, for example, a method described in Organic & Biomolecular Chemistry 2018, 16(41), 7753-7759, etc.

[0119] Compound (8a) or compound (8b) is prepared by reacting compound (22) with a catalytic amount of osmium tetroxide in the presence of an oxidizing agent such as sodium periodate in a suitable inert solvent. The reaction temperature is usually in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, reagents, raw materials, and solvents used, but is usually 10 minutes to 48 hours.

[0120] Specific examples of the inert solvent include, for example, 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, dimethylformamide, and N-methyl-2-pyrrolidinone; water, and mixed solvents thereof.

[0121] Compound (22) is prepared by reacting compound (6) with an alkylating agent represented by formula (21) 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 conditions such as the reaction temperature, reagents, raw materials, and solvents used, but is usually 10 minutes to 48 hours.

[0122] Specific examples of the base include, for example, 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. Specific examples of the inert solvent include, for example, 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; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0123] Manufacturing method 8 Among the compounds represented by formula (2), compound (2a) is produced, for example, by the method shown below. [Chemical formula] [In the formula, W, m, and ring Q 3 are as defined in item 1, R 4 represents an optionally substituted C 1-6 alkyl, LG represents a leaving group (for example, iodine, bromine, chlorine, substituted sulfonyl (for example, trifluoromethanesulfonyl, p-toluenesulfonyl, etc.)), and BG represents boric acid (-B(OH)2), boronic acid ester (for example, pinacol boronic acid ester), or trifluoroborate.

[0124] Commercially available compound (23) can be used, or it can be produced according to a known method, for example, the method described in Journal of Medicinal Chemistry 2011, 54(2), 635-654, etc.

[0125] For compounds (24a) and (24b), commercially available ones can be used, or they can be produced according to known methods, such as the methods described in Tetrahedron Letters 2004, 45(11), 2467-2471, etc.

[0126] Compound (2a) is produced by treating compound (25a) with a suitable acid in a suitable inert solvent and then undergoing intramolecular cyclization in the presence of a suitable base as needed. The treatment temperature is usually in the range from -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0127] Specific examples of the inert solvent include, for example, 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 dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the base include, for example, 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. Specific examples of the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0128] Compound (2a) is also produced by hydrogenolysis of compound (25b) in a suitable inert solvent under normal pressure or pressurized hydrogen atmosphere, followed by intramolecular cyclization in the presence of a suitable base if necessary. Specific examples of the catalyst used in this hydrogenolysis reaction include palladium-based catalysts such as palladium-carbon and palladium hydroxide-carbon. The reaction temperature is usually in the range from 0 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the catalyst used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0129] Specific examples of the inert solvent include, for example, ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the base include, for example, 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.

[0130] Compound (25a) is produced by coupling compound (23) and compound (24a) in a suitable inert solvent in the presence of a suitable transition metal catalyst. The reaction can be carried out in the presence of a suitable ligand, a suitable base, a suitable additive, etc. if necessary. The reaction temperature is usually in the range from -10 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the transition metal catalyst used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0131] Specific examples of the transition metal catalyst include, for example, palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium chloride(II), dichlorobis(tri-O-tolylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc. Specific examples of the ligand include, for example, triphenylphosphine, tri-O-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, etc. Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc. Specific examples of the additive include, for example, inorganic salts such as lithium chloride, cesium fluoride, copper(I) iodide, copper(I) bromide, etc. Specific examples of the inert solvent include, for example, water, acetonitrile, halogenated hydrocarbons such as chloroform, dichloromethane; aromatic hydrocarbons such as benzene, toluene; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, alcohol solvents such as methanol, ethanol, 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, or a mixed solvent thereof, etc.

[0132] Compound (25b) is produced by coupling compound (23) and compound (24b) in a suitable inert solvent in the presence of a suitable transition metal catalyst. The reaction can be carried out in the presence of a suitable ligand, a suitable base, a suitable additive, etc., if necessary. The reaction temperature is usually in the range from -10 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the transition metal catalyst used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0133] Specific examples of the transition metal catalyst include, for example, palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium chloride(II), dichlorobis(tri-O-tolylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc. Specific examples of the ligand include, for example, triphenylphosphine, tri-O-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, etc. Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc. Specific examples of the additive include, for example, inorganic salts such as lithium chloride, cesium fluoride, copper(I) iodide, copper(I) bromide, etc. Specific examples of the inert solvent include, for example, 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, or a mixed solvent thereof, and the like.

[0134] Manufacturing method 9 Among the compounds represented by formula (2), the compound represented by formula (2b) is produced, for example, by the method shown below.

Chemical formula

[0135] For compound (26), a commercially available product can be used, or it can be produced according to a known method, for example, the method described in Organic Letters 2009, 11(10), 2133-2136, etc.

[0136] Compound (2b) is produced by reacting compound (26) with an alkylhydrazine such as hydrazine or methylhydrazine in a suitable inert solvent, and if necessary, in the presence of a suitable acid, and then reacting with an amide acetal such as dimethylformamide dimethylacetal or dimethylacetamide dimethylacetal. Alternatively, compound (2b) can also be produced by reacting compound (26) with an amide acetal such as dimethylformamide dimethylacetal or dimethylacetamide dimethylacetal and then reacting with an alkylhydrazine such as hydrazine or methylhydrazine. The reaction temperature is usually in the range from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reagents, raw materials, and solvents used, but is usually from 10 minutes to 48 hours.

[0137] Specific examples of the inert solvent include, for example, 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 dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the acid include, for example, organic acids such as acetic acid.

[0138] Manufacturing method 10 Among the compounds represented by formula (1), the compound represented by formula (1d) is produced, for example, by the method shown below.

Chemical formula

[0139] Compound (1d) is produced by reacting compound (29) with 2,2-dimethoxy-N-methylethan-1-amine in the presence of a suitable dehydrating agent and a suitable acid in a suitable inert solvent. The reaction temperature is usually in the range from about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the reagents, raw materials, and solvents used, but is usually from 10 minutes to 48 hours.

[0140] Specific examples of the inert solvent include, for example, 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 dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the dehydrating agent include, for example, magnesium sulfate, sodium sulfate, and the like. Specific examples of the acid include, for example, organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

[0141] Compound (29) is produced by treating compound (28) with a suitable acid in a suitable inert solvent. The treatment temperature is usually in the range from -20 °C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

[0142] Specific examples of the inert solvent include, for example, 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 acetone, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof. Specific examples of the acid include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0143] Compound (28) is produced by reacting compound (5) with compound (27) in a suitable inert solvent in the presence of a suitable base. The reaction may be carried out in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature is usually in the range 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 from 10 minutes to 48 hours.

[0144] Specific examples of the base include, for example, 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. Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate. Specific examples of the inert solvent include, for example, 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.

[0145] Compound (27) is produced by reacting compound (26) with a suitable alcohol in a suitable inert solvent in the presence of a suitable acid. The reaction may be carried out under azeotropic dehydration conditions using a Dean-Stark apparatus, 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 from 10 minutes to 48 hours.

[0146] Specific examples of the inert solvent include, for example, 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. Specific examples of the acid include, for example, organic acids such as methanesulfonic acid and p-toluenesulfonic acid. Specific examples of the alcohol include, for example, lower alcohols such as methanol, ethanol, and ethane-1,2-diol.

[0147] By appropriately combining the above production methods, the compound of the present invention having a desired substituent at a desired position can be obtained. Isolation and purification of the intermediates and products in the above production methods can be carried out by appropriately combining methods commonly used in organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various chromatographies. Further, in the case of an intermediate, it can also be used in the next reaction without particular purification.

[0148] The starting compounds or intermediates in the above production methods may exist in the form of salts such as hydrochloride depending on the reaction conditions and the like, but they can be used as they are or in the free form. When the starting compound or intermediate is obtained in the form of a salt and it is desired to use or obtain the starting compound or intermediate in the free form, they can be dissolved or suspended in an appropriate solvent and converted to the free form by neutralizing with a base such as an aqueous sodium hydrogen carbonate solution.

[0149] Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, there may be isomers such as tautomers like keto-enol forms, positional isomers, geometric isomers or optical isomers. However, all possible isomers including these and mixtures in any ratio of these isomers are encompassed by the present invention. In addition, the optical isomers can be separated by carrying out known separation steps such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. Further, an optically active substance can also be used as a starting material.

[0150] 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 may be purified as it is. When the compound represented by formula (1) is obtained in a free form, the compound represented by formula (1) may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt.

[0151] The compound of the present invention has 1A agonist activity against the 5-HT 2A receptor and antagonist activity against the 5-HT receptor, and has a mechanism of action different from that of existing drugs for treating mental diseases. Therefore, it can provide a new option for drug treatment in various mental diseases. That is, the compound of the present invention is effective for the treatment of mental diseases. Further, the compound of the present invention is also effective for central nervous system diseases.

[0152] Mental disorders or central nervous system disorders for which efficacy is expected include, for example, 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: Non - organic sleep disorders, F52: Sexual dysfunction not due to organic disorders or diseases, 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 diseases of the nervous system, G47: Sleep disorders, etc. in the 10th Revision of the International Classification of Diseases (ICD - 10).

[0153] Specific examples of F00 - F09: Organic mental disorders including symptomatic include, for example, dementia in Alzheimer's disease, vascular dementia, dementia with Lewy bodies, dementia in Parkinson's disease, mental disorders associated with diseases such as brain injury, other mental disorders due to cerebral insufficiency and physical diseases, etc. Specific examples of F10 - F19: Mental and behavioral disorders due to psychoactive substance use include, for example, delirium tremens, psychotic disorders, amnestic syndrome, etc. due to various substance use. Specific examples of F20 - F29: Schizophrenia, schizophrenia - type disorders and delusional disorders include, for example, paranoid schizophrenia, simple schizophrenia, delusional disorders, etc. Specific examples of F30 - F39: Mood [affective] disorders include, for example, manic episodes, bipolar affective disorder, depressive episodes, etc. Specific examples of F40 - F48: Neurotic disorders, stress - related disorders and somatoform disorders include, for example, phobic anxiety disorders, obsessive - compulsive disorder, somatoform disorders, etc. Specific examples of F51: Non - organic sleep disorders include, for example, non - organic insomnia, sleepwalking, nightmares, etc. Specific examples of F52: Sexual dysfunction not due to organic disorders or diseases include, for example, lack of sexual desire, or loss of sexual desire, sexual dysfunction of unknown etiology, etc. Examples of pervasive developmental disorders include, for example, autism, mental retardation, and hyperkinetic disorders associated with stereotyped movements, etc. F90 - F98: Examples of disorders of behavior and emotions that usually occur in childhood and adolescence with hyperkinetic disorders include, for example, hyperkinetic disorders, conduct disorders, mixed disorders of behavior and emotions, etc. G20 - G26: Examples of extrapyramidal disorders and abnormal movements include, for example, Parkinson's disease, secondary Parkinson's syndrome, dyskinesia, spinocerebellar degeneration, etc. G30 - G32: Examples of other degenerative diseases of the nervous system include, for example, Alzheimer's disease, frontotemporal dementia, frontotemporal degeneration, dementia with Lewy bodies, senile cerebral degeneration, progressive supranuclear palsy, etc. G47: Examples of sleep disorders include, for example, disorders of sleep onset and maintenance [insomnia], sleep - wake schedule disorders, narcolepsy, and cataplexy, etc. The compound of the present invention is also useful for the treatment or prevention of recurrence of various symptoms (psychotic symptoms, restlessness, aggressiveness, irritability and irascibility, sleep disorders, depressive symptoms, anxiety symptoms, cognitive function disorders, etc.) associated with these diseases.

[0154] Mental disorders or central nervous system disorders for which efficacy is expected preferably include schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or anxiety, excitement or aggressiveness associated with Alzheimer's disease, more preferably schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, or anxiety, excitement or aggressiveness associated with Alzheimer's disease.

[0155] The compound of the present invention is 5 - HT 1A receptor and 5 - HT 2Ashows strong binding affinity for the receptor (Test Example 1), 5-HT 1A has agonist activity against the receptor, 5-HT 2A has antagonist activity against the receptor. In a preferred embodiment of the compound of the present invention, 5-HT 1A receptor and 5-HT 2A receptors with a binding affinity 100-fold or more stronger than that of the D2 receptor can be mentioned. Therefore, at blood concentrations where side effects such as extrapyramidal symptoms and hyperprolactinemia, which are considered to be caused by D2 receptor antagonist activity, do not occur, 5-HT 1A receptor agonist activity and 5-HT 2A pharmacological effects based on receptor antagonist activity can be exerted. That is, the concentration at which the pharmacological effect is expressed and the concentration at which the side effect is expressed are different.

[0156] Also, in a preferred embodiment of the compound of the present invention, the hERG channel inhibition concentration, which is an expression index of arrhythmia due to QT prolongation, and 5-HT 1A receptor agonist activity and 5-HT 2A Since the concentration at which the pharmacological effect based on receptor antagonist activity is expressed is different (Test Example 5), it can be expected that the influence on the cardiovascular system is small. That is, the concentration at which the pharmacological effect is expressed and the concentration at which the side effect is expressed are different.

[0157] The elimination half-life (hereinafter, sometimes referred to as "T1 / 2") in a drug is a factor that determines the number of doses required to maintain its effect. When T1 / 2 is short, multiple doses per day are required, which may lead to forgetting to take or leaving some doses, interfering with appropriate drug treatment. In addition, with an increase in the number of doses, there is a concern that the tolerance may decrease due to an increase in the side effect incidence rate or a limitation to high-dose administration. From the above viewpoints, by achieving a long T1 / 2, it can be expected to create a long-acting drug with less of the above concerns, leading to a reduction in the burden on patients taking the drug. In a preferred embodiment of the compound of the present invention, the predicted human elimination half-life (hereinafter sometimes referred to as "predicted human T1 / 2") is as long as 8 hours or more (Test Example 4). That is, in a preferred embodiment of the compound of the present invention, in the human body, it is expected that the drug efficacy lasts for a long time, thereby improving the medication adherence of drug-treated patients and showing high tolerance at the time of dosing.

[0158] 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. Parenterally, it can be administered in the form of topical agents, injections, transdermal agents, nasal agents, etc. Examples of oral agents or rectal administration agents include capsules, tablets, pills, powders, cachets, suppositories, solutions, etc. Examples of injections include sterile solutions or suspensions, etc. Examples of topical agents include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents), etc.

[0159] The above dosage forms are formulated by ordinary methods together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. Examples of pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Capsules can be formulated by putting the compound of the present invention together with a pharmaceutically acceptable carrier therein. The compound of the present invention can be mixed with a pharmaceutically acceptable excipient or put into a capsule without an excipient. Cachets can also be manufactured in the same way.

[0160] Examples of the injectable liquid preparation include solutions, suspensions, emulsions and the like. For example, aqueous solutions, water-propylene glycol solutions and the like can be mentioned. The liquid preparation can also be produced in the form of a solution of polyethylene glycol or / and propylene glycol which may contain water. The liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavoring agent, a stabilizer, a sweetening agent, a solubilizer, a thickening agent and the like as necessary. Further, the liquid preparation suitable for oral administration can also be produced by adding the compound of the present invention to water together with a dispersing agent and making it viscous. Examples of the thickening agent include pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or known suspending agents and the like.

[0161] The dosage varies depending on the individual compound and also on the disease, age, weight, sex, symptoms, route of administration, etc. of the patient. Usually, for an adult (body weight 50 kg), the compound of the present invention is administered at 0.1 to 1000 mg / day, preferably 1 to 300 mg / day, once a day or divided into 2 to 3 times a day. Further, it can also be administered once every few days to a few weeks.

[0162] The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects. Hereinafter, the drugs that can be used in combination with the compound of the present invention are abbreviated as combination drugs.

[0163] Specific examples of the combination drugs include, for example, antidepressants, anxiolytics, schizophrenia treatment drugs, dopamine replacement drugs, dopamine receptor agonists, Parkinson's disease treatment drugs, antiepileptic drugs, anticonvulsants, analgesics, hormone preparations, migraine treatment drugs, adrenergic β-receptor antagonists, dementia treatment drugs, mood disorder treatment drugs, antiemetics, sleep inducers, anticonvulsants and the like. Preferred examples of the combination drugs include anxiolytics such as selective serotonin reuptake inhibitors.

[0164] The administration period of the compound of the present invention and the concomitant agent is not limited, and they may be administered simultaneously or at different times to the administration subject. Further, they may be formulated as a combination preparation of the compound of the present invention and the concomitant agent. The dosage of the concomitant agent can be appropriately selected based on the clinically used dosage. Further, the mixing ratio of the compound of the present invention and the concomitant agent can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant agent may be used with respect to 1 part by weight of the compound of the present invention. Further, for the purpose of suppressing its side effects, it can be used in combination with drugs (concomitant agents) such as antiemetics, sleep-inducing agents, and anticonvulsants.

Examples

[0165] The present invention will be described more specifically below with reference examples, examples and test examples, but the present invention is not limited thereto. The compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature. The identification of the compound was carried out using proton nuclear magnetic resonance absorption spectrum ( 1 1H-NMR), LC-MS, etc.

[0166] LC-MS was measured using the following conditions. The retention time (R.T.) represents the time when the mass spectrum peak appears in the LC-MS measurement. Condition A Analytical device: Shimadzu LCMS-2020 Column: Phenomenex Kinetex 1.7 μm C18 (50 mm × 2.10 mm) Elution solvent: Solution A: MeOH, Solution B: 0.05% TFA / H2O Gradient conditions: 0.0 min; A / B = 30:70 0.0 - 1.90 min; A / B = 99:1 1.91 - 3.00 min; A / B = 30:70 Flow rate: 0.5 mL / min Wavelength: 220 nm Column temperature: 40 °C

[0167] The following abbreviations may be used in this specification. Me: Methyl DMF: N,N-Dimethylformamide THF: Tetrahydrofuran tert-: Tertiary CDCl3: Deuterochloroform DMSO-d6: Deuterodimethyl sulfoxide

[0168] The proton nuclear magnetic resonance spectrum was measured using a JEOL FT-NMR measuring apparatus (300 MHz or 400 MHz). The chemical shift values were described in δ values (ppm). As symbols used in NMR, s means singlet, d means doublet, dd means double doublet, dt means double triplet, t means triplet, q means quartet, m means multiplet, br means broad, brs means broad singlet, and J means coupling constant.

[0169] Example 1 7-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6,7-dihydro-1,7-naphthyridin-8(5H)-one

Chemical formula

[0170] Example 2 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one [Chemical Structure] To a toluene solution (3.7 mL) of the compound of Reference Example 10 (99.0 mg) were added the compound of Reference Example 2 (164 mg), potassium hydroxide (46.8 mg), and tetrabutylammonium bromide (59.1 mg) at room temperature. After stirring under reflux heating for 15 hours, water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and further recrystallized from 2-propanol to obtain the title compound (160 mg). 1H-NMR (400 MHz, CDCl3) δ: 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.93 (2H, t, J = 6.4 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 6.49 (1H, s), 7.31-7.36 (1H, m), 7.42-7.47 (1H, m), 7.77-7.80 (1H, m), 7.86-7.89 (1H, m), 8.80 (1H, s).

[0171] Example 3 2-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chemical formula

[0172] Examples 4 to 21 According to the method described in Example 3, the compounds of Examples 4 to 21 were obtained from the compounds of the corresponding reference examples.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0173] Example 22 7-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-6,7-dihydro-1,7-naphthyridin-8(5H)-one

Chemical formula

[0174] Examples 23 to 31 According to the method described in Example 22, the compounds of Examples 23 to 31 were obtained from the corresponding compounds of the reference examples. [Table 2-1] [Table 2-2]

[0175] Example 32 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-3-methyl-6,7-dihydro[1,2]oxazolo[4,5-c]pyridin-4(5H)-one [Chemical formula] A mixture of the compound of Reference Example 1 (40.0 mg), 3-methyl-6,7-dihydro[1,2]oxazolo[4,5-c]pyridin-4(5H)-one (22.9 mg), cesium carbonate (98.0 mg), potassium iodide (12.0 mg) and acetonitrile (2.0 mL) was stirred at 150 °C for 2 hours under microwave irradiation. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by amino silica gel column chromatography (hexane / ethyl acetate), and further separated and purified by preparative thin layer chromatography (chloroform / methanol) to obtain the title compound (10.0 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 2.50 (3H, s), 2.66 (2H, t, J = 6.6 Hz), 2.73 (4H, t, J = 5.0 Hz), 3.09 (2H, t, J = 7.1 Hz), 3.56 (4H, t, J = 4.8 Hz), 3.66 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 7.1 Hz), 7.20-7.25 (1H, m), 7.43-7.51 (2H, m), 7.68 (1H, d, J = 7.8 Hz).

[0176] Examples 33 to 34 According to the method described in Example 32, the compounds of Examples 33 to 34 were obtained from the corresponding compounds of the reference examples.

Table 3

[0177] Example 35 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-6,7-dihydro[1,3]oxazolo[5,4-c]pyridin-4(5H)-one

Chemical formula

[0178] Example 36 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0179] Example 37 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0180] Examples 38 to 87 Compounds of Examples 38 to 87 were obtained from the corresponding reference example compounds according to the method described in Example 37. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10]

[0181] Example 88 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one [Chemical formula] A mixture of the compound of Reference Example 3 (852 mg), the compound of Reference Example 42 (500 mg), 55% sodium hydride (134 mg) and N,N-dimethylformamide (15 mL) was stirred at 60 °C for 3.5 hours. Then, water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (90 / 10), dried over anhydrous sodium sulfate, filtered and concentrated. After the remaining N,N-dimethylformamide was removed by azeotropic distillation with toluene, the residue was separated and purified by silica gel column chromatography (ethyl acetate), and further recrystallized from ethanol (12 mL) to obtain the title compound (710 mg). 1 H-NMR (400 MHz, CDCl3) δ: 1.98 - 2.15 (4H, m), 2.23 - 2.31 (2H, m), 2.69 (2H, t, J = 6.4 Hz), 2.78 (3H, s), 3.05 - 3.17 (5H, m), 3.70 - 3.79 (4H, m), 7.27 - 7.31 (1H, m), 7.50 - 7.59 (2H, m), 7.70 (1H, d, J = 7.8 Hz), 9.15 (1H, s).

[0182] Examples 89 to 92 According to the method described in Example 88, the compounds of Examples 89 to 92 were obtained from the compounds of the corresponding reference examples. [Table 5]

[0183] Example 93 6-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-2-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one [Chemical formula] To a dimethyl sulfoxide solution (1.0 mL) of the compound of Reference Example 43 (100 mg) were sequentially added potassium hydroxide (38.0 mg) and the compound of Reference Example 2 (159 mg), and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was purified by silica gel column chromatography (chloroform / methanol), and further separated and purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (92.7 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 1.38 (3H, t, J = 7.7 Hz), 2.69 - 2.80 (6H, m), 3.01 (2H, q, J = 7.0 Hz), 3.14 (2H, t, J = 6.7 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.72 - 3.79 (4H, m), 7.33 - 7.38 (1H, m), 7.44 - 7.49 (1H, m), 7.81 (1H, dd, J = 8.2, 0.9 Hz), 7.90 (1H, dd, J = 8.0, 0.7 Hz), 9.17 (1H, s).

[0184] Examples 94 to 95 According to the method described in Example 93, the compounds of Examples 94 to 95 were obtained from the compounds of the corresponding reference examples.

Table 6

[0185] Example 96 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Chemical formula

[0186] Example 97 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one

Chem.

[0187] Example 98 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Chem.

[0188] Example 99 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [Chemical formula] To the compound of Reference Example 48 (103 mg), 48% hydrobromic acid (1.50 mL) was added at room temperature. After stirring at room temperature for 2 hours, an aqueous solution of 4 mol / L sodium hydroxide was added to the reaction mixture, and the reaction mixture was adjusted to pH 7 and then extracted with chloroform / methanol (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To a methylene chloride solution (1.2 mL) of the obtained concentrated residue (84.7 mg), pyridine (0.0401 mL), magnesium chloride (23.6 mg), and acetic anhydride (0.0257 mL) were added at room temperature. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To an ethanol solution (0.71 mL) of the obtained concentrated residue (81.7 mg), an aqueous solution (0.355 ml) of hydrazine (10.7 mg) was added at room temperature. After stirring at room temperature for 48 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (1.1 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 2.01-2.14 (4H, m), 2.22-2.32 (2H, m), 2.55 (3H, s), 2.61-2.69 (2H, m), 2.92 (2H, t, J = 6.9 Hz), 3.05-3.18 (2H, m), 3.66 (2H, t, J = 6.9 Hz), 7.26-7.31 (1H, m), 7.48-7.57 (2H, m), 7.71 (1H, d, J = 7.8 Hz).

[0189] Example 100 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydroimidazo[4,5-c]azepin-4(3H)-one [Chemical formula] A mixture of the compound of Reference Example 51 (401 mg), 20% palladium hydroxide-carbon (1.25 g) and methanol (4.5 mL) was stirred in a hydrogen atmosphere (1 atm) at 60 °C for 1.5 hours. Then, after filtering the reaction mixture, the filtrate was concentrated under reduced pressure. A mixture of the obtained residue (283 mg), triethylamine (915 mg) and ethanol (4.5 mL) was stirred at 80 °C for 72 hours. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (chloroform / methanol). To a N,N-dimethylformamide solution (0.37 mL) of the obtained purified product (10.5 mg), 55% sodium hydride (2.98 mg) was added under ice-cooling. After stirring for 30 minutes under ice-cooling, the compound of Reference Example 2 (11.0 mg) and potassium iodide (3.10 mg) were added, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). The obtained purified product was dissolved in dichloromethane (0.37 mL), and trifluoroacetic acid (0.37 mL) was added. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated. Then, the reaction mixture was separated and purified by reverse phase liquid chromatography (water / acetonitrile) to obtain the title compound (0.87 mg). 1 H-NMR (400 MHz, CDCl3) δ: 2.11-2.18 (2H, m), 2.63-2.84 (6H, m), 2.95 (2H, t, J = 6.6 Hz), 3.40-3.62 (6H, m), 3.73 (2H, t, J = 6.4 Hz), 7.36 (1H, dd, J = 7.1, 7.1 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.64 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz).

[0190] Example 101 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepin-4(1H)-one [Chemical formula] A mixture of the compound of Reference Example 51 (697 mg), 20% palladium hydroxide-carbon (3310 mg) and methanol (7.9 mL) was stirred at 60 °C for 1.5 hours under a hydrogen atmosphere (1 atm). Then, the reaction mixture was filtered and concentrated under reduced pressure. The obtained residue (492 mg), a mixture of triethylamine (2.18 mL) and ethanol (7.9 mL) was heated to reflux for 72 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). The obtained purified product (5.9 mg) was dissolved in dichloromethane (0.42 mL), and trifluoroacetic acid (0.42 mL) was added. This mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, the residue was dissolved in N,N-dimethylformamide (0.42 mL), and an 8 mol / L aqueous potassium hydroxide solution (2.88 μL) and iodomethane (3.27 mg) were added at 0 °C. This mixture was stirred at 0 °C for 3 hours and then concentrated. To a solution of the obtained residue (3.47 mg) in N,N-dimethylformamide (0.21 mL), 55% sodium hydride (1.68 mg) was added under ice-cooling. After stirring for 30 minutes under ice-cooling, the compound of Reference Example 3 (5.84 mg) and potassium iodide (1.74 mg) were added, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.64 mg). 1 H-NMR (400 MHz, CDCl3) δ: 2.00 - 2.14 (2H, m), 2.20 - 2.34 (4H, m), 2.63 (2H, t, J = 6.6 Hz), 3.05 - 3.19 (2H, m), 3.33 - 3.45 (2H, m), 3.54 - 3.74 (6H, m), 3.92 (3H, s), 7.26 - 7.32 (1H, m), 7.41 (1H, s), 7.49 - 7.59 (2H, m), 7.73 (1H, d, J = 8.3 Hz).

[0191] Example 102 7-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carbonitrile

Chem.

[0192] Example 103 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one

Chem.

[0193] Example 104 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-ethyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chemical Structure

[0194] Example 105 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-1,3-dimethyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0195] Example 106 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-3-methoxy-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0196] Example 107 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-[( 2 H3)methyloxy](4,4- 2 H2)-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chemical formula

[0197] Example 108 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one [Chemical Structure] To a solution of the compound of Example 62 (84.0 mg) in 1,2-dimethoxyethane (1.6 mL) were added potassium carbonate (98.0 mg), trimethylboroxine (0.0820 mL), and tetrakis(triphenylphosphine)palladium (41.1 mg) at room temperature. After stirring at 100 °C for 3 hours under microwave irradiation, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (7.0 mg). 1H-NMR (400 MHz, CDCl3) δ: 2.56 (3H, s), 2.71 (2H, t, J = 6.6 Hz), 2.75 (4H, t, J = 4.8 Hz), 2.94 (2H, t, J = 6.6 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.6 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.96 (1H, s), 7.32-7.36 (1H, m), 7.43-7.47 (1H, m), 7.79 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 9.06 (1H, s).

[0198] Example 109 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one

Chem.

[0199] Example 110 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-(trifluoromethyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one [Chemical formula] Sodium triacetoxyborohydride (78.0 mg) was added to a mixture of the compound of Reference Example 53 (70.0 mg), the compound of Reference Example 52 (86.0 mg), triethylamine (0.082 mL) and dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour. Then, an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.20 mg). 1H-NMR (400 MHz, CDCl3) δ: 2.72 - 2.81 (6H, m), 3.11 (2H, t, J = 6.4 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.72 - 3.81 (4H, m), 7.36 (1H, dd, J = 7.3, 7.3 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.54 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 9.29 (1H, s).

[0200] Example 111 2-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-[(oxetan-3-yl)oxy]-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chemical Structure

[0201] Example 112 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-2-fluoro-1-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Chemical Structure

[0202] Example 113 2-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-2,7-naphthyridin-1(2H)-one

Chem.

[0203] Example 114 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2,4-dimethylpyrido[4,3-d]pyrimidin-5(6H)-one

Chemical Structure

[0204] Examples 115 to 139 According to the method described in Example 3, the compounds of Examples 115 to 139 were obtained from the compounds of the corresponding reference examples.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

[0205] Examples 140 to 152 According to the method described in Example 22, the compounds of Examples 140 to 152 were obtained from the corresponding reference example compounds.

Table 8-1

Table 8-2

Table 8-3

[0206] Example 153 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one

Chemical Structure

[0207] Examples 154 to 175 According to the method described in Example 37, the compounds of Examples 154 to 175 were obtained from the corresponding reference example compounds.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

[0208] Examples 176 to 179 According to the method described in Example 88, the compounds of Examples 176 to 179 were obtained from the compounds of the corresponding reference examples.

Table 10

[0209] Examples 180 to 182 According to the method described in Example 93, the compounds of Examples 180 to 182 were obtained from the compounds of the corresponding reference examples.

Table 11

[0210] Examples 183 to 185 According to the method described in Example 108, the compounds of Examples 183 to 185 were obtained from the compounds of the corresponding Example 144 or Example 146.

Table 12

[0211] Examples 186 to 187 According to the method described in Example 106, the compounds of Examples 186 to 187 were obtained from the compounds of the corresponding Example 144 or Example 146.

Table 13

[0212] Example 188 7-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-fluoro-6,7-dihydro-1,7-naphthyridin-8(5H)-one

Chem.

[0213] Example 189 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chem.

[0214] Example 190 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-4(5H)-one [Chemical formula] The title compound was obtained from 3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride by the same method as in Example 110 and Reference Example 52. 11H-NMR (400 MHz, CDCl3) δ: 1.92 - 2.09 (4H, m), 2.14 - 2.24 (2H, m), 2.59 (2H, t, J = 6.4 Hz), 2.98 - 3.09 (5H, m), 3.61 (2H, t, J = 6.4 Hz), 3.76 (2H, t, J = 7.3 Hz), 7.20 - 7.25 (1H, m), 7.44 - 7.52 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.77 (1H, s).

[0215] Example 191 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-6,7-dihydro[1,3]imidazo[4,5-c]pyridin-4(5H)-one

Chemical Structure

[0216] Example 192 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-3-bromo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0217] Example 193 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

Chem.

[0218] Example 194 6-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

Chem.

[0219] Reference Example 1 3-[4-(2-Chloroethyl)piperazin-1-yl]-1,2-benzisoxazole

Chem.

[0220] Reference Example 2 3-[4-(2-Chloroethyl)piperazin-1-yl]-1,2-benzisothiazole

Chem.

[0221] Reference Example 3 3-[1-(2-Chloroethyl)piperidin-4-yl]-1,2-benzisoxazole

Chem.

[0222] Reference Examples 4 to 5 According to the method described in Reference Example 3, using the corresponding starting materials, the compounds of Reference Examples 4 - 5 were obtained.

Table 14

[0223] Reference Example 6 3-[1-(2-Chloroethyl)piperidin-4-yl]-6-fluoro-5-methyl-1,2-benzisoxazole

Chemical formula

[0224] 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-dimethylhydroxylamine 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, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed twice with an aqueous saturated ammonium chloride solution, an aqueous saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (4.52 g). 1 H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.63 - 1.76 (4H, m), 2.70 - 2.86 (3H, m), 3.19 (3H, s), 3.72 (3H, s), 4.03 - 4.24 (2H, m).

[0225] b) Preparation of tert-butyl 4-(2,4-difluoro-5-methylbenzoyl)piperidine-1-carboxylate (Compound IN-1-2) To a solution of 1-bromo-2,4-difluoro-5-methylbenzene (2.28 g) in tetrahydrofuran (36 mL) was added dropwise 1.63 mol / L n-butyllithium / hexane (7.43 mL) at -78°C over 3 minutes. After stirring at -78°C for 1 hour, Compound IN-1-1 (1.50 g) was added and the mixture was stirred at -78°C for 2.5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.01 g). 1 H-NMR (400 MHz, CDCl3) δ: 1.45 (9H, s), 1.59 - 1.69 (2H, m), 1.83 - 1.92 (2H, m), 6.80 - 6.87 (1H, m), 7.17 - 7.25 (1H, m).

[0226] c) Preparation of tert-butyl 4-(6-fluoro-5-methyl-1,2-benzisoxazol-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, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). A mixture of the obtained product (335 mg), cesium carbonate (615 mg) and acetonitrile (9.0 mL) was stirred in a sealed tube at 130 °C for 3.5 hours. Then, the reaction mixture was filtered, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (90.8 mg). 1 H-NMR (400 MHz, CDCl3) δ: 1.87-1.99 (2H, m), 2.01-2.10 (2H, m), 2.38 (3H, d, J = 1.7 Hz), 2.89-3.03 (2H, m), 3.16-3.26 (1H, m), 4.11-4.36 (2H, m), 7.21 (1H, d, J = 9.0 Hz), 7.47 (1H, d, J = 7.1 Hz).

[0227] d) Preparation of 3-[1-(2-chloroethyl)piperidin-4-yl]-6-fluoro-5-methyl-1,2-benzisoxazole (Reference Example 6) To a dichloromethane solution (1.0 mL) of compound IN-1-3 (131 mg) was added 4 mol / L hydrochloric acid / ethyl acetate (1.0 mL), and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was concentrated to obtain a solid (114 mg). The obtained solid (114 mg), potassium carbonate (232 mg), 1-bromo-2-chloroethane (301 mg), and a mixture of tetrahydrofuran (1.7 mL) and water (0.42 mL) were stirred at room temperature overnight. Then, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (41.8 mg). 1 1H-NMR (300 MHz, CDCl3) δ: 1.98 - 2.45 (9H, m), 2.76 - 2.88 (2H, m), 3.00 - 3.15 (3H, m), 3.58 - 3.75 (2H, m), 7.20 (1H, d, J = 9.2 Hz), 7.52 (1H, d, J = 7.0 Hz).

[0228] Reference Example 7 3-[1-(2-Chloroethyl)piperidin-4-yl]-5-methyl-1,2-benzisoxazole

Chemical Structure

[0229] Reference Example 8 3-(Piperidin-4-yl)-1,2-benzisothiazole [Chemical formula]

[0230] a) Preparation of tert-butyl 4-[2-(benzylsulfanyl)benzoyl]piperidine-1-carboxylate (Compound IN-2-1) Sodium sulfide anhydrous (554 mg) was added to a dimethyl sulfoxide solution (5.0 mL) of tert-butyl 4-(2-fluorobenzoyl)piperidine-1-carboxylate (664 mg), and the mixture was stirred at 80 °C for 2 hours. Then, additional sodium sulfide anhydrous (560 mg) was added, and the mixture was stirred at 110 °C for 3 hours. Potassium carbonate (895 mg) and benzyl bromide (0.270 mL) were added to the reaction mixture. After stirring at room temperature for 5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (391 mg). LC-MS: R.T. = 2.12 min ObsMS = 412 [M+1]

[0231] b) Preparation of tert-butyl 4-(1,2-benzisothiazol-3-yl)piperidine-1-carboxylate (Compound IN-2-2) Thionyl chloride (0.081 mL) was added to a dichloromethane solution (5.0 mL) of Compound IN-2-1 (391 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Then, the reaction mixture was concentrated, and 2 mol / L ammonia-ethanol (4.75 mL) was added to a tetrahydrofuran solution (5.0 mL) of the resulting residue, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (187 mg). 1 H-NMR (400 MHz, CDCl3) δ: 1.46 (9H, s), 1.86 - 2.10 (4H, m), 2.85 - 3.04 (2H, m), 3.31 - 3.44 (1H, m), 4.15 - 4.35 (2H, m), 7.38 - 7.44 (1H, m), 7.47 - 7.53 (1H, m), 7.92 (1H, d, J = 8.0 Hz), 7.97 (1H, d, J = 8.0 Hz).

[0232] c) Preparation of 3-(piperidin-4-yl)-1,2-benzisothiazole (Reference Example 8) To a chloroform solution (5.0 mL) of Compound IN-2-2 (173 mg) was added 4 mol / L hydrochloric acid-ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 15 minutes. Then, the reaction mixture was concentrated to obtain the title compound (119 mg). LC-MS: R.T. = 1.28 min ObsMS = 219 [M+1]

[0233] Reference Example 9 6-Fluoro-3-(piperazin-1-yl)-1,2-benzisothiazole

Chemical Structure

[0234] a) Preparation of tert-butyl 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperazine-1-carboxylate (Compound IN-3-1) A mixture of 6-fluorobenzo[d]isothiazol-3(2H)-one (2.00 g), triethylamine (8.22 mL) and 1,4-dioxane (59 mL) was added with bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (6.06 g). After stirring at room temperature for 1 hour, tert-butyl piperazine-1-carboxylate (6.61 g) was added to the reaction mixture, and the mixture was stirred at 80 °C for 48 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.260 g). 1 1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 3.46 (4H, t, J = 5.0 Hz), 3.65 (4H, t, J = 5.0 Hz), 7.12 (1H, ddd, J = 8.7, 8.7, 2.3 Hz), 7.47 (1H, dd, J = 8.3, 2.3 Hz), 7.84 (1H, dd, J = 8.9, 4.8 Hz).

[0235] b) Preparation of 6-fluoro-3-(piperazin-1-yl)-1,2-benzisothiazole (Reference Example 9) Trifluoroacetic acid (6.8 mL) was added to a dichloromethane solution (6.8 mL) of compound IN-3-1 (912 mg), and the mixture was stirred at room temperature for 13 hours. Then, the reaction mixture was concentrated, saturated sodium hydrogen carbonate was added, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (639 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 3.12 (4H, t, J = 5.0 Hz), 3.50 (4H, t, J = 4.8 Hz), 7.10 (1H, ddd, J = 8.7, 8.7, 2.3 Hz), 7.46 (1H, dd, J = 8.3, 1.8 Hz), 7.85 (1H, dd, J = 8.9, 4.8 Hz).

[0236] Reference Example 10 6-Methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chem.

[0237] Reference Example 11 5-Methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one

Chem.

[0238] a) Preparation of methyl 3-(cyanomethyl)pyridine-2-carboxylate (Compound IN-4-1) To a chloroform solution (27 mL) of methyl 3-methylpicolinate (1.00 g) was added N-bromosuccinimide (1.53 g) and benzoyl peroxide (0.214 g) at room temperature. After stirring at 70 °C for 16 hours, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). To a N,N-dimethylformamide solution (3.3 mL) of the obtained product (0.304 g) was added sodium cyanide (0.0712 g) at room temperature. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.0440 g). 1 1H-NMR (400 MHz, CDCl3) δ: 4.01 (3H, s), 4.28 (2H, s), 7.55 (1H, dd, J = 7.8, 4.6 Hz), 8.01 (1H, dd, J = 7.8, 1.4 Hz), 8.73 (1H, dd, J = 4.6, 1.4 Hz).

[0239] b) Preparation of methyl 3-(1-cyanoethyl)pyridine-2-carboxylate (Compound IN-4-2) To a tetrahydrofuran solution (1.2 mL) of Compound IN-4-1 (63.0 mg) was added 55% sodium hydride (15.6 mg) under ice-cooling. After stirring at 0 °C for 30 minutes, a tetrahydrofuran solution (0.30 mL) of methyl iodide (0.0291 mL) was added dropwise. After stirring at 0 °C for 30 minutes, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (35.0 mg). 1H-NMR (400 MHz, CDCl3) δ: 1.66 (3H, d, J = 7.2 Hz), 4.00 (3H, s), 5.09 (1H, q, J = 7.2 Hz), 7.55 (1H, dd, J = 7.6, 4.4 Hz), 8.08 (1H, dd, J = 7.6, 1.2 Hz), 8.70 (1H, dd, J = 4.4, 1.2 Hz).

[0240] c) Production of 5-methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Reference Example 11) To a solution of Compound IN-4-2 (35.0 mg) in ethanol (2.17 mL) was added Raney nickel (15.8 mg) under ice-cooling. After stirring at 50 °C for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (22.3 mg). 1 H-NMR (400 MHz, CDCl3) δ: 1.32 (3H, d, J = 7.2 Hz), 3.10 - 3.21 (1H, m), 3.26 - 3.32 (1H, m), 3.60 - 3.65 (1H, m), 7.34 (1H, dd, J = 8.0, 4.8 Hz), 7.56 - 7.58 (1H, m), 7.80 (1H, br s), 8.64 (1H, dd, J = 4.6, 1.4 Hz).

[0241] Reference Example 12 1-Methyl-1,5,6,7-tetrahydro-4H-imidazo[4,5-c]pyridin-4-one

Chemical Structure

[0242] a) Production of 1-methyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (Compound IN-5-1) A mixture of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine (100 mg) and formic acid (1.40 mL) was heated under reflux for 5 hours. Thereafter, an aqueous solution of saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (127 mg). 1 1H-NMR (300 MHz, CD3OD) δ: 4.03 (3H, s), 6.91 (1H, d, J = 7.3 Hz), 7.55 (1H, d, J = 7.3 Hz), 8.07 (1H, s), 9.20 (1H, s).

[0243] b) Preparation of 1-methyl-1,5,6,7-tetrahydro-4H-imidazo[4,5-c]pyridin-4-one (Reference Example 12) A mixture of Compound IN-5-1 (0.106 g), 20% palladium hydroxide-carbon (1.25 g) and acetic acid (7.1 mL) was stirred at 70 °C for 8 hours under a hydrogen atmosphere (1 atm). Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (13.9 mg). 1 1H-NMR (300 MHz, CD3OD) δ: 3.01-2.91 (2H, m), 3.74 (3H, s), 3.66-3.57 (2H, m), 7.97 (1H, s).

[0244] Reference Example 13 2-Methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical formula

[0245] Reference Example 14 2-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical formula

[0246] Reference Example 15 1-Methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical formula

[0247] Reference Example 16 1,7-Dimethyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical Structure

[0248] Reference Example 17 1-Methyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one

Chemical Structure

[0249] a) Preparation of N-(1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-ylidene)hydroxylamine (Compound IN-6-1) A mixture of 1-methyl-6,7-dihydro-1H-indazol-4(5H)-one (855 mg), hydroxylamine hydrochloride (475 mg), sodium acetate (560 mg) and ethanol (28 mL) was stirred at 60 °C for 14 h. Then, the reaction mixture was filtered and concentrated. The concentrated residue was triturated with hexane:ethyl acetate (1:1), and then collected by filtration and dried to obtain the title compound (635 mg). 1 H-NMR (400 MHz, CDCl3) δ: 2.00 - 2.08 (2H, m), 2.48 (2H, t, J = 6.2 Hz), 2.73 (2H, t, J = 6.2 Hz), 3.81 (3H, s), 8.19 (1H, s).

[0250] b) Preparation of 1-methyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one (Reference Example 17) A mixture of compound IN-6-1 (7.86 g), triethylamine (9.95 mL) and dichloromethane (95 mL) was added with p-toluenesulfonyl chloride (10.4 g), and heated to reflux for 30 minutes. Then, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated. Ethyl acetate (18 mL) was added to the residue, heated at 80 °C, and after confirming that all the solids had dissolved, it was gradually cooled to room temperature, and hexane (18 mL) and ethyl acetate (3.0 mL) were added in sequence. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration, washed with hexane:ethyl acetate (2:3, 50 mL) and hexane (20 mL), and dried to obtain a solid (13.6 g). A mixture of the obtained solid (13.6 g) and trifluoroacetic acid (22.9 mL) was heated to reflux for 30 minutes. Then, the reaction mixture was concentrated and purified by amino silica gel column chromatography (chloroform / methanol). Ethanol (60 mL) was added to the obtained solid, stirred at 80 °C for 1 hour, gradually cooled to room temperature, stirred at 0 °C for 1 hour, and collected by filtration. The obtained solid was washed with ethanol:hexane (1:1, 10 mL) and dried to obtain the title compound (5.52 g). 1 H-NMR (400 MHz, CDCl3) δ: 2.13-2.20 (2H, m), 2.91 (2H, t, J = 6.4 Hz), 3.38 (2H, td, J = 5.0, 5.0 Hz), 3.79 (3H, s), 6.10 (1H, brs), 7.99 (1H, s).

[0251] Reference Example 18 1,3-Dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-one

Chemical Structure

[0252] Reference Example 19 6-Methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

Chemical formula

[0253] a) Preparation of methyl 4-chloro-6-methylpyridine-3-carboxylate (Compound IN-7-1) To a toluene solution (6.5 mL) of 4-hydroxy-6-methylnicotinic acid (1.00 g), N,N-dimethylformamide (0.0200 mL) was added at room temperature, and then oxalyl chloride (3.00 mL) was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Toluene (3.0 mL) was added to the residue, and then methanol (10 mL) was added at 0 °C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.20 g). 1 H-NMR (400 MHz, CDCl3) δ: 2.57 (3H, s), 3.93 (3H, s), 7.27 (1H, s), 8.92 (1H, s).

[0254] b) Preparation of methyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-methylpyridine-3-carboxylate (Compound IN-7-2) To a mixture of compound IN-7-1 (5.03 g) and toluene / water (3:1, 54 mL) was added potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (10.2 g), cesium carbonate (22.1 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane adduct (1.98 g) at room temperature. After stirring at 100 °C for 3 hours under a nitrogen atmosphere, water (55 mL) and ethyl acetate (30 mL) were added to the reaction mixture, followed by filtration through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.84 g). 1 1H-NMR (400 MHz, CDCl3) δ: 1.39 (9H, s), 2.57 (3H, s), 3.11 - 3.17 (2H, m), 3.36 - 3.42 (2H, m), 3.90 (3H, s), 7.08 (1H, s), 8.97 (1H, s).

[0255] c) Preparation of 6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one (Reference Example 19) To a solution of compound IN-7-2 (1.25 g) in ethyl acetate / methanol (1:1, 4.2 mL) was added 4 mol / L hydrochloric acid-ethyl acetate (21.2 mL, 85.0 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5.0 mL), and 28% sodium methoxide-methanol solution (3.27 g) was added at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. 2 mol / L hydrochloric acid (10.0 ml) was added to the residue, and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized by adding 1 mol / L aqueous sodium hydroxide solution and then extracted with chloroform / methanol (4:1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethanol / hexane to obtain the title compound (519 mg). 1H-NMR (400 MHz, CDCl3) δ: 2.60 (3H, s), 2.97 (2H, t, J = 6.6 Hz), 3.59 (2H, td, J = 6.6, 2.9 Hz), 6.36 (1H, s), 7.03 (1H, s), 9.08 (1H, s).

[0256] Reference Example 20 6'-Methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-1'-one

Chemical Structure

[0257] a) Preparation of methyl 6-chloro-4-(cyanomethyl)pyridine-3-carboxylate (Compound IN-8-1) To a solution of methyl 4,6-dichloronicotinate (5.00 g) in N,N-dimethylformamide (49 mL) were added potassium carbonate (6.71 g) and tert-butyl cyanoacetate (3.77 g) at room temperature. After stirring at 100 °C for 2 hours, water (100 mL) was added to the reaction mixture, followed by neutralization with 2 mol / L hydrochloric acid (35 mL), and extraction with toluene (100 mL × 4). The organic layer was washed with 0.1 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until the solvent volume reached 300 mL. p-Toluenesulfonic acid monohydrate (0.462 g) was added. After stirring at 100 °C for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.35 g). 1 H-NMR (400 MHz, CDCl3) δ: 3.97 (3H, s), 4.28 (2H, s), 7.65 (1H, s), 9.02 (1H, s).

[0258] b) Preparation of Methyl 4-(cyanomethyl)-6-methylpyridine-3-carboxylate (Compound IN-8-2) To a solution of Compound IN-8-1 (2.55 g) in 1,2-dimethoxyethane (17 mL) were added potassium carbonate (2.51 g), trimethyl boroxine (5.08 mL), and tetrakis(triphenylphosphine)palladium (1.40 g) at room temperature. After stirring at 100 °C for 2 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (465 mg). 1 H-NMR (400 MHz, CDCl3) δ: 2.66 (3H, s), 3.95 (3H, s), 4.25 (2H, s), 7.44 (1H, s), 9.11 (1H, s).

[0259] c) Preparation of Methyl 4-(1-cyanocyclopropyl)-6-methylpyridine-3-carboxylate (Compound IN-8-3) To a solution of Compound IN-8-2 (101 mg) in acetonitrile (1.8 mL) were added 1,2-dibromoethane (0.0554 mL) and potassium carbonate (220 mg) at room temperature. After stirring at 70 °C for 48 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (67.1 mg). 1 H-NMR (400 MHz, CDCl3) δ: 1.32 (2H, dd, J = 7.8, 5.5 Hz), 1.76 (2H, t, J = 3.7 Hz), 2.60 (3H, s), 3.99 (3H, s), 7.18 (1H, s), 9.05 (1H, s).

[0260] d) Preparation of 6’-Methyl-2’,3’-dihydro-1’H-spiro[cyclopropane-1,4’-[2,7]naphthyridin]-1’-one (Reference Example 20) To a solution of compound IN-8-3 (61.0 mg) in ethanol (3.3 mL) was added 50% Raney nickel - water suspension (0.17 mL) under ice - cooling. After stirring at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (35.4 mg). 1 1H - NMR (400 MHz, CDCl3) δ: 1.07 (2H, t, J = 2.9 Hz), 1.12 (2H, t, J = 2.9 Hz), 2.55 (3H, s), 3.39 (2H, d, J = 2.7 Hz), 6.59 (1H, s), 7.40 (1H, brs), 9.06 (1H, s).

[0261] Reference Example 21 4,4,6 - Trimethyl - 3,4 - dihydro - 2,7 - naphthyridin - 1(2H) - one

Chemical formula

[0262] Reference Example 22 7 - (2 - Hydroxy - 2 - methoxyethyl) - 6,7 - dihydro - 1,7 - naphthyridin - 8(5H) - one

Chemical formula

[0263] a) Preparation of 7-(prop-2-en-1-yl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Compound IN-9-1) To a solution of 6,7-dihydro-1,7-naphthyridin-8(5H)-one (1.29 g) in N,N-dimethylformamide (20 mL) was added 55% sodium hydride (0.456 g) under ice-cooling, and the mixture was stirred for 1 hour. Then, allyl iodide (0.949 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. Toluene was added to the residue and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.97 g). 1 1H-NMR (300 MHz, CDCl3) δ: 3.03 (2H, t, J = 6.6 Hz), 3.56 (2H, t, J = 6.6 Hz), 4.23 - 4.29 (2H, m), 5.20 - 5.32 (2H, m), 5.80 - 5.95 (1H, m), 7.34 (1H, dd, J = 7.7, 4.6 Hz), 7.56 (1H, d, J = 7.7 Hz), 8.71 (1H, d, J = 4.6 Hz).

[0264] b) Preparation of 7-(2-hydroxy-2-methoxyethyl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Reference Example 22) To a mixture of Compound IN-9-1 (1.69 g), tetrahydrofuran (44 mL) and water (22 mL) were added sodium periodate (4.80 g) and osmium tetroxide (0.183 g) under ice-cooling. After stirring for 6 hours under ice-cooling, the reaction mixture was filtered through Celite and washed with chloroform / methanol (4 / 1). Aqueous saturated sodium thiosulfate solution was added to the filtrate, and the mixture was extracted with chloroform / methanol (4 / 1, 50 mL × 12 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.65 g). 1H-NMR (300 MHz, CDCl3) δ: 3.02 - 3.11 (2H, m), 3.43 (3H, s), 3.68 (2H, dd, J = 13.8, 5.1 Hz), 3.75 - 3.89 (2H, m), 4.61 - 4.72 (1H, m), 4.80 - 4.88 (1H, m), 7.36 (1H, dd, J = 7.7, 4.8 Hz), 7.55 - 7.60 (1H, m), 8.68 - 8.72 (1H, m).

[0265] Reference Examples 23 to 25 According to the method described in Reference Example 22, using the corresponding starting materials, the compounds of Reference Examples 23 to 25 were obtained. [Table 15]

[0266] Reference Example 26 2-Methyl-6,7-dihydro[1,3]oxazolo[5,4-c]pyridin-4(5H)-one [Chemical formula]

[0267] a) Preparation of Ethyl 5-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate (Compound IN-10-1) 3-([(Benzyloxy)carbonyl]amino)propionic acid (10.0 g) was dissolved in tetrahydrofuran (180 mL), and carbonyl-1,1'-diimidazole (7.99 g) was added. After stirring at room temperature for 1.5 hours, potassium ethyl malonate (9.91 g) was added, and then magnesium chloride (5.54 g) was slowly added. After stirring for 15 minutes, the mixture was heated and stirred at 50 °C for 1.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (8.58 g). 11H-NMR (400 MHz, CDCl3) δ: 1.14 (3H, t, J = 7.1 Hz), 2.08 - 2.20 (2H, m), 3.22 - 3.34 (2H, m), 3.98 (2H, q, J = 6.9 Hz), 4.72 (1H, s), 5.00 (2H, s), 5.25 (1H, brs), 7.27 - 7.37 (5H, m).

[0268] b) Preparation of Ethyl 5-{[(Benzyloxy)Carbonyl]Amino}-2-Chloro-3-Oxopentanoate (Compound IN-10-2) Compound IN-10-1 (8.58 g) was dissolved in methylene chloride (150 mL), and sulfuryl chloride (2.38 mL) was added dropwise at 0 °C. After stirring at 0 °C for 2 hours, an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (9.47 g). 1 1H-NMR (400 MHz, CDCl3) δ: 1.29 (3H, t, J = 7.1 Hz), 2.96 - 3.03 (2H, m), 3.46 - 3.53 (2H, m), 4.27 (2H, q, J = 7.3 Hz), 4.77 (1H, s), 5.09 (2H, s), 5.16 (1H, brs), 7.29 - 7.43 (5H, m).

[0269] c) Preparation of Ethyl 2-(Acetyloxy)-5-{[(Benzyloxy)Carbonyl]Amino}-3-Oxopentanoate (Compound IN-10-3) Compound IN-10-2 (1.50 g) was dissolved in acetonitrile (5.0 mL), acetic acid (0.786 mL) and triethylamine (3.19 mL) were added, and the mixture was stirred at room temperature overnight. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.57 g). 1H-NMR (300 MHz, CDCl3) δ: 1.29 (3H, t, J = 7.2 Hz), 2.22 (3H, s), 2.89 - 2.97 (2H, m), 3.45 - 3.53 (2H, m), 4.26 (2H, q, J = 7.2 Hz), 5.08 (2H, s), 5.18 (1H, brs), 5.47 (1H, s), 7.30 - 7.37 (5H, m).

[0270] d) Production of ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-4) Compound IN-10-3 (9.11 g) and ammonium acetate (4.00 g) were dissolved in acetic acid (40 mL) and heated at 120 °C for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (8.74 g). 1 H-NMR (300 MHz, CDCl3) δ: 1.34 (3H, t, J = 7.0 Hz), 2.47 (3H, s), 3.02 (2H, t, J = 6.2 Hz), 3.53 (2H, td, J = 6.1, 6.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 5.06 (2H, s), 5.30 (1H, s), 7.26 - 7.36 (5H, m).

[0271] e) Production of ethyl 4-(2-aminoethyl)-2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-5) Compound IN-10-4 (3.44 g) and 5% Pd-C (2.00 g) were dissolved in ethanol (25 mL). Then, the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.78 g). 1H-NMR (400 MHz, CDCl3) δ: 1.39 (3H, t, J = 7.1 Hz), 2.22 (3H, s), 2.51 (3H, s), 2.99 (2H, dd, J = 10.1, 3.7 Hz), 3.05 - 3.08 (2H, m), 4.38 (2H, q, J = 7.2 Hz).

[0272] f) Production of 2-methyl-6,7-dihydro[1,3]oxazolo[5,4-c]pyridin-4(5H)-one (Reference Example 26) A mixture of Compound IN-10-5 (0.749 g), potassium carbonate (0.627 g), dimethoxyethane (1.0 mL) and water (1.0 mL) was stirred at room temperature for 3 days, and then the solvent was distilled off. Thereafter, the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.322 g). 1 H-NMR (400 MHz, CDCl3) δ: 2.55 (3H, s), 2.90 (2H, t, J = 7.1 Hz), 3.65 (2H, td, J = 7.1, 2.3 Hz), 5.96 (1H, s).

[0273] Reference Examples 27 to 30 According to the method described in Reference Example 26, using the corresponding starting materials, the compounds of Reference Examples 27 to 30 were obtained.

Table 16

[0274] Reference Example 31 2-methyl-6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-4(5H)-one

Chemical formula

[0275] a) Preparation of Ethyl 5-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylate (Compound IN-11-1) To a solution of 3-([(Benzyloxy)carbonyl]amino)propionic acid (5.00 g) in tetrahydrofuran (50 mL) was added carbonyl-1,1’-diimidazole (4.00 g) at room temperature. After stirring at room temperature for 1.5 hours, triethylamine (4.06 mL) and ethyl isocyanoacetate (3.20 mL) were added. After stirring at 65 °C for 24 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.99 g). 1 H-NMR (400 MHz, CDCl3) δ: 1.36 (3H, t, J = 7.1 Hz), 3.27 (2H, t, J = 6.4 Hz), 3.53 (2H, dd, J = 6.4, 6.4 Hz), 4.35 (2H, q, J = 7.1 Hz), 5.00 (1H, brs), 5.05 (2H, s), 7.29 - 7.33 (5H, m), 7.74 (1H, s).

[0276] b) Preparation of Ethyl 5-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-2-iodo-1,3-oxazole-4-carboxylate (Compound IN-11-2) To a solution of compound IN-11-1 (446 mg) in tetrahydrofuran (2.1 mL) was added a 1.0 mol / L solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (3.08 mL) at -40 °C. After stirring at -40 °C for 15 minutes, a 0.5 mol / L solution of zinc chloride in tetrahydrofuran (6.17 mL) was added, and the temperature was raised to 0 °C over 45 minutes, followed by the addition of iodine (462 mg). After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (510 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, t, J = 7.1 Hz), 3.27 (2H, t, J = 6.4 Hz), 3.52 (2H, dd, J = 6.4, 6.4 Hz), 4.34 (2H, q, J = 7.1 Hz), 5.00 (1H, brs), 5.07 (2H, s), 7.32 (5H, dd, J = 10.1, 8.3 Hz).

[0277] c) Preparation of ethyl 5-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-1,3-oxazole-4-carboxylate (Compound IN-11-3) To a solution of compound IN-11-2 (265 mg) in N,N-dimethylformamide (1.5 mL) were added potassium carbonate (247 mg), trimethylboroxine (97.0 mg), and tetrakis(triphenylphosphine)palladium (68.9 mg) at room temperature. The reaction was carried out at 120 °C for 1.5 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (100 mg). 1H-NMR (400 MHz, CDCl3) δ: 1.30 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 3.16 (2H, t, J = 6.6 Hz), 3.46 (2H, dd, J = 6.3, 6.3 Hz), 4.28 (2H, q, J = 7.2 Hz), 5.01 (2H, s), 5.00 - 5.03 (1H, br s) 7.27 - 7.35 (5H, m).

[0278] d) Preparation of 2-methyl-6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-4(5H)-one (Reference Example 31) To a solution of Compound IN-11-3 (710 mg) in ethanol (11 mL) was added palladium carbon (227 mg) at room temperature. After stirring at room temperature for 15 h under a hydrogen atmosphere, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To a 1,2-dimethoxyethane / aqueous solution (1 / 1, 1.9 mL) of the obtained residue (423 mg) was added potassium carbonate (384 mg) at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (209 mg). 1 H-NMR (400 MHz, CDCl3) δ: 2.48 (3H, s), 2.99 (2H, t, J = 7.1 Hz), 3.64 (2H, td, J = 7.1, 2.5 Hz), 5.40 (1H, brs).

[0279] Reference Example 32 2-methyl-5,6,7,8-tetrahydro-4H-[1,3]oxazolo[4,5-c]azepin-4-one

Chemical Structure

[0280] Reference Example 33 1-Methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8(1H)-one

Chemical Structure

[0281] a) Preparation of methyl 4-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-methyl-1H-pyrazole-5-carboxylate (Compound IN-12-1) To a solution of methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate (600 mg) in N,N-dimethylformamide (5.0 mL) were added benzyl prop-2-yn-1-ylcarbamate (640 mg), triethylamine (2.20 mL), bis(triphenylphosphine)palladium(II) dichloride (158 mg), and copper(I) iodide (43.0 mg). The mixture was stirred at 90 °C for 3 hours. Then, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate / toluene (1 / 1). After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (610 mg). 1 H-NMR (300 MHz, CDCl3) δ: 3.89 (3H, s), 4.15 (3H, s), 4.24 (2H, d, J = 5.3 Hz), 4.99 (1H, brs), 5.15 (2H, s), 7.29 - 7.43 (5H, m), 7.54 (1H, s).

[0282] b) Production of 1-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8(1H)-one (Reference Example 33) To a methanol solution (10 mL) of Compound IN-12-1 (610 mg) was added 10% palladium-carbon (600 mg), and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) for 6 hours. The reaction mixture was filtered through Celite and concentrated. Triethylamine (0.519 mL) was added to an ethanol solution (10 mL) of the obtained residue, and the mixture was heated under reflux for 140 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (130 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 1.99 - 2.07 (2H, m), 2.86 (2H, t, J = 7.1 Hz), 3.28 - 3.34 (2H, m), 4.14 (3H, s), 5.93 (1H, brs), 7.31 (1H, s).

[0283] Reference Example 34 2-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8(2H)-one

Chemical formula

[0284] Reference Example 35 3-methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepin-4(3H)-one

Chemical formula

[0285] a) Preparation of methyl 4-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-methyl-1H-imidazole-5-carboxylate (Compound IN-13-1) A mixture of methyl 4-imidazolecarboxylate (375 mg), N-bromosuccinimide (529 mg) and acetonitrile (15 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). To a solution of the obtained purified product (0.267 g) in N,N-dimethylformamide (6.5 mL) was added 55% sodium hydride (0.0680 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, iodomethane (0.277 g) was added, and the mixture was stirred at room temperature for 4 hours. Methanol was added to the reaction mixture, followed by concentration, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol). A mixture of the obtained purified product (176 mg), N-(tert-butoxycarbonyl)propargylamine (228 mg), copper(I) iodide (15.3 mg), triethylamine (0.569 g), bis(triphenylphosphine)palladium(II) dichloride (56.4 mg) and N,N-dimethylformamide (15 mL) was irradiated with microwave and stirred at 100 °C for 1.5 hours. Then, the reaction mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (101 mg). 1 H-NMR (400 MHz, CDCl3) δ: 3.79 - 3.91 (5H, m), 4.27 (2H, d, J = 5.1 Hz), 5.13 (3H, s), 7.28 - 7.42 (5H, m), 7.49 - 7.61 (1H, m).

[0286] b) Preparation of 3-methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepin-4(3H)-one (Reference Example 35) A mixture of compound IN-13-1 (101 mg), 20% palladium hydroxide-carbon (0.173 g) and methanol (1.7 mL) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. Then, the reaction mixture was filtered and concentrated. The obtained residue (60.9 mg), a mixture of triethylamine (125 mg) and ethanol (1.6 mL) was stirred at 100 °C for 72 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (6.6 mg). 1 1H-NMR (400 MHz, CD3OD) δ: 1.97 - 2.08 (2H, m), 2.91 - 3.00 (2H, m), 3.26 - 3.36 (2H, m), 3.87 (3H, s), 7.71 (1H, s).

[0287] Reference Example 36 1-Methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Chemical Structure

[0288] Reference Example 37 1,7-Dimethyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Chem.

[0289] Reference Example 38 2,3-Dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chem.

[0290] Reference Examples 39 and 40 3-Bromo-1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 39) 3-Bromo-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 40)

Chemical Formula

[0291] a) Preparation of 3-bromo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound IN-14-1) Bromine (0.451 mL) was added to a mixture of 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (600 mg), sodium acetate (1.44 g), ethanol (21 mL) and water (14 mL) under ice-cooling. After stirring for 2 hours under ice-cooling, sodium acetate (1.44 g) and bromine (0.451 mL) were further added. After further stirring for 2 hours under ice-cooling, an aqueous solution of saturated sodium thiosulfate was added to the reaction mixture, filtered through celite, and concentrated under reduced pressure. The residue was dissolved in methanol, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.02 g). 1 1H-NMR (400 MHz, CD3OD) δ: 2.96 (2H, t, J = 6.9 Hz), 3.54 (2H, t, J = 6.9 Hz).

[0292] b) Preparation of 3-bromo-1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 39) and 3-bromo-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 40) To a solution of compound IN-14-1 (1.02 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (1.31 g) and methyl iodide (0.354 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Reference Example 39 (341 mg) and Reference Example 40 (205 mg). Reference Example 39: 1 H-NMR (400 MHz, DMSO-D6) δ: 2.88 (2H, t, J = 6.9 Hz), 3.37 (2H, td, J = 6.9, 2.6 Hz), 3.73 (3H, s), 7.34 (1H, brs). Reference Example 40: 1 H-NMR (400 MHz, DMSO-D6) δ: 2.73 (2H, t, J = 6.6 Hz), 3.34 (2H, td, J = 6.6, 3.1 Hz), 3.78 (3H, s), 7.47 (1H, brs).

[0293] Reference Example 41 2-Methyl-3-(trifluoromethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chemical formula

[0294] Reference Example 42 2-Methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

Chemical formula

[0295] a) Preparation of (3E)-3-[(dimethylamino)methylene]piperidine-2,4-dione (Compound IN-15-1) To a solution of piperidine-2,4-dione (2.50 g) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamide dimethylacetal (3.52 mL), and the mixture was stirred at 90 °C for 4 hours. Then, the reaction mixture was concentrated to obtain the title compound (3.72 g). 1 1H-NMR (400 MHz, DMSO-D6) δ: 2.28 (2H, t, J = 6.5 Hz), 3.05 (3H, s), 3.12 - 3.18 (2H, m), 3.28 (3H, s), 7.12 (1H, brs), 7.82 (1H, s).

[0296] b) Preparation of 2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (Reference Example 42) A mixture of compound IN-15-1 (150 mg), N,N-diisopropylethylamine (300 mg), acetamidine monohydrate (101 mg) and ethanol (4.5 mL) was stirred at 100 °C for 2 hours. Then, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (87.9 mg). 1H-NMR (400 MHz, CDCl3) δ: 2.78 (3H, s), 3.13 (2H, t, J = 6.6 Hz), 3.68 (2H, td, J = 6.6, 2.8 Hz), 5.97 (1H, s), 9.15 (1H, s).

[0297] Reference Examples 43 to 44 According to the method described in Reference Example 42, using the corresponding reagents, the compounds of Reference Examples 43 to 44 were obtained.

Table 17

[0298] Reference Example 45 2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethane-1-amine dihydrochloride

Chemical formula

[0299] a) Preparation of tert-butyl {2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}carbamate (Compound IN-16-1) To a mixture of 3-(piperidin-4-yl)benzo[d]isoxazole (3.00 g), tetrahydrofuran (56 mL) and water (18 mL), tert-butyl (2-bromoethyl)carbamate (6.65 g), tetrabutylammonium bromide (0.956 g) and potassium carbonate (10.3 g) were added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (5.70 g). 1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 2.05 - 2.13 (4H, m), 2.13 - 2.25 (2H, m), 2.52 (2H, t, J = 6.0 Hz), 3.00 - 3.16 (3H, m), 3.21 - 3.33 (2H, m), 5.05 (1H, brs), 7.28 - 7.33 (1H, m), 7.51 - 7.60 (2H, m), 7.75 (1H, d, J = 7.8 Hz).

[0300] b) Preparation of 2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethane-1-amine dihydrochloride (Reference Example 45) The title compound was obtained from Compound IN-16-1 by the same method as in the preparation of Reference Example 8. 1 H-NMR (400 MHz, DMSO-D6) δ: 2.16 - 2.32 (2H, m), 2.33 - 2.46 (2H, m), 3.15 - 3.29 (1H, m), 3.30 - 3.44 (4H, m), 3.45 - 3.59 (2H, m), 3.63 - 3.78 (2H, m), 7.41 (1H, dd, J = 7.4, 7.4 Hz), 7.66 (1H, dd, J = 7.7, 7.7 Hz), 7.75 (1H, d, J = 8.5 Hz), 8.14 (1H, d, J = 8.0 Hz), 8.46 (3H, brs), 11.35 (1H, brs).

[0301] Reference Example 46 Methyl 1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxylate

Chemical Structure

[0302] a) Preparation of methyl 4-[(Z)-2-ethoxyethenyl]-1-methyl-1H-pyrazole-5-carboxylate (Compound IN-17-1) The title compound was obtained from methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate by the same method as for the production of compound IN-12-1. 1 H-NMR (400 MHz, CDCl3) δ: 1.36 (3H, t, J = 7.1 Hz), 3.91 (3H, s), 3.99 (2H, q, J = 7.1 Hz), 4.13 (3H, s), 5.79 (1H, d, J = 6.6 Hz), 6.24 (1H, d, J = 6.8 Hz), 8.02 (1H, s).

[0303] b) Production of methyl 1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxylate (Reference Example 46) To a solution of compound IN-17-1 (95.8 mg) in tetrahydrofuran (1.1 mL) was added 1 mol / L hydrochloric acid (1.1 mL) under ice-cooling, and the mixture was stirred at 40 °C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (79.2 mg). 1 H-NMR (400 MHz, CDCl3) δ: 3.78 (2H, d, J = 1.4 Hz), 3.88 (3H, s), 4.19 (3H, s), 7.42 (1H, s), 9.68 (1H, t, J = 1.6 Hz).

[0304] Reference Example 47 1-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}azepane-2,4-dione

Chemical formula

[0305] a) Production of 1,4-dioxa-8-azaspiro[4.6]undecan-7-one (Compound IN-18-1) To a toluene solution (15 mL) of azepane-2,4-dione (1.07 g) were added ethan-1,2-diol (0.570 mL) and methanesulfonic acid (0.0270 mL), and the mixture was heated under reflux for 4 hours using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, hexane (15 mL) was added, and after stirring at room temperature for 30 minutes, the precipitated solid was collected by filtration and washed with toluene / hexane = 1 / 1 (2.0 mL) to obtain the title compound (1.37 g). 1 1H-NMR (400 MHz, CDCl3) δ: 1.82-1.90 (2H, m), 1.93-1.99 (2H, m), 2.83 (2H, s), 3.24-3.31 (2H, m), 3.93-4.11 (4H, m), 5.95 (1H, brs).

[0306] b) Preparation of 1-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}azepane-2,4-dione (Reference Example 47) To a N,N-dimethylformamide solution (4.4 mL) of compound IN-18-1 (375 mg) was added 55% sodium hydride (96.0 mg) under ice-cooling. After stirring for 20 minutes under ice-cooling, the compound of Reference Example 3 (580 mg) and potassium iodide (109 mg) were added, and the mixture was stirred at 50 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. In order to distill off the remaining N,N-dimethylformamide, the residue was concentrated by adding toluene twice. Tetrahydrofuran (7.3 mL) and 6 mol / L hydrochloric acid (7.30 mL) were added to the obtained concentrated residue, and the mixture was stirred at 60 °C for 1 hour. Then, 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to 7 or higher, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (630 mg). 1H-NMR (400 MHz, CDCl3) δ: 1.96 - 2.15 (6H, m), 2.17 - 2.29 (2H, m), 2.54 - 2.63 (2H, m), 2.67 (2H, t, J = 7.3 Hz), 3.02 - 3.14 (3H, m), 3.55 (2H, s), 3.62 (4H, t, J = 5.8 Hz), 7.25 - 7.30 (1H, m), 7.48 - 7.57 (2H, m), 7.70 (1H, d, J = 7.9 Hz).

[0307] Reference Example 48 8-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1,4-dioxa-8-azaspiro[4.5]decan-7-one

Chem.

[0308] Reference Example 49 1-{2-[4-(1,2-Benzisoxazol-3-yl)piperazin-1-yl]ethyl}azepane-2,4-dione

Chem.

[0309] Reference Example 50 Methyl 4-[2-({2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}amino)ethyl]-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3-carboxylate

Chemical formula

[0310] a) Preparation of methyl 4-iodo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3-carboxylate (Compound IN-19-1) A mixture of methyl 4-iodo-1H-pyrazole-5-carboxylate (413 mg) and acetonitrile (8.2 mL) was added with potassium carbonate (339 mg) and 4-methoxybenzyl chloride (0.268 mL), and the mixture was stirred at 50 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (467 mg). 1 H-NMR (400 MHz, CDCl3) δ: 3.81 (3H, s), 3.95 (3H, s), 5.30 (2H, s), 6.90 (2H, d, J = 9.2 Hz), 7.22 (2H, d, J = 8.7 Hz), 7.38 (1H, s).

[0311] b) Preparation of methyl 1-[(4-methoxyphenyl)methyl]-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (Compound IN-19-2) The title compound was obtained from Compound IN-19-1 by the same method as in Reference Example 46. 1 H-NMR (400 MHz, CDCl3) δ: 3.81 (3H, s), 3.86 (2H, d, J = 0.9 Hz), 3.93 (3H, s), 5.30 (2H, s), 6.89 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.33 (1H, s), 9.72 (1H, t, J = 1.4 Hz).

[0312] c) Preparation of methyl 4-[2-({2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}amino)ethyl]-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3-carboxylate (Reference Example 50) To a dichloromethane solution (1.7 mL) of the compound of Reference Example 45 (105 mg) was added N,N-diisopropylethylamine (0.144 mL), and the mixture was stirred at room temperature for 5 minutes. Then, compound IN-19-2 (47.6 mg) and acetic acid (0.0283 mL) were added, and after stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (70.0 mg) was added, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (26.2 mg). 1 1H-NMR (400 MHz, CDCl3) δ: 1.99 - 2.23 (6H, m), 2.52 (2H, t, J = 6.2 Hz), 2.75 (2H, t, J = 10.0 Hz), 2.84 (2H, t, J = 6.9 Hz), 2.93 (2H, t, J = 6.6 Hz), 2.98 - 3.12 (3H, m), 3.79 (3H, s), 3.92 (3H, s), 5.27 (2H, s), 6.87 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 7.8 Hz), 7.27 - 7.32 (1H, m), 7.50 - 7.59 (3H, m), 7.75 (1H, d, J = 8.3 Hz).

[0313] Reference Example 51 Methyl 4-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-5-carboxylate

Chemical Structure

[0314] Reference Example 52 [4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]acetaldehyde

Chemical formula

[0315] a) Preparation of 3-[4-(2,2-diethoxyethyl)piperazin-1-yl]-1,2-benzisothiazole (Compound IN-20-1) To a solution of 3-(piperazin-1-yl)benzo[d]isothiazole (2.00 g) in acetonitrile (9.1 mL) were added 2-bromo-1,1-diethoxyethane (2.16 g), potassium carbonate (2.52 g) and potassium iodide (0.151 g). After heating under reflux for 13 hours, ethyl acetate (30 mL) was added to the reaction mixture, which was then filtered and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.04 g). 1 H-NMR (400 MHz, CDCl3) δ: 1.22 (6H, t, J = 6.9 Hz), 2.63 (2H, d, J = 5.0 Hz), 2.77 (4H, t, J = 4.8 Hz), 3.50 - 3.61 (6H, m), 3.65 - 3.74 (2H, m), 4.69 (1H, t, J = 5.3 Hz), 7.30 - 7.35 (1H, m), 7.42 - 7.47 (1H, m), 7.79 (1H, d, J = 7.8 Hz), 7.89 (1H, d, J = 8.3 Hz).

[0316] b) Preparation of [4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]acetaldehyde (Reference Example 52) To compound IN-20-1 (3.04 g) was added 47% hydrobromic acid (15.0 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was poured into ice water (40 mL), 20% aqueous sodium hydroxide solution (27 mL) was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (2.48 g). 11H-NMR (400 MHz, CDCl3) δ: 2.77 (4H, t, J = 5.0 Hz), 3.27 (2H, d, J = 1.4 Hz), 3.61 (4H, t, J = 5.0 Hz), 7.32 - 7.37 (1H, m), 7.43 - 7.48 (1H, m), 7.80 (1H, d, J = 8.3 Hz), 7.87 (1H, d, J = 8.3 Hz), 9.75 (1H, t, J = 1.4 Hz).

[0317] Reference Example 53 Methyl 4-(2-aminoethyl)-6-(trifluoromethyl)pyridine-3-carboxylate monohydrochloride [Chemical formula]

[0318] a) Preparation of methyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)pyridine-3-carboxylate (Compound IN-21-1) Using a method similar to the preparation of Compound IN-7-2, the title compound was obtained from methyl 4-iodo-6-trifluoromethylpyridine-3-carboxylate. LC-MS: R.T. = 1.693 min ObsMS = 249 [M+1]

[0319] b) Preparation of methyl 4-(2-aminoethyl)-6-(trifluoromethyl)pyridine-3-carboxylate monohydrochloride (Reference Example 53) To a mixture of Compound IN-21-1 (1.13 g), ethyl acetate (3.0 mL) and methanol (6.0 mL) was added 4 mol / L hydrochloric acid-ethyl acetate (20 mL), and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to obtain the title compound (0.942 g). LC-MS: R.T. = 1.002 min ObsMS = 249 [M+1]

[0320] Reference Example 54 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-(triphenylmethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

Chem.

[0321] a) Preparation of 2-(triphenylmethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound IN-22-1) To a solution of 6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (0.500 g) in N,N-dimethylformamide (7.0 mL) were added triethylamine (0.762 mL) and trityl chloride (1.02 g). After stirring at room temperature for 18 hours, water and hexane were added to the reaction mixture, and the precipitated solid was collected by filtration to obtain the title compound (0.796 g). 1 1H-NMR (400 MHz, DMSO-D6) δ: 2.77 (2H, t, J = 6.6 Hz), 3.36 - 3.41 (2H, m), 7.03 - 7.09 (6H, m), 7.33 - 7.41 (9H, m), 7.46 - 7.50 (2H, m).

[0322] b) Preparation of 5-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-(triphenylmethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 54) The title compound was obtained from the compound of Reference Example 3 and Compound IN-21-1 in the same manner as in Example 3. 1H-NMR (400 MHz, DMSO-D6) δ: 1.76 - 1.88 (2H, m), 1.98 - 2.05 (2H, m), 2.12 - 2.21 (2H, m), 2.50 - 2.54 (2H, m), 2.87 (2H, t, J = 6.6 Hz), 2.99 - 3.06 (2H, m), 3.08 - 3.18 (1H, m), 3.52 (2H, t, J = 6.8 Hz), 3.65 (2H, t, J = 6.8 Hz), 7.04 - 7.10 (6H, m), 7.32 - 7.41 (10H, m), 7.49 (1H, s), 7.59 - 7.64 (1H, m), 7.70 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 7.8 Hz).

[0323] Test Example 1: Human-type 5-HT 1A Receptor, Human-type 5-HT 2A Receptor and Human-type D 2 Binding activity evaluation for receptors The human type 5-HT of the compound of the present invention 1A receptor, human type 5-HT 2A The binding affinities for the receptor and the human type D2 receptor were measured by the following method. Human type 5-HT 1A receptor, human type 5-HT 2A The CHO cell membrane fractions expressing the receptor, human type 5-HT receptor and human type D2 receptor were purchased from PerkinElmer. In the binding evaluation test, the test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and for the 5-HT 1A receptor, [3H]8-OH-DPAT, 5-HT 2AFor the receptor, [3H]Ketanserin was mixed with [3H]Spiperone (both manufactured by PerkinElmer) for the D2 receptor, and after incubating for 60 minutes at room temperature respectively, they were quickly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.3% polyethyleneimine solution and suction filtered. The radioactivity remaining on the filter was measured using a liquid scintillation counter (manufactured by PerkinElmer). The binding inhibition rate was calculated according to the following formula.

[0324] 5-HT 1A Binding inhibition rate for the receptor (%) = 100 - 100 × {([3H]8-OH-DPAT binding amount in the presence of the test substance) - ([3H]8-OH-DPAT binding amount in the presence of 10 μmol / L 8-OH-DPAT)} / {([3H]8-OH-DPAT binding amount in the absence of the test substance) - ([3H]8-OH-DPAT binding amount in the presence of 10 μmol / L 8-OH-DPAT)} 3 H]8-OH-DPAT binding amount)}-(10 μmol / L 8-OH-DPAT presence of 3 H]8-OH-DPAT binding amount)} / {(test substance absence of 3 H]8-OH-DPAT binding amount)}-(10 μmol / L 8-OH-DPAT presence of 3 H]8-OH-DPAT binding amount)}

[0325] 5-HT 2A Binding inhibition rate for the receptor (%) = 100 - 100 × {([3H]Ketanserin binding amount in the presence of the test substance) - ([3H]Ketanserin binding amount in the presence of 10 μmol / L Mianserin)} / {([3H]Ketanserin binding amount in the absence of the test substance) - ([3H]Ketanserin binding amount in the presence of 10 μmol / L Mianserin)} 3 H]Ketanserin binding amount)}-(10 μmol / L Mianserin presence of 3 H]Ketanserin binding amount)} / {(test substance absence of 3 H]Ketanserin binding amount)}-(10 μmol / L Mianserin presence of 3 H]Ketanserin binding amount)}

[0326] Binding inhibition rate for the D2 receptor (%) = 100 - 100 × {([3H]Spiperone binding amount in the presence of the test substance) - ([3H]Spiperone binding amount in the presence of 10 μmol / L Spiperone)} / {([3H]Spiperone binding amount in the absence of the test substance) - ([3H]Spiperone binding amount in the presence of 10 μmol / L Spiperone)} 3 H]Spiperone binding amount)}-(10 μmol / L Spiperone presence of 3 H]Spiperone binding amount)} / {(test substance absence of 3H]Spiperone binding amount)}-(in the presence of 10 μmol / L Spiperone 3 H]Spiperone binding amount)}

[0327] IC 50 values were calculated by Hill analysis (Physiology, 1910, 40, 190 - 200). Also, the Ki of each compound was calculated by the following formula. Binding inhibition constant (Ki)=IC 50 / (1 + S / Kd) Here, S represents the concentration of the added ligand. The Kd value represents the binding dissociation constant of the ligand to the membrane and was the value calculated from a saturation binding experiment separately performed using the same cell membrane. The smaller the Ki value, the stronger the binding to the receptor.

Table 18 - 1

Table 18 - 2

Table 18 - 3

Table 18 - 4

Table 18 - 5

Table 18 - 6

[0328] Test Example 2: Agonist activity evaluation for human-type 5-HT 1A Receptor A CHO membrane fraction expressing the same human 5 - HT 1A receptor as used in Test Example 1 was purchased. The test compound dissolved in DMSO, various receptor membrane specimens diluted with buffer, and 35S] Guanosine 5’-O-[gamma-thio]triphosphate (GTPγS) was mixed and incubated at room temperature for 60 minutes, and then quickly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) and suction filtered. The radioactivity bound to the receptor was measured using a liquid scintillation counter. The agonist activity was calculated by the following formula.

[0329] 5-HT 1A Agonist activity (%) for the receptor = 100 × {( 35 S] GTPγS binding amount in the presence of the test substance) - ( 35 S] GTPγS binding amount in the presence of 20 μmol / L GTPγS)} / {( 35 S] GTPγS binding amount in the presence of 100 μmol / L 5-HT) - ( 35 S] GTPγS binding amount in the presence of 20 μmol / L GTPγS)} Here, the agonist activity in the presence of 10 μM of each compound was defined as the maximum activity (E max ) of each compound, and the concentration showing half of the activity of E max was calculated as EC 50 .

Table 19-1

Table 19-2

Table 20-1

Table 20-2

[0330] Test Example 3: Antagonist activity evaluation for human-type 5-HT 2A Receptor After transiently expressing apoaequorin, Gα16 protein, and each receptor in CHO-K1 cells (Chinese hamster ovary) and culturing them at 37°C in a CO2 incubator overnight, they were seeded in a 384-well plate and allowed to stand at room temperature for 2 hours or more. Various compounds dissolved in DMSO were added, and the change in luminescence was measured using an FDSS / μCELL drug discovery screening support system (manufactured by Hamamatsu Photonics). The antagonist activity was calculated by the following formula.

[0331] Antagonist activity (%) = { (luminescence of the well in the presence of 1 nmol / L 5-HT - luminescence of the well with solvent added) - (luminescence of the well in the presence of the test substance and 1 nmol / L 5-HT - luminescence of the well with solvent added)} / (luminescence of the well in the presence of 1 nmol / L 5-HT - luminescence of the well with solvent added) Here, the concentration of the test substance at which the antagonist activity reaches 50% was calculated as IC 50 and the results are shown in the table below.

Table 21-1

Table 21-2

Table 22-1

Table 22-2

[0332] Test Example 4: Human liver microsome metabolism stability test The human liver microsomal metabolic stability of the compounds of the present invention was evaluated by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and the test substance were mixed in 25 mmol / L phosphate buffer (pH 7.4) to the following concentrations and incubated at 37°C for 30 minutes. · Human liver microsomes: 0.1 mg / mL · NAPDH: 3.2 mmol / L, · Test substance: 0.1 μmol / L The residual rate of the test substance in the sample after 30 minutes was measured by LC-MS, and the human liver microsomal metabolic stability was calculated from the following formula. Human liver microsomal metabolic stability (mL / min / mg protein) = -LN(residual rate) / 30 / 0.1 The results are shown in the following table.

Table 23-1

Table 23-2

Table 24-1

Table 24-2

[0333] Test Example 5: Human half-life prediction test The elimination half-life of the compound of the present invention in humans was predicted by the following method. The compound of the present invention was intravenously administered to cynomolgus monkeys in an aqueous solution of 0.01 mol / L hydrochloric acid, and blood was collected at 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, the drug concentration in the plasma was measured by LC-MS, and the monkey distribution volume was calculated from this concentration change. The unbound fraction in the sera of humans and monkeys of the compound of the present invention was measured using the equilibrium dialysis method. The half-life in humans was calculated by applying the monkey distribution volume, the unbound fractions in the sera of humans and monkeys, and the results of the human liver microsomal metabolic stability obtained in Test Example 3 to the following formula. · Human distribution volume = monkey distribution volume × unbound fraction in human serum / unbound fraction in monkey serum · Human liver clearance = (human liver blood flow × unbound fraction in human serum × 56.7 × human liver microsomal metabolic stability) / (human liver blood flow + unbound fraction in human serum × 56.7 × human liver microsomal metabolic stability) · Human half-life = 0.693 × Human volume of distribution / Human hepatic clearance The results are shown in the following table.

Table 25

[0334] Test Example 6-1: Evaluation of hERG channel inhibition activity The hERG channel inhibitory effect of the compound of the present invention was measured by the whole-cell patch-clamp method using an automated patch-clamp system with CHO cells that forcibly express the hERG channel involved in the human rapidly activating delayed rectifier potassium current (I Kr Kr ). (Preparation of cell suspension) hERG-CHO cells purchased from ChanTest were cultured at 37°C in a CO2 incubator, detached from the flask using trypsin immediately before measuring the hERG current, and a cell suspension was prepared. (Solution preparation) The extracellular fluid and intracellular fluid used for the measurement were prepared as follows. Extracellular fluid: 2 mmol / L CaCl2, 1 mmol / L MgCl2, 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose Intracellular fluid: 5.4 mmol / L CaCl2, 1.8 mmol / L MgCl2, 10 mmol / L HEPES, 31 mmol / L KOH, 10 mmol / L EGTA, 120 mmol / L KCl, 4 mmol / L Na2-ATP 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. Further, the test substance solution was diluted 200-fold with extracellular fluid, and by serially diluting it with extracellular fluid, test substance solutions at each concentration required for calculating the hERG inhibition IC 50 value were prepared and applied. (Measurement of current value and data analysis) An auto patch clamp system was installed with a cell suspension, extracellular fluid, intracellular fluid, and a measurement plate, and hERG current measurement was performed by the whole cell patch clamp method. The voltage protocol was set with a holding potential of -80 mV. After applying a depolarizing pulse from -50 mV to +20 mV for 5 seconds, a repolarizing pulse was applied at -50 mV for 5 seconds, and then the potential was returned to the holding potential. The interval between each pulse was 15 seconds. For data analysis, Assay software for the Qpatch system (manufactured by Biolin Scientific) was used. Four concentrations were applied incrementally for each test substance, and the average value of the maximum outward current (Tail peak current) obtained from the last three stimulations at each applied concentration was used as the evaluation data. Also, from the inhibition rate of the current at each concentration of each test substance relative to the pre-application value, the IC 50 value was calculated using the Hill equation with this software. The results are shown in the following table.

Table 26-1

Table 26-2

Table 26-3

Table 26-4

Table 26-5

[0335] Test Example 6-2: Evaluation of hERG channel inhibition activity The inhibitory effect of the compound of the present invention on the hERG channel was measured by the whole cell patch clamp method using an auto patch clamp system with CHO cells that forcibly express the hERG channel involved in human rapidly activating delayed rectifier potassium current (I Kr ). (Preparation of cell suspension) The hERG-CHO cells purchased from ChanTest were cultured at 37°C in a CO2 incubator. Immediately before measuring the hERG current, the cells were detached from the flask using trypsin to prepare a cell suspension. (Solution Preparation) The extracellular fluid and intracellular fluid used for the measurement were prepared as follows. Extracellular fluid: 2 mmol / L CaCl2, 1 mmol / L MgCl2, 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose Intracellular fluid: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF Test substance solution: The test substance was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test substance solution. Further, the test substance solution was diluted 200-fold with extracellular fluid, and by serially diluting it with extracellular fluid, test substance solutions at each concentration required for calculating the hERG inhibition IC 50 values were prepared and applied. (Measurement of Current Values and Data Analysis) A cell suspension, extracellular fluid, intracellular fluid, and a measurement plate were set up in an automated patch clamp system, and hERG current measurement was performed using the whole cell patch clamp method. The voltage protocol was set with a holding potential of -80 mV. After applying a depolarizing pulse from -50 mV to +20 mV for 5 seconds, a repolarizing pulse was applied at -50 mV for 5 seconds, and then returned to the holding potential. The interval between each pulse was 15 seconds. For data analysis, analysis software for Qube (manufactured by Sophion Sophion) was used. Four concentrations were applied incrementally for each test substance, and the average value of the maximum outward current (Tail peak current) obtained from the last three stimulations at each applied concentration was used as the evaluation data. Also, from the inhibition rate of the current at each concentration of each test substance with respect to the pre-application value, the IC 50 value was calculated using the Hill equation with the software. The results are shown in the following table.

Table 27

[0336] Test Example 7: MK-801-induced hyperkinesia inhibition test Seven-week-old male SD rats were used. A 0.5% methylcellulose solution was used as a solvent for preparing the test compound administration solution, which was used after being turbid. For preparing the MK-801 administration solution, physiological saline was used as a solvent and was used after being dissolved. The MK-801-induced hyperkinesia inhibition test was carried out as follows by using Supermax manufactured by Muromachi Kikai Co., Ltd., the data recording program CompACT AMS, and a transparent plastic cage. Animals were placed in the above-mentioned cage, and the measurement of the amount of movement was started. Forty-five minutes later, the rats were gently taken out of the cage together with the cage, and the compound administration solution (solvent or test compound turbid solution) and the MK-801 administration solution (solvent or MK-801 solution) were orally administered and subcutaneously administered respectively, and the cage was returned to the measurement position. The measurement was terminated 2 hours and 30 minutes after the start of the measurement of the amount of movement. The data for 90 minutes from 1 hour after the start of the measurement of the amount of movement (15 minutes after the administration of the compound and MK-801) to 2 hours and 30 minutes were used as the test results, and the total amount of movement of each individual for 90 minutes was calculated. The analysis of the test results was carried out as follows. In the test compound administration group and the solvent administration group, parametric Dunnett-type multiple comparisons (significance level: 5% two-sided) were performed. In the test compound administration group, when it showed significant suppression of the amount of movement compared with the solvent administration group, it was judged to have an antipsychotic effect. The results of the above test are shown in FIGS. 1 and 2.

[0337] Test Example 8: Binding activity evaluation for side-effect related receptors The binding affinity of the compound of the present invention for side effect-related receptors (for example, adrenergic α receptor, histamine receptor, muscarinic receptor, etc.) can be measured by the following method. Using the CHO cell membrane fraction expressing the human-type target receptor, a binding evaluation test is carried out as follows. A test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with a buffer, and a [3H] labeled ligand having strong binding activity to each target receptor are mixed and incubated at room temperature respectively, and then quickly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore Corporation) and filtered under reduced pressure. The radioactivity remaining on the filter is measured using a liquid scintillation counter (manufactured by PerkinElmer). The binding inhibition rate is calculated by the following formula. For calculating the non-specific binding amount to the receptor membrane specimen, a control compound having strong binding activity to the target receptor is used instead of the test substance.

[0338] Binding inhibition rate (%) to the target receptor = 100 - 100 × {( 3 H] labeled ligand binding amount in the presence of the test substance)} - ( 3 H] labeled ligand binding amount in the presence of 10 μmol / L control compound)} / {( 3 H] labeled ligand binding amount in the absence of the test substance)} - ( 3 H] labeled ligand binding amount in the presence of 10 μmol / L control compound)}

[0339] Test Example 9: P-gp substrate property evaluation The NFR (Net Flux Ratio), which is an index of P-gp substrate property, can be calculated by the following method. Using MDCKII (Madin-Darby canine kidney strain II) cells and MDR1-MDCKII cells overexpressing MDR1 (multidrug resistance protein 1), the apparent permeability coefficient (Papp A-B) from the luminal side (side A) to the basolateral side (side B) and the apparent permeability coefficient (Papp B-A) from the basolateral side (side B) to the luminal side (side A) were measured for each of MDCKII cells and MDR1-MDCKII cells. The NFR (Net Flux Ratio) was calculated from the ratio of the Ratio of the apparent permeability coefficient of MDR1-MDCKII cells (Papp B-A / Papp A-B) to the Ratio of the apparent permeability coefficient of MDCKII cells.

[0340] The results of Test Example 9 are shown in the following table.

Table 28

[0341] Test Example 10: Evaluation of brain permeability (rat brain permeability test) In this test, the brain transferability of the compound of the present invention can be evaluated by the following method. For 7-week-old SD or WKY rats, the compound of the present invention was administered subcutaneously with a physiological saline aqueous solution or orally with a methylcellulose suspension solution. Plasma and brain were collected 0.5 hour, 1 hour, or 2 hours after administration, and the drug concentrations in plasma and brain were measured by LC-MS. The serum and brain protein binding rates of the compound of the present invention were measured using the equilibrium dialysis method. By applying the compound concentrations in plasma and brain and the plasma and brain protein binding rates obtained from the above tests to the following formula, Kp,uu,brain (the ratio of unbound drug concentrations between brain and plasma) can be calculated. Kp,uu,brain = (brain compound concentration × (100 - brain protein binding rate (%)) / 100) / (plasma compound concentration × (100 - plasma protein binding rate (%)) / 100)

[0342] The results of Test Example 10 are shown in the following table. [Table 29]

[0343] Test Example 11: Evaluation of liver toxicity risk (dansyl glutathione (dGSH) trapping assay) The compound of the present invention was metabolized with liver microsomes by the following method, and reactive metabolites that react with dansylated glutathione (dGSH) were detected and quantified from the generated metabolites. The metabolic reaction was carried out using a screening robot (manufactured by Tecan), and the metabolite-dGSH conjugate concentration was measured using a fluorescence detection UPLC system (manufactured by Waters).

[0344] (Solution Preparation) The compound of the present invention was dissolved in DMSO to prepare a test substance solution of 10 mmol / L. 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (manufactured by Xenotech, 20 mg protein / mL), and 1.27 mL of pure water were mixed to prepare a microsome solution. 0.67 mL of pure water was added to 3.78 mL of the microsome solution to prepare a microsome (dGSH(-)) solution. 1.14 mL of a dGSH solution (20 mmol / L) was added to 6.48 mL of the microsome solution to prepare a microsome (dGSH(+)) solution. 80.9 mg of NADPH was dissolved in 30 mL of pure water to prepare a cofactor solution. 33 mg of Tris(2-carboxyethyl)phosphin (TECP) was dissolved in 115 mL of methanol to prepare a reaction stop solution.

[0345] (Reaction) 12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL each was dispensed into 6 wells of a 96-well plate. The above 6 wells were divided into 3 groups of 2 wells each, and were designated as the "reaction group", the "non-reaction group", and the "group without added dGSH", respectively. 50 μL each of microsome (dGSH(+)) solution was added to the "reaction group" and the "non-reaction group", and 50 μL each of microsome (dGSH(-)) was added to the "group without added dGSH". 50 μL each of cofactor solution was added to the "reaction group" and the "group without added dGSH", and 50 μL of pure water was added to the "non-reaction group". After incubating at 37 °C for 60 minutes, 450 μL each of the reaction stopping solution was added to stop the reaction. 50 μL each of pure water was added to the "reaction group" and the "group without added dGSH", and 50 μL each of cofactor solution was added to the "non-reaction group. After cooling the plate at -20 °C for 1 hour, centrifugation (4000 rpm, 10 minutes) was performed. The supernatant was collected into another plate and used for analysis.

[0346] (Analysis) Using a fluorescence detection UPLC system (manufactured by Waters), the metabolite-dGSH conjugate concentration was measured under the following conditions. Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 × 10 mm Elution solvent: A, 0.2% aqueous formic acid solution; B, 0.2% formic acid / acetonitrile Gradient: B, 20% (0 min) → 70% (9.33 min) → 90% (10.63 min) → 20% (11 min) → 20% (14 min) Since the fluorescence intensity changes depending on the organic solvent composition, correction was performed with the organic solvent composition at the time of elution.

[0347] The results of Test Example 11 are shown in the table below.

Table 30-1

Table 30-2

Table 31

[0348] Test Example 12: Evaluation of enzyme induction ability The enzyme induction ability of the compound of the present invention was measured by the following method. · Preparation of induction medium A DMSO solution (10 mmol / L) of the test compound was diluted with HepaRG serum-free Induction Medium to prepare an induction medium (containing 0.1% DMSO) at 1 μmol / L or 10 μmol / L. · Cell culture After thawing HepaRG cells, they were diluted to 1.25×106 viable cells / mL with HepaRG Thawing Medium, and seeded into each well of a collagen I-coated 96-well plate at 1.0×10 5 cells / well. Incubated at 37°C and 5% CO2 for 6 hours, after confirming cell adhesion, it was replaced with fresh HepaRG Thawing Medium and incubated at 37°C and 5% CO2 for 3 days. Then, the HepaRG Thawing Medium was removed, and the induction medium containing the test substance at each concentration was added and incubated for 48 hours. The induction medium was changed every 24 hours. · Analysis of mRNA expression variation RNA was purified using RNeasy 96, and cDNA was synthesized using SuperScript IV VILO Master Mix. The measurement of mRNA expression level was performed by real-time PCR using TaqMan Gene Expression Assays and TaqMan Fast Advanced Master Mix. · Calculation of induction fold (Fold Induction) The induction fold of each CYP molecular species was calculated as follows. Induction fold = 2 ^(-ΔΔCt) ΔΔCt = ΔCt (treatment with test substance) - ΔCt (treatment with solvent control) ΔCt = Ct (target gene) - Ct (endogenous control gene) Ct: Cycle number at a certain fluorescence intensity (Threshold Cycle)

[0349] The results of Test Example 12 are shown in the following table. [Table 32]

Industrial Applicability

[0350] The compound of the present invention has antagonist activity against serotonin 5-HT 2A receptor and agonist activity against serotonin 5-HT 1A receptor, and thus is useful as a therapeutic agent for psychoneurological diseases.

Claims

1. Formula (1): 【Chemical Formula 1】 [In the formula, V represents CR Ａ R Ｂ ; n represents 1 or 2; Z represents a nitrogen atom, a carbon atom or -CR J -; t represents 1, 2 or 3; The bond (a) including a dashed line represents a single bond or a double bond; R Ａ and R Ｂ are each independently, and when there are a plurality of R Ａ or R Ｂ they are each independently a hydrogen atom, C １－６ alkyl, C １－６ alkoxy or C ３－１０ cycloalkyl (the alkyl, the alkoxy and the cycloalkyl may each independently be substituted with the same or different 1 to 3 halogen atoms); R １ａ , R １ｂ , R １ｃ and R １ｄ are each independently a hydrogen atom, a halogen or C １－６ alkyl which may be substituted with the same or different 1 to 3 halogen atoms; Ring Q 1 is any group selected from the group consisting of the following formulas: 【Chemical Formula 5】 【Chemical Formula 8】 ; Ring Q ２ is the following formula (3a) or (3b): 【Chemical Formula 4】 {In the formula, R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are each independently a hydrogen atom, a halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy (the alkyl and the alkoxy may each independently be substituted with the same or different 1 to 3 halogen atoms) or amino which may be substituted with the same or different 1 to 2 C １－６ alkyl, represents a group represented by {}; RJ is a hydrogen atom, C １－６ alkyl, C １－６ alkoxy or C ３－１０ cycloalkyl (the alkyl, the alkoxy and the cycloalkyl may each independently be substituted with the same or different 1 to 3 halogen atoms); Herein, (I) When ring Q1 contains a 5-membered aromatic heterocyclic ring which may be substituted, R ２ａ , R ２ｂ , R ２ｃ , and R ２ｄ are both hydrogen atoms; (II) When the bond (a) including a dashed line is a double bond, Z is a carbon atom] a compound represented by or a pharmaceutically acceptable salt thereof.

2. Formula (1) is formula (1a): 【Chemical formula 10】 [Wherein, Q １ , Q 2 , V, Z, n, R １ａ , R １ｂ , R １ｃ , R １ｄ and the bond (a) including a dashed line have the same meanings as described above], the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ａ , R １ｂ , R １ｃ and R １ｄ are both hydrogen atoms, the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. R Ａ and R ＢThe compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein both are hydrogen atoms.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein n is 2.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the bond (a) including a dashed line is a single bond.

7. The formula (1) is the following formula (1b): 【Chemical Formula 11】 [wherein, Q １ , Q ２ and Z are as defined above], the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein Z is a nitrogen atom.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein Z is -CH-.

10. Ring Q ２ is the formula (3a), the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. Ring Q ２ is the formula (3b), the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

12. R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are both hydrogen atoms, the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of the following. [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 14] [Chemical Formula 15]

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