Condensed lactam derivatives

Abstract

The present invention relates to a therapeutic agent for neuropsychiatric disorders, which contains a compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

Technical Field

[0001] The present invention relates to serotonin 5-HT 2A 5-HT receptor antagonist activity and 1A A fused lactam derivative or a pharmaceutically acceptable salt thereof having agonist activity on a receptor, and a drug for treating neuropsychiatric diseases comprising the same as an active ingredient. Background Art

[0002] Serotonin (5-hydroxytryptamine; hereinafter, also referred to as "5-HT") is known to be one of the main neurotransmitters in the central nervous system, and serotonin is also known to be involved in various brain functions such as emotional response and cognitive function.

[0003] 5-HT 1A The 5-HT receptor (which is one of the 5-HT receptor subtypes) is a Gi / o protein-coupled receptor and is expressed in the cerebral cortex, hippocampus, spinal cord nucleus, amygdala, etc. 1A Compounds having agonist activity at the receptor include, for example, tandospirone and buspirone. Tandospirone is used as a drug for treating restlessness and fear in neurological diseases, physical symptoms in psychosomatic diseases (autonomic dysregulation, essential hypertension, peptic ulcer), as well as restlessness, anxiety, irritation, and sleep disorders. Buspirone is used as a drug for treating generalized anxiety disorder (Non-Patent Document 1).

[0004] 5-HT 2A The receptor is a Gq / 11 protein-coupled receptor and is highly expressed in the cerebral cortex, hippocampus, spinal cord nucleus, etc. 2A Drugs with antagonist activity at 5-HT receptors include the antidepressants mianserin and mirtazapine. 2A Atypical antipsychotic drugs that also have antagonist activity at receptors are used as drugs for treating schizophrenia, bipolar disorder, major depression, autism spectrum disorder, and the like (Non-Patent Documents 2 and 3).

[0005] As mentioned above, 5-HT 1A 5-HT receptor agonists and 2A Antagonists of 5-HT receptors can be used to treat neuropsychiatric diseases, but no studies have been reported that selectively and effectively inhibit 5-HT receptors. 1A The receptor has agonist activity and is responsive to 5-HT 2A Drugs that have antagonist activity at receptors.

[0006] [Non-patent document 1] DP Taylor, Neuropeptides. 19 Suppl.: 15-19, 1991

[0007] [Non-patent document 2] P. Seeman, Can. J. Psychiatry. 47: 27-38, 2002

[0008] [Non-patent document 3] CJ Schmidt, Life Science. 56 (25): 2209-2222, 1995. SUMMARY OF THE INVENTION

[0010] Problems to be solved by the present invention

[0011] One object of the present invention is to provide novel compounds which have a 2A 5-HT receptor antagonist activity and 1A The receptors have agonist activity and are useful as drugs for the treatment of neuropsychiatric disorders.

[0012] Ways to solve the problem

[0013] The inventors of the present invention have conducted extensive studies to achieve the above object, and have then found that the compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "the compound of the present invention") has an inhibitory effect on serotonin 5-HT 2A 5-HT receptors have antagonist activity and are antagonists to serotonin 1A The receptor has agonist activity. Based on the novel findings, the present invention has been completed.

[0014] The following examples illustrate the present invention.

[0015] [Clause 1] A compound of formula (1) or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Where V is CR A R B ;

[0018] n is 1 or 2;

[0019] Z is a nitrogen atom, a carbon atom or -CR J -;

[0020] t is 1, 2, or 3;

[0021] The bond (a) accompanying the dashed line is a single bond or a double bond;

[0022] R A and R B are independent of each other, wherein when each symbol exists in plural, each symbol may be independently the same or different, and is a hydrogen atom, C1-6 Alkyl, C 1-6 Alkoxy or C 3-10 Cycloalkyl (wherein alkyl, alkoxy and cycloalkyl groups may be each independently and optionally substituted by the same or different 1 to 3 halogen atoms);

[0023] R 1a 、R 1b 、R 1c and R 1d are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl;

[0024] Ring Q 1 is a group of the following formula (2):

[0025]

[0026] Among them, ring Q 3 is an optionally substituted 5- or 6-membered aromatic heterocycle;

[0027] W is CR C R D ;

[0028] m is 0 or 1;

[0029] X is -CR E -or-CR F R G -;

[0030] Y is a nitrogen atom or -CR H -;

[0031] The bond accompanying the dashed line (b) is a single bond or a double bond;

[0032] Ring Q 2 is a group of the following formula (3a) or (3b):

[0033]

[0034] where R 2a 、R 2b 、R 2c and R 2d are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy (wherein the alkyl and alkoxy groups may be each independently and optionally substituted by the same or different 1 to 3 halogen atoms), or optionally substituted by the same or different 1 or 2 C 1-6 an alkyl-substituted amino group;

[0035] R C、R D 、R E 、R F 、R G 、R H and R J are independently hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-10 Cycloalkyl (wherein alkyl, alkoxy and cycloalkyl groups may be each independently and optionally substituted by the same or different 1-3 halogen atoms), provided that when R F and R G It is C 1-6 When alkyl, these groups can be combined with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic ring;

[0036] The prerequisite is that

[0037] (I) When the ring Q 3 is an optionally substituted 5-membered aromatic heterocycle, then R 2a 、R 2b 、R 2c and R 2d It is a hydrogen atom;

[0038] (II) When ring Q 3 is an optionally substituted 6-membered aromatic heterocycle, then m is 0;

[0039] (III) When the bond (a) accompanying the dashed line is a double bond, then Z is a carbon atom;

[0040] (IV) When the bond (b) accompanying the dashed line is a single bond, then X is -CR F R G -;and

[0041] (V) When the bond (b) accompanying the dashed line is a double bond, then X is -CR E -.

[0042] [Clause 2] The compound according to clause 1 or a pharmaceutically acceptable salt thereof, wherein ring Q 3 is a 5- or 6-membered aromatic heterocyclic ring optionally substituted by 1 to 3 identical or different groups selected from the following groups: hydrogen atoms, halogen atoms, cyano groups, C 1-6 Alkyl, C 3-10 Cycloalkyl (wherein the alkyl and cycloalkyl groups may be each independently and optionally substituted by the same or different 1 to 3 halogen atoms) and C 1-6 Alkoxy (wherein the alkoxy group may be optionally substituted by the same or different 1 to 3 halogen atoms or 4 to 8-membered saturated heterocyclic groups).

[0043] [Clause 3] The compound according to clause 1 or 2 or a pharmaceutically acceptable salt thereof, wherein formula (1) is formula (1a):

[0044]

[0045] where Q 1 , Q 2 ,V,Z,n,R 1a 、R 1b 、R 1c 、R 1d and the bond (a) accompanied by the dashed line is as defined above.

[0046] [Clause 4] The compound according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 1c and R 1d It's a hydrogen atom.

[0047] [Clause 5] A compound according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R A and R B They are all hydrogen atoms.

[0048] [Clause 6] The compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0049] [Clause 7] The compound according to any one of clauses 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the bond (a) accompanied by the dotted line is a single bond.

[0050] [Clause 8] The compound according to clause 1 or 2 or a pharmaceutically acceptable salt thereof, wherein formula (1) is represented by the following formula (1b):

[0051]

[0052] where Q 1 , Q 2 and Z are as defined above.

[0053] [Clause 9] The compound according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is a nitrogen atom.

[0054] [Clause 10] The compound according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is -CH-.

[0055] [Item 11] The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is a nitrogen atom.

[0056] [Clause 12] The compound according to any one of clauses 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the bond (b) accompanied by the dotted line is a single bond and X is -CH2-.

[0057] [Clause 13] The compound according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is any one of the following formulas (4a), (4b), (4c), (4d), (4e) or (4f):

[0058]

[0059] where R 3a and R 3b are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy (wherein the alkyl and alkoxy groups may be each independently and optionally substituted by the same or different 1-3 halogen atoms) or optionally substituted by the same or different 1-2 C 1-6 Alkyl-substituted amino groups.

[0060] [Clause 14] A compound according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is any one of the following formulas (5a), (5b), (5c), (5d), (5e), ​​(5f) or (5g):

[0061]

[0062] where R 4a It is C 1-6 Alkyl or C 1-6 Alkoxy,

[0063] R 4b is a hydrogen atom or C 1-6 alkyl,

[0064] R 4c and R 4d are each independently a hydrogen atom or a C 1-6 Alkyl, provided that when R 4c or R 4d If one is a hydrogen atom, then the other is a C 1-6 alkyl, or alternatively, R 4c and R 4d They can be combined with the carbon atoms to which they are attached to form a 3-6 membered saturated carbocyclic ring.

[0065] [Clause 15] A compound according to any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring Q 2It is a group of formula (3a).

[0066] [Clause 16] A compound according to any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring Q 2 It is a group of formula (3b).

[0067] [Clause 17] A compound according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2a 、R 2b 、R 2c and R 2d It's a hydrogen atom.

[0068] [Clause 18] The compound according to clause 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by one of the following formulae:

[0069] .

[0070] [Clause 19] A medicament comprising the compound according to any one of Clauses 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0071] [Clause 20] A medicament for treating a mental disorder or a central nervous system disease, comprising the compound according to any one of clauses 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0072] [Clause 21] A medicament according to clause 20, wherein the mental illness or central nervous system disease is organic in nature, including symptomatic mental disorders; mental and behavioural disorders caused by the use of psychoactive substances; schizophrenia, schizotypal disorder and delusional disorder; mood [affective] disorders; neurotic disorders, stress-related disorders and somatic disorders; non-organic sleep disorders; sexual dysfunction not caused by an organic disorder or disease; general developmental delay; behavioural and mood disorders that often occur in childhood and adolescence; extrapyramidal and movement disorders; other degenerative diseases of the nervous system; or sleep disorders.

[0073] [Clause 22] The medicament according to claim 20, wherein the mental illness or central nervous system disease 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 dementia with Lewy bodies, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or irritation, agitation or aggression associated with Alzheimer's disease.

[0074] [Clause 23] The medicament according to clause 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 irritation, agitation or aggression associated with Alzheimer's disease.

[0075] [Clause 24] A method for treating a mental disorder or a central nervous system disease, comprising administering a therapeutically effective amount of a compound according to any one of Clauses 1 to 18 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0076] [Clause 25] Use of a compound according to any one of clauses 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a mental disorder or a central nervous system disease.

[0077] [Clause 26] The compound according to any one of clauses 1 to 18 or a pharmaceutically acceptable salt thereof for use in treating a mental disorder or a central nervous system disease.

[0078] [Clause 27] A drug for treating a mental disorder or a central nervous system disease, comprising a compound according to any one of clauses 1 to 18 or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of antidepressants, antianxiety drugs, antischizophrenia agents, dopamine supplements, dopamine receptor agonists, anti-Parkinson's disease drugs, anti-epileptic drugs, analgesics, hormone preparations, anti-migraine drugs, adrenergic beta-receptor antagonists, anti-dementia drugs, drugs for treating mood disorders, antiemetic drugs, sleep-inducing drugs and anticonvulsants.

[0079] [Clause 28] A medicament for treating mental illness or central nervous system disease, comprising a compound according to any one of clauses 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient, for use in combination with at least one medicament selected from the group consisting of antidepressants, antianxiety drugs, antischizophrenia agents, dopamine supplements, dopamine receptor agonists, anti-Parkinson's disease drugs, anti-epileptic drugs, analgesics, hormone preparations, anti-migraine drugs, adrenergic beta-receptor antagonists, anti-dementia drugs, drugs for treating mood disorders, antiemetic drugs, sleep-inducing drugs and anticonvulsants.

[0080] Effects of the present invention

[0081] The compounds of the present invention have the effect of 5-HT 2A antagonist activity of 5-HT receptors and 1A In a preferred embodiment, the compounds of the present invention have good metabolic stability, providing a long disappearance half-life (T 1 / 2), and exhibit higher selectivity for these receptors compared to other GPCRs such as dopamine D2 receptor (hereinafter, referred to as "D2 receptor") and hERG channel. Thus, some preferred compounds of the present invention can be used as drugs for treating neuropsychiatric diseases, which have long-lasting effects and high safety in humans. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The results of the compound of Example 37 in the inhibition test of MK-801-induced locomotor hyperactivity (Test 7) ​​are shown.

[0084] Figure 2 The results of the compound of Example 103 in the inhibition test of MK-801-induced locomotor hyperactivity (Test 7) ​​are shown.

[0085] Description of the implementation plan

[0086] Hereinafter, the present invention is described in detail. In the description, the number of carbon atoms in the definition of "substituent" may be indicated, for example, "C 1-6 "Specifically define "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0087] The "halogen atom" used herein includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0088] The “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is "C 1-4 More preferably, it is "C 1-3 Alkyl". "C 1-3 "Alkyl" includes, for example, methyl, ethyl, propyl and 1-methylethyl. "C 1-4 "Alkyl" includes, for example, in addition to the above-listed "C 1-3 In addition to the examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl and 2-methylpropyl. "C 1-6 "Alkyl" includes, for example, in addition to the above-listed "C 1-4 In addition to the examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl and hexyl.

[0089] The “C 3-10 "Cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, including those having partially unsaturated bonds and bridged structures. Preferably, it is "C 3-7 Cycloalkyl". "C3-7 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. "C 3-10 "Cycloalkyl" includes, for example, in addition to the above-listed "C 3-7 In addition to the examples of "cycloalkyl", cyclooctyl, cyclononyl, cyclodecyl and adamantyl are included.

[0090] The “C 1-6 "Alkoxy" refers to a group wherein "C 1-6 Alkyl" group as above "C 1-6 "C" as defined in "alkyl" 1-6 Preferably, it is "C 1-4 More preferably, it is "C 1-3 Alkoxy". "C 1-3 "Alkoxy" includes, for example, methoxy, ethoxy, propoxy and 1-methylethoxy. "C 1-4 "Alkoxy" includes, for example, in addition to the above-listed "C 1-3 In addition to the examples of "alkyl", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy and 2-methylpropoxy. "C 1-6 "Alkoxy" includes, for example, in addition to the above-listed "C 1-4 In addition to the examples of "alkyl", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy and hexyloxy are also included.

[0091] As used herein, "4-8 yuan saturated heterocyclic group" refers to a 4-8 yuan saturated ring comprising 1-2 atoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, and carbon atoms, including those with partially unsaturated bonds and bridged structures. "4-8 yuan saturated heterocyclic group" is preferably a "4-6 yuan monocyclic saturated heterocyclic group", and more preferably a "5 or 6 yuan monocyclic saturated heterocyclic group". "5 or 6 yuan monocyclic saturated heterocyclic group" includes, for example, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneimine, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxoxazolidinyl, dioxoxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl. The “4- to 6-membered monocyclic saturated heterocyclic group” includes, for example, oxetanyl and azetidinyl in addition to the examples of the “5- or 6-membered monocyclic saturated heterocyclic ring” listed above. The “4- to 8-membered saturated heterocyclic ring” includes, for example, azepanyl and oxepanyl in addition to the examples of the “4- to 8-membered monocyclic saturated heterocyclic ring” listed above.

[0092] As used herein, a "3-6 membered saturated carbocycle" refers to a cyclic saturated hydrocarbon having 3-6 carbon atoms, including those having a partially unsaturated bond and a bridged structure. A "3-6 membered saturated carbocycle" is preferably a "5- or 6-membered monocyclic saturated carbocycle". A "5- or 6-membered monocyclic saturated carbocycle" includes, for example, cyclopentane and cyclohexane. A "3-6 membered saturated carbocycle" includes, for example, cyclopropane and cyclobutane in addition to the examples of the "5- or 6-membered monocyclic saturated carbocycle" listed above.

[0093] As used herein, a "5- or 6-membered aromatic heterocycle" refers to a 5- or 6-membered monocyclic aromatic heterocycle containing 1 to 3 atoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Preferably, it includes pyrrole, imidazole, pyrazole, oxazole, isoxazole, pyridine, and pyrimidine. More preferably, it includes pyrrole, pyrazole, and pyridine. A "5- or 6-membered aromatic heterocycle" includes, for example, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0094] As used herein, the "optionally substituted 5- or 6-membered aromatic heterocycle" is preferably a 5- or 6-membered aromatic heterocycle optionally substituted by the same or different 1 to 5 groups selected from the group consisting of:

[0095] (a) halogen atoms,

[0096] (b) hydroxyl groups,

[0097] (c) cyano,

[0098] (d) C 1-6 Alkyl, which is optionally substituted by the same or different 1-3 groups selected from the following groups: halogen atoms and C 1-6 Alkoxy,

[0099] (e) C 1-6 an alkoxy group, which is optionally substituted by 1 to 3 halogen atoms which are the same or different, and

[0100] (f) amino, which is optionally replaced by the same or different 1-2 C 1-6 Alkyl substitution.

[0101] More preferably, it is a 5- or 6-membered aromatic heterocyclic ring optionally substituted by the same or different 1-5 groups selected from the group consisting of: optionally substituted by the same or different 1-3 groups selected from the group consisting of halogen atoms and C 1-6 Alkoxy substituted C 1-6 Alkyl; optionally substituted by the same or different 1-3 halogen atoms C 1-6 More preferably, it is a 5- or 6-membered aromatic heterocyclic ring optionally substituted by: a C 1-6Alkyl, or C optionally substituted by 1-4 fluorine atoms 1-6 Particularly preferably, it is optionally C 1-6 Alkyl or C 1-6 Alkoxy-substituted 5- or 6-membered aromatic heterocycle.

[0102] In the compound of the present invention of formula (1), n, t, Z, the bond (a) with a dotted line, R A 、R B 、R 1a 、R 1b 、R 1c 、R 1d , Q 3 , m, X, Y, the bond with the dotted line (b), 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 However, the scope of the present invention is not intended to be limited to the scope of those compounds exemplified below.

[0103] n is preferably 2.

[0104] One embodiment of Z is a nitrogen atom. Another embodiment of Z is -CH-.

[0105] t is preferably 2.

[0106] The bond (a) accompanying the dashed line is preferably a single bond.

[0107] R A and R B Preferably, it is a hydrogen atom or a C 1-6 More preferably, they are hydrogen atoms or C 1-3 More preferably, they are hydrogen atoms, methyl groups or ethyl groups. Most preferably, they are hydrogen atoms.

[0108] R 1a 、R 1b 、R 1c and R 1d Preferably, it is a hydrogen atom or a C 1-6 More preferably, they are hydrogen atoms or C 1-3 More preferably, they are hydrogen atoms, methyl groups or ethyl groups. Most preferably, they are hydrogen atoms.

[0109] Q 3An embodiment of is an optionally substituted 5-membered aromatic heterocycle. 3 Another embodiment of is an optionally substituted 5-membered nitrogen-containing aromatic heterocycle. 3 Yet another embodiment is a 5-membered nitrogen-containing aromatic heterocycle optionally substituted by the same or different 1-5 groups selected from the group consisting of: optionally substituted by the same or different 1-3 halogen atoms or C 1-6 Alkoxy-substituted C 1-6 Alkyl; optionally substituted by the same or different 1-3 halogen atoms C 1-6 an alkoxy group; and a halogen atom. 3 Another embodiment is optionally 1-2 identical or different selected from C 1-6 Alkyl and C 1-6 A 5-membered nitrogen-containing aromatic heterocyclic ring substituted with an alkoxy group.

[0110] Q 3 An embodiment of is an optionally substituted 6-membered aromatic heterocycle. 3 Another embodiment of is an optionally substituted 6-membered nitrogen-containing aromatic heterocycle. 3 Yet another embodiment is a 6-membered nitrogen-containing aromatic heterocycle optionally substituted by the same or different 1-5 groups selected from the group consisting of: optionally substituted by the same or different 1-3 halogen atoms or C 1-6 Alkoxy-substituted C 1-6 Alkyl; optionally substituted by the same or different 1-3 halogen atoms C 1-6 an alkoxy group; and a halogen atom. 3 Another embodiment is optionally 1-2 identical or different selected from C 1-6 Alkyl and C 1-6 A 6-membered nitrogen-containing aromatic heterocyclic ring substituted with an alkoxy group.

[0111] One embodiment of m is 0. Another embodiment of m is 1.

[0112] Y is preferably a nitrogen atom.

[0113] The bond (b) accompanying the dashed line is preferably a single bond.

[0114] Q 2 One embodiment of is formula (3a). 2 Another embodiment of is formula (3b).

[0115] R 2a 、R 2b 、R 2c and R 2d Preferably, it is a hydrogen atom or a C 1-6More preferably, they are hydrogen atoms or C 1-3 More preferably, they are hydrogen atoms, methyl groups or ethyl groups. Most preferably, they are hydrogen atoms.

[0116] R C 、R D 、R E 、R F 、R G 、R H and R J Preferably, it is a hydrogen atom or a C 1-6 More preferably, they are hydrogen atoms or C 1-3 More preferably, they are hydrogen atoms, methyl groups or ethyl groups. Most preferably, they are hydrogen atoms.

[0117] One embodiment of the compound of the present invention of formula (1) includes the following embodiment (A).

[0118] (A)

[0119] A compound or a pharmaceutically acceptable salt thereof, wherein formula (1) is formula (1b), wherein Z is -CH-,

[0120] Ring Q 2 is formula (3a),

[0121] R 2a 、R 2b 、R 2c and R 2d It's a hydrogen atom,

[0122] Ring Q 1 is formula (4c) or (4f), and

[0123] R 3a and R 3b are independently hydrogen atoms, C 1-6 Alkyl or C 1-6 Alkoxy.

[0124] Another embodiment of the compounds of the present invention of formula (1) includes the following embodiment (B).

[0125] (B)

[0126] A compound or a pharmaceutically acceptable salt thereof, wherein formula (1) is formula (1b), wherein Z is a nitrogen atom,

[0127] Ring Q 2 is formula (3a),

[0128] R 2a 、R 2b 、R2c and R 2d It's a hydrogen atom,

[0129] Ring Q 1 is formula (4a), and

[0130] R 3a and R 3b are independently hydrogen atoms, C 1-6 Alkyl or C 1-6 Alkoxy.

[0131] Another embodiment of the compounds of the present invention of formula (1) includes the following embodiment (C).

[0132] (C)

[0133] A compound or a pharmaceutically acceptable salt thereof, wherein formula (1) is formula (1b), wherein Z is a nitrogen atom,

[0134] Ring Q 2 is formula (3b),

[0135] R 2a 、R 2b 、R 2c and R 2d It's a hydrogen atom,

[0136] Ring Q 1 is formula (4a) or (4c), and

[0137] R 3a and R 3b are independently hydrogen atoms, C 1-6 Alkyl or C 1-6 Alkoxy.

[0138] The compound of formula (1) may exist as its tautomers. Therefore, the compounds of the present invention also include tautomers of the compound of formula (1).

[0139] The compound of formula (1) may have at least one chiral carbon atom. Thus, the compounds of the present invention also include racemates of the compound of formula (1) and optically active compounds thereof. When the compound of formula (1) has two or more chiral carbon atoms, the compound may be in stereoisomeric form. Thus, the compounds of the present invention also include stereoisomers and mixtures of stereoisomers thereof.

[0140] In addition, any one or more 1 H atoms are 2 Compounds of formula (1) substituted with H (D) atoms (deuterium form) are also within the scope of compounds of formula (1).

[0141] The compounds of formula (1) and their pharmaceutically acceptable salts may also be in the form of hydrates and / or solvates, and thus, the compounds of the present invention encompass such hydrates and solvates such as ethanolates. In addition, the compounds of the present invention also include any embodiment of their crystalline forms.

[0142] When the compound has an acidic group, pharmaceutically acceptable salts of the compound of formula (1) include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; and organic base salts such as triethylamine, triethanolamine, tris(hydroxymethyl)aminomethane and amino acids.

[0143] When the compound has a basic group, pharmaceutically acceptable salts of the compound of formula (1) include, 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.

[0144] Hereinafter, methods for preparing the compounds of the present invention are explained together with Examples, but the present invention should not be limited thereto.

[0145] Preparation method

[0146] The compounds of the present invention can be produced by means of the production methods mentioned below or those in combination with known methods.

[0147] Each compound appearing in the following schemes may also be in the form of its salt, and such salts may include, for example, the corresponding salts exemplified as salts of the compound of formula (1). The reactions mentioned below are merely examples, and thus the compounds of the present invention may be prepared by other means based on the knowledge of those skilled in the art of organic synthesis.

[0148] If there are functional groups that require protection in the preparation methods described below, the functional groups can be protected where appropriate and then deprotected after completion of the reaction or reaction sequence to give the desired compound, even if the use of any protecting groups is not specifically stated.

[0149] Protecting groups used herein include, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons, inc., New York (1999) more specifically, for an amino group, it includes, for example, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an acetyl group and a benzyl group; and for a hydroxy group, it includes, for example, a trialkylsilyl group, an acetyl group and a benzyl group.

[0150] The protection and deprotection can be carried out by conventional means in organic synthetic chemistry (e.g., T.W. Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons, inc., New York (1999) ) or similar methods.

[0151] Preparation method 1

[0152] For example, the compound of formula (1) can be produced by the following method.

[0153]

[0154] In this scheme, V, n, Z, t, the bond with the dashed line (a), R 1a 、R 1b 、R 1c 、R 1d 、Ring Q 1 and Ring Q 2 As defined in clause 1 above; LG 1 Examples of such leaving groups are iodo, bromo, chloro, and substituted sulfonyl groups (eg, methanesulfonyl and p-toluenesulfonyl).

[0155] Compound (5) is available as a commercial product or can be prepared according to a known synthesis method (eg, European Journal of Medicinal Chemistry 2002, 37(9), 721-730).

[0156] Compound (6) is available as a commercial product or can be prepared according to a known synthesis method (eg, European Journal of Medicinal Chemistry 2012, 55, 58-66).

[0157] Compound (1) is prepared by reacting compound (5) and compound (6) in a suitable inert solvent in the presence of a suitable base. Where appropriate, the reaction can be carried out in the presence of a suitable phase transfer catalyst. The reaction temperature is usually in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as reaction temperature, base, starting materials and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0158] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0159] Examples of the phase transfer catalyst used herein include tetrabutylammonium hydrogen sulfate.

[0160] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0161] Preparation method 2

[0162] Among the compounds of formula (1), the compound of formula (1c) can be produced, for example, by the following method.

[0163]

[0164] In this scheme, V, n, Z, t, the bond with the dashed line (a), R 1a 、R 1b 、R 1c 、R 1d 、Ring Q 1 and Ring Q 2 As defined in clause 1 above; and R 4 is optionally substituted C 1-6 alkyl.

[0165] Compound (7) is available as a commercial product or can be prepared according to a known synthesis method (eg, Journal of Medicinal Chemistry 1985, 28(6), 761-769).

[0166] Compound (1c) is prepared by reacting compound (7) with an aldehyde of formula (8a) or a hemiacetal of formula (8b) in a suitable inert solvent under reductive amination with a suitable reducing agent. Where appropriate, the reaction can be achieved in the presence of a suitable base or acid. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, reducing agent, starting material and solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0167] Examples of the reducing agent used herein include complex hydride compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, and sodium cyanoborohydride; and borane complexes such as borane-dimethyl sulfide complex and borane-tetrahydrofuran complex.

[0168] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0169] Examples of the acid used herein include organic acids such as acetic acid, trifluoroacetic acid, and methanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid.

[0170] Examples of the inert solvent used herein include: water; halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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 acetonitrile, dimethylformamide and N-methyl-2-pyrrolidone; and mixture solvents thereof.

[0171] Preparation method 3

[0172] For example, the compound of formula (5) can be produced by the following method.

[0173]

[0174] In this scheme, V, n, Z, t, the bond with the dashed line (a), R 1a 、R 1b 、R 1c 、R 1d and Ring Q 2 As defined in clause 1 above; LG 1 and LG 2 Examples of such leaving groups are iodo, bromo, chloro, and substituted sulfonyl groups (eg, methanesulfonyl and p-toluenesulfonyl).

[0175] Compound (9) is available as a commercial product or can be prepared according to a known synthesis method (eg, Organic Process Research & Development 2005, 9(6), 774-781).

[0176] Compound (10) is available as a commercial product or can be prepared according to a known synthesis method (eg, Journal of the Chemical Society, Perkin Transactions 1 2001, 10, 1204-1211).

[0177] Compound (5) is prepared by reacting compound (7) with an alkylating agent of formula (9) in a suitable inert solvent. Where appropriate, the reaction can be carried out in the presence of a suitable base and in the presence of a suitable phase transfer catalyst. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0178] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0179] Examples of the phase transfer catalyst used herein include tetrabutylammonium hydrogen sulfate.

[0180] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0181] Compound (5) is prepared by converting the hydroxyl group of compound (11) into a halogen atom or a substituted sulfonyloxy group such as p-toluenesulfonyloxy and methanesulfonyloxy in a suitable inert solvent according to a conventional method.

[0182] For example, the compound (11) can be prepared by reacting carbon tetrachloride or carbon tetrabromide in a suitable inert solvent in the presence of triphenylphosphine. 1 It is a compound containing a halogen atom (5).

[0183] Compound (11) is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride in an inert solvent in the presence of a suitable base to prepare 1 is a compound (5) having a substituted sulfonyloxy group. The reaction temperature is usually in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, base used herein, starting material and solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0184] Examples of the inert solvent used herein include: 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 mixture solvents thereof.

[0185] Examples of the base used herein include: organic bases such as triethylamine and pyridine; and inorganic bases such as potassium carbonate and sodium hydroxide.

[0186] By reacting compound (5) (wherein LG 1 is substituted sulfonyloxy) and lithium bromide or lithium chloride, etc., and LG 1 It is a compound containing a halogen atom (5).

[0187] Compound (11) is prepared by reacting compound (7) with an alkylating agent of formula (10) in a suitable inert solvent. Where appropriate, the reaction can be carried out in the presence of a suitable base and in the presence of a suitable phase transfer catalyst. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0188] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0189] Examples of the phase transfer catalyst used herein include tetrabutylammonium hydrogen sulfate.

[0190] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0191] Preparation method 4

[0192] Among the compounds of formula (7), the compound of formula (7a) can be produced, for example, by the following method.

[0193]

[0194] In this scheme, R 2a 、R 2b 、R 2c and R 2d As defined in clause 1 above; and A is a halogen atom such as iodine, bromine and chlorine.

[0195] Compound (13) can be obtained as a commercially available product or can be prepared according to a known synthesis method (eg, Chemical Communications 2016, 52(5), 958-961).

[0196] Compound (7a) is prepared by treating compound (16) with a suitable acid in a suitable inert solvent. The reaction temperature is generally in the range of -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the acid used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0197] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0198] Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as trifluoroacetic acid.

[0199] Compound (16) is prepared by treating compound (15) with a suitable base in a suitable inert solvent. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0200] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0201] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0202] Compound (15) is prepared by reacting compound (14) with hydroxylamine or a salt thereof in a suitable inert solvent and, if necessary, in the presence of a suitable base. The reaction temperature is usually in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0203] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, 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.

[0204] Examples of the inert solvent used herein include: aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidone; water; and mixture solvents thereof.

[0205] Compound (14) is prepared by treating compound (13) with an organolithium such as n-butyllithium in a suitable inert solvent to obtain a lithiated compound, which is then reacted with compound (12). The reaction temperature is generally in the range of from about -78°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as the reaction temperature, the reagents used herein, the starting materials, and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0206] Examples of the inert solvent used herein include: aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixture solvents thereof.

[0207] Compound (12) is prepared by reacting 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid and N,O-dimethylhydroxylamine or its hydrochloride in a suitable inert solvent in the presence of a suitable condensing agent. Where appropriate, the reaction can be carried out in the presence of a suitable base. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the condensing agent used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0208] Compound (12) is also prepared by reacting N,O-dimethylhydroxylamine or a salt thereof with an acid halide or anhydride compound 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 of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as the reaction temperature, the condensing agent used herein, the starting material, and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0209] Examples of the condensing agent used herein include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphonodiamide (DPPA), N,N-carbonyldiimidazole (CDI) and benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU). Where appropriate, the reaction can be achieved by adding additives such as N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt).

[0210] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0211] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; basic solvents such as pyridine; and mixture solvents thereof.

[0212] Preparation method 5

[0213] Among the compounds of formula (7), the compound of formula (7b) can be produced, for example, by the following method.

[0214]

[0215] In this scheme, R 2a 、R 2b 、R 2c and R 2d As defined in clause 1 above.

[0216] Compound (17) can be obtained as a commercially available product or can be prepared according to a known synthesis method (e.g., European Journal of Organic Chemistry 2018, 40, 5520-5523).

[0217] Compound (7b) is prepared by treating compound (18) with a suitable acid in a suitable inert solvent. The reaction temperature is generally in the range of -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the acid used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0218] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0219] Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as trifluoroacetic acid.

[0220] Compound (18) is prepared by activating compound (17) with a reagent (including phosphorus oxyhalides such as phosphorus oxychloride, sulfonylating agents such as methanesulfonyl chloride and tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V) bromide) in a suitable inert solvent, followed by reaction with tert-butylpiperazine-1-carboxylate in the presence of a suitable base. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as the reaction temperature, the reagents used herein, the starting materials and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0221] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0222] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0223] Preparation Method 6

[0224] Among the compounds of formula (7), the compound of formula (7c) can be produced, for example, by the following method.

[0225]

[0226] In this scheme, R 2a 、R 2b 、R 2c and R 2d As defined in clause 1 above.

[0227] Compound (7c) is prepared by treating compound (20) with a suitable acid in a suitable inert solvent. The reaction temperature is generally in the range of -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the acid used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0228] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0229] Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as trifluoroacetic acid.

[0230] Compound (20) is prepared by treating compound (19) with sulfuryl chloride in a suitable inert solvent, followed by reaction with ammonia. The reaction temperature is usually in the range of from -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, starting materials and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0231] Examples of the inert solvent used herein include halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; and mixture solvents thereof.

[0232] Compound (19) is prepared by reacting compound (14) with sodium sulfide in a suitable inert solvent, followed by treatment with a benzyl halide such as benzyl bromide in the presence of a suitable base. Compound (19) is also prepared 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 of from -20°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as the reaction temperature, the reagents used herein, the starting materials and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0233] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0234] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0235] Preparation Method 7

[0236] For example, the compound of formula (8a) or (8b) can be prepared by the following method.

[0237]

[0238] In this scheme, V, n and ring Q 1 As defined in clause 1 above; R 4 is optionally substituted C 1-6 Alkyl; and LG1 Examples of such leaving groups are iodo, bromo, chloro, and substituted sulfonyl groups (eg, methanesulfonyl and p-toluenesulfonyl).

[0239] Compound (21) can be obtained as a commercially available product or can be prepared according to a known synthesis method (e.g., Organic & Biomolecular Chemistry 2018, 16(41), 7753-7759).

[0240] Compound (8a) or compound (8b) is prepared by reacting compound (22) with a catalytic amount of osmium tetroxide in a suitable inert solvent in the presence of an oxidizing agent such as sodium periodate. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, reagents used herein, starting materials and solvents used herein, and is generally in the range of 10 minutes to 48 hours.

[0241] Examples of the inert solvent used herein include: aromatic hydrocarbon solvents 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-pyrrolidone; water; and mixture solvents thereof.

[0242] Compound (22) is prepared by reacting compound (6) with an alkylating agent of formula (21) in a suitable inert solvent in the presence of a suitable base. The reaction temperature is usually in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on the reaction conditions such as reaction temperature, the reagents used herein, the starting materials and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0243] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0244] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0245] Preparation method 8

[0246] Among the compounds of formula (2), the compound of formula (2a) can be produced, for example, by the following method.

[0247]

[0248] In this scheme, W, m and ring Q 3 As defined in clause 1 above; R 4 is optionally substituted C 1-6 alkyl; LG is a leaving group such as iodine, bromine, chloride, and substituted sulfonyl (e.g., trifluoromethanesulfonyl and p-toluenesulfonyl); and BG is boronic acid (-B(OH)2), boronic ester (e.g., pinacol borate), or trifluoroborate.

[0249] Compound (23) can be obtained as a commercially available product or can be prepared according to a known synthesis method (eg, Journal of Medicinal Chemistry 2011, 54(2), 635-654).

[0250] Compounds (24a) and (24b) are available as commercial products or can be prepared according to a known synthesis method (eg, Tetrahedron Letters 2004, 45(11), 2467-2471).

[0251] Compound (2a) is prepared by treating compound (25a) with a suitable acid in a suitable inert solvent, followed by intramolecular cyclization in the presence of a suitable base (where appropriate). The reaction temperature is usually in the range of -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the acid used herein, the starting material and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0252] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0253] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0254] Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as trifluoroacetic acid.

[0255] Compound (2a) is also prepared as follows: hydrogenolysis of compound (25b) in a suitable inert solvent under normal pressure or a pressurized hydrogen atmosphere, followed by intramolecular cyclization in the presence of a suitable base (where appropriate). Examples of the catalyst used in the hydrogenolysis include palladium catalysts such as palladium-carbon and palladium hydroxide-carbon. The reaction temperature is generally in the range of from 0° C. to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the catalyst used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0256] Examples of the inert solvent used herein include: ester solvents such as ethyl acetate; aromatic hydrocarbon solvents 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-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0257] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0258] Compound (25a) is prepared by coupling reaction of compound (23) with compound (24a) in a suitable inert solvent in the presence of a suitable transition metal catalyst. Where appropriate, the reaction can be carried out in the presence of a suitable ligand, a suitable base and a suitable additive. The reaction temperature is generally in the range of -10°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the transition metal catalyst used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0259] Examples of the transition metal catalyst used herein include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, dichlorobis(tri-o-tolylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0260] Examples of the ligand used herein include triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

[0261] Examples of the base used herein include: organic bases such as triethylamine and diisopropylethylamine; and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.

[0262] Examples of the additive used herein include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.

[0263] Examples of the inert solvent used herein include: water; acetonitrile; halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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-pyrrolidone; and mixture solvents thereof.

[0264] Compound (25b) is prepared by coupling reaction of compound (23) with compound (24b) in a suitable inert solvent in the presence of a suitable transition metal catalyst. Where appropriate, the reaction can be carried out in the presence of a suitable ligand, a suitable base or a suitable additive. The reaction temperature is generally in the range of -10°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the transition metal catalyst used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0265] Examples of the transition metal catalyst used herein include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, dichlorobis(tri-o-tolylphosphine)palladium(II), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0266] Examples of the ligand used herein include triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

[0267] Examples of the base used herein include: organic bases such as triethylamine and diisopropylethylamine; and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.

[0268] Examples of the additive used herein include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.

[0269] Examples of the inert solvent used herein include: water; acetonitrile; halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents 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-pyrrolidone; and mixture solvents thereof.

[0270] Preparation method 9

[0271] Among the compounds of formula (2), the compound of formula (2b) can be produced, for example, by the following method.

[0272]

[0273] In this embodiment, W and m are as defined in clause 1 above; and R 3a and R 3b As defined in clause 13 above.

[0274] Compound (26) is available as a commercial product or can be prepared according to a known synthesis method (eg, Organic Letters 2009, 11(10), 2133-2136).

[0275] Compound (2b) is prepared as follows: in a suitable inert solvent, and if necessary, in the presence of a suitable acid, compound (26) and an alkyl hydrazine such as hydrazine and methylhydrazine are reacted, followed by reaction with an amide acetal such as dimethylformamide dimethyl acetal and dimethylacetamide dimethyl acetal. Alternatively, compound (2b) is also prepared as follows: compound (26) and an amide acetal such as dimethylformamide dimethyl acetal and dimethylacetamide dimethyl acetal are reacted, followed by reaction with an alkyl hydrazine such as hydrazine and methylhydrazine. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, reagents used herein, starting materials and solvents used herein, and is generally in the range of 10 minutes to 48 hours.

[0276] Examples of the inert solvent used herein include: aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0277] Examples of the acid used herein include organic acids such as acetic acid.

[0278] Preparation method 10

[0279] Among the compounds of formula (1), the compound of formula (1d) can be produced, for example, by the following method.

[0280]

[0281] In this scheme, V, W, m, n, Z, t, the bond with the dashed line (a), R 1a 、R 1b 、R 1c 、R 1d and Ring Q 2 As defined in clause 1 above; LG 1 is a leaving group such as iodine, bromine, chloride and substituted sulfonyl (eg, methanesulfonyl and p-toluenesulfonyl); and R 5a and R 5b is optionally substituted C 1-6 alkyl group, or these groups may be combined with each other to form a 5-7 membered cyclic acetal.

[0282] Compound (1d) is prepared by reacting compound (29) with 2,2-dimethoxy-N-methylethane-1-amine in a suitable inert solvent in the presence of a suitable dehydrating agent and a suitable acid. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, reagents used herein, starting materials and solvents used herein, and is generally in the range of 10 minutes to 48 hours.

[0283] Examples of the inert solvent used herein include: aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0284] Examples of the dehydrating agent used herein include magnesium sulfate and sodium sulfate.

[0285] Examples of the acid used herein include organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

[0286] Compound (29) is prepared by treating compound (28) with a suitable acid in a suitable inert solvent. The reaction temperature is usually in the range of -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the acid used herein, the starting material and the solvent used herein, and is usually in the range of 10 minutes to 48 hours.

[0287] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetone, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0288] Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as trifluoroacetic acid.

[0289] Compound (28) is prepared by reacting compound (5) and compound (27) in a suitable inert solvent in the presence of a suitable base. Where appropriate, the reaction can be carried out in the presence of a suitable phase transfer catalyst. The reaction temperature is generally in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material and the solvent used herein, and is generally in the range of 10 minutes to 48 hours.

[0290] Examples of the base used herein include organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, 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.

[0291] Examples of the phase transfer catalyst used herein include tetrabutylammonium hydrogen sulfate.

[0292] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0293] Compound (27) is prepared by reacting compound (26) with a suitable alcohol in a suitable inert solvent in the presence of a suitable acid. Where appropriate, the reaction can be achieved under azeotropic dehydration using a Dean-Stark apparatus. The reaction temperature is typically in the range of from about -20°C to the boiling point of the solvent used herein. The reaction time depends on reaction conditions such as reaction temperature, the base used herein, the starting material, and the solvent used herein, and is typically in the range of 10 minutes to 48 hours.

[0294] Examples of the inert solvent used herein include: halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; lower alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide; and mixture solvents thereof.

[0295] Examples of the acid used herein include organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

[0296] Examples of the alcohol used herein include lower alcohol solvents such as methanol, ethanol, and ethane-1,2-diol.

[0297] By appropriately combining the above preparation methods, the compounds of this invention having desired functional groups at desired positions can be prepared. The separation and purification of each intermediate or product in the above preparation methods can be achieved by conventional methods in organic synthesis, for example, by appropriately combining filtration, extraction, washing, drying, concentration, crystallization, various chromatography methods, etc. Alternatively, some intermediates can sometimes be used in the next step without purification.

[0298] Some of the starting compounds or intermediates in the above preparation methods may exist in the form of salts such as hydrochlorides (depending on the reaction conditions, etc.), but can be used as they are or in their free form. When starting compounds or intermediates in the form of salts need to be used or obtained as their free form, they can be converted into their free form by dissolving or suspending them in a suitable solvent and neutralizing the solution or suspension with a base (such as aqueous sodium bicarbonate solution).

[0299] Some compounds of formula (1) or pharmaceutically acceptable salts thereof may exist as isomers such as tautomers (e.g., keto-enol forms), positional isomers, geometric isomers, and optical isomers. The present invention encompasses each possible isomer (including the aforementioned) and mixtures thereof having different mixture ratios.

[0300] Furthermore, optical isomers thereof can be resolved by known methods such as chromatography using an optically active column and fractional crystallization at appropriate steps in the above-mentioned preparation methods.Also, optically active starting materials can also be used for starting materials.

[0301] In order to obtain the compound of formula (1) as its salt, when the product is a salt of the compound of formula (1), the product should be directly purified; or when the product is a free form of the compound of formula (1), the product should be dissolved or suspended in an appropriate solvent, and then an acid or base should be added thereto to form its salt.

[0302] The compounds of the present invention have the effect of 5-HT 1A Agonist activity of 5-HT receptors and 2A The compounds of the present invention have antagonist activity against serotonin receptors, have a mechanism different from existing drugs for treating mental illness, and can provide new options for the drug treatment of various mental illnesses. Specifically, the compounds of the present invention are beneficial for the treatment of mental illness. The compounds of the present invention are also beneficial for the treatment of central nervous system diseases.

[0303] Psychiatric disorders or central nervous system diseases that are expected to be effectively treated include, for example, F00-F09: organic, including symptomatic mental disorders, F10-F19: mental and behavioral disorders caused by the use of psychoactive substances, F20-F29: schizophrenia, schizotypal disorders and delusional disorders, F30-F39: mood [affective] disorders, F40-F48: neurotic disorders, stress-related disorders and somatic disorders, F51: non-organic sleep disorders, F52: sexual dysfunction not due to an organic disorder or disease, F84: general developmental delay, F90-F98: behavioral and emotional disorders often with onset in childhood and adolescence, G20-G26: extrapyramidal and movement disorders, G30-G32: other degenerative diseases of the nervous system, and G47: sleep disorders in the International Classification of Diseases, 10th Revision (ICD-10).

[0304] F00-F09: Organic, including symptomatic mental disorders, including, for example, dementia in Alzheimer's disease, vascular dementia, dementia with Lewy bodies, dementia in Parkinson's disease, mental disorders caused by other diseases such as brain injury, and other mental disorders caused by brain dysfunction and physical illness.

[0305] F10-F19: Mental and behavioural disorders caused by the use of psychoactive substances include, for example, delirium tremens, psychotic disorders and amnestic syndromes caused by the use of various substances.

[0306] F20-F29: Schizophrenia, schizotypal disorder and delusional disorder include, for example, paranoid schizophrenia, simple schizophrenia and delusional disorder.

[0307] F30-F39: Mood [affective] disorders include, for example, manic episodes, bipolar disorder, and depressive episodes.

[0308] F40-F48: Neurotic disorders, stress-related disorders and somatic disorders include, for example, phobic anxiety disorders, obsessive-compulsive disorders and somatic disorders.

[0309] F51: Non-organic sleep disorders include, for example, non-organic insomnia, sleepwalking and nightmares.

[0310] F52: Sexual dysfunction not due to an organic disorder or disease includes, for example, lack of or absence of sexual desire and unspecified sexual dysfunction.

[0311] F84: Pervasive developmental delay includes, for example, autism and hyperactivity disorder associated with mental retardation and stereotyped movements.

[0312] F90-F98: Hyperactivity disorder, behavioral and mood disorders with frequent onset during childhood and adolescence include, for example, hyperactivity disorder, conduct disorganization, and mixed behavioral and mood disorders.

[0313] G20-G26: Extrapyramidal and movement disorders include, for example, Parkinson's disease, secondary parkinsonism, movement disorders, and spinocerebellar degeneration.

[0314] G30-G32: Other degenerative diseases of the nervous system include, for example, Alzheimer's disease, frontotemporal dementia, frontotemporal lobar degeneration, dementia with Lewy bodies, senile degeneration, and progressive supranuclear palsy.

[0315] G47: Sleep disorders include, for example, disorders of initiating and maintaining sleep [insomnia], sleep-wake schedule disorders, as well as narcolepsy and cataplexy.

[0316] The compounds of the present invention are also useful in treating or preventing the recurrence of various symptoms associated with these disorders, such as psychotic symptoms, anxiety, aggression, irritability and temper tantrums, sleep disturbances, depressive symptoms, anxiety symptoms and cognitive dysfunction.

[0317] Psychiatric disorders or central nervous system diseases that are expected to be effectively treated 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 Lewy body dementia, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, and irritation, agitation, or aggression associated with Alzheimer's disease. More preferably, it includes schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with Lewy body dementia, and irritation, agitation, or aggression associated with Alzheimer's disease.

[0318] The compounds of the present invention have the effect of 5-HT 1A Receptors and 5-HT 2A effective binding affinity for 5-HT receptors (Test 1); i.e., 1A Agonist activity of 5-HT receptors and 2A In a preferred embodiment, the compounds of the present invention have antagonist activity against 5-HT 1A Receptors and 5-HT 2A The binding affinity of the present invention to the D2 receptor is 100 or more times that of the D2 receptor, so the compounds of the present invention can exert a 5-HT-based 1A Receptor agonism and 5-HT 2A The pharmacological effects of D2 receptor antagonism are achieved without reaching blood levels that cause side effects (such as extrapyramidal symptoms and hyperprolactinemia, which are believed to be caused by D2 receptor antagonism). In other words, the concentration that expresses the pharmacological effects is different from the concentration that expresses the side effects.

[0319] In another preferred embodiment, the compounds of the present invention are expected to have very little effect on the cardiovascular system because at the inhibitory concentrations of the hERG channel (which is a clear indicator of long QT arrhythmias) and the expected pharmacological effects (based on 5-HT 1A Receptor agonism and 5-HT 2A There was a large difference between the concentrations that clearly showed a pharmacological effect (receptor antagonism) (Test 5). In other words, the concentration that showed a pharmacological effect was different from the concentration that showed a side effect.

[0320] The disappearance half-life of the drug (hereinafter also referred to as "T 1 / 2 ”) is a factor in determining the frequency of application to maintain the effect. Multiple daily applications are believed to have a short T 1 / 2The drug may cause forgetting to take the drug or not completing the drug, which may hinder appropriate drug treatment. In addition, if the frequency of administration increases, there is a concern that the incidence of side effects may increase or tolerance may decrease in association with high-dose administration. From the above viewpoint, if it is found that a drug with a long T 1 / 2 It is foreseen that the drug is a long-acting drug with almost no above-mentioned concerns, which can reduce the inconvenience of patients taking the drug.

[0321] In a preferred embodiment, the estimated human disappearance half-life (hereinafter also referred to as "estimated human T 1 / 2 ”) is 8 hours or longer (Test 4). That is, it is expected that the drug efficacy can be maintained for a long period in the human body, the drug dependence of the patients taking the drug can be improved, and high tolerability can be shown when administered.

[0322] The compounds of the present invention can be administered orally or parenterally. In the case of oral administration, the compound can be administered in conventional dosage forms. In the case of parenteral administration, the compound can be administered in topical forms, injection forms, transdermal forms, nasal forms, and the like. Oral or rectal administration forms include, for example, capsules, tablets, pills, powders, cachets, suppositories, and liquids. Injections include, for example, sterile solutions and suspensions. Topical administration forms include, for example, creams, ointments, lotions, and transdermal formulations (e.g., standard patches and matrices).

[0323] The above dosage forms can be prepared in a conventional manner using pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients and additives include carriers, binders, flavoring agents, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents and preservatives.

[0324] Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter. Capsules can be prepared by filling capsules with the compound of the invention and a pharmaceutically acceptable carrier. The compound of the invention can be placed in the capsule with or without pharmaceutically acceptable excipients. Cachets can also be prepared in a similar manner.

[0325] Injectable liquid forms include solutions, suspensions, and emulsions, for example, aqueous solutions, water-propylene glycol, and the like. The liquid form may contain water, and it may also be prepared in a solution of polyethylene glycol and / or propylene glycol. A liquid form suitable for oral administration may be prepared by adding the compound of the invention to water and also adding colorants, flavorings, stabilizers, sweeteners, solubilizers, thickeners, and the like (where appropriate). Alternatively, a liquid form suitable for oral administration may be prepared by adding the compound of the invention to water together with a dispersant and making the liquid viscous. Thickeners used herein include, for example, pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and known suspending agents.

[0326] The dosage of each compound may depend on the patient's disease, age, weight, sex, symptoms, and route of administration. Generally speaking, the compound of the present invention is administered to an adult (body weight: 50 kg) at a dose of 0.1-1000 mg / day, preferably 1-300 mg / day, once a day or in 2-3 doses. Alternatively, it may be administered once every few days to several weeks.

[0327] In order to enhance the effects and / or reduce the side effects thereof, the compounds of the present invention may be used in combination with another drug. Hereinafter, drugs with which the compounds of the present invention may be used in combination are abbreviated as "concomitant drugs".

[0328] The example of concomitant drug used herein includes antidepressant, antianxiety drug, anti-schizophrenia agent, dopamine supplement, dopamine receptor agonist, anti-Parkinson's disease drug, anti-epileptic drug, analgesic, hormone preparation, anti-migraine drug, adrenergic beta receptor antagonist, anti-dementia drug, the drug for the treatment of mood disorder, antiemetic drug, sleep induction drug and anticonvulsant. Concomitant drug is preferably antianxiety drug such as selective serotonin reuptake inhibitor.

[0329] The administration interval of the compounds of this invention and its concomitant drug is not limited, that is, the concomitant drug can be administered to the subject patient simultaneously with the compounds of this invention or at suitable intervals. Alternatively, the compounds of this invention and its concomitant drug can be formulated into a combination drug. The dosage of the concomitant drug can be appropriately determined based on the dosage standard used clinically. The combination ratio of the compounds of this invention and its concomitant drug can be appropriately determined based on its subject patient, route of administration, disease, pathology and their combination. For example, when the subject patient is human, a concomitant drug of 0.01-100 parts by weight per portion of the compounds of this invention can be used. In order to reduce the purpose of side effects, antiemetic drugs, sleep-inducing drugs, anticonvulsants, etc. can be used in combination as concomitant drugs. Example

[0330] The present invention is explained in more detail below by referring to reference examples, examples and tests; however, the technical scope of the present invention is not limited thereto. The compound names used in the reference examples and examples are not always based on the IUPAC nomenclature system. 1 H-NMR), LC-MS, etc.

[0331] LC-MS was performed using the following conditions: Retention time (RT) indicates the time when a peak of a mass spectrum appears in LC-MS measurement results.

[0332] Condition A

[0333] Analytical equipment: Shimadzu LCMS-2020

[0334] Column: Phenomenex Kinetex 1.7 μm C18 (50 mm x 2.10 mm)

[0335] Eluent: A: MeOH, B: 0.05% TFA / H2O

[0336] Gradient conditions:

[0337] 0.0 min; A / B = 30:70

[0338] 0.0-1.90 min; A / B = 99:1

[0339] 1.91-3.00 min; A / B = 30:70

[0340] Flow rate: 0.5 mL / min

[0341] Wavelength: 220 nm

[0342] Column temperature: 40℃

[0343] In this document, the following abbreviations are used.

[0344] Me: methyl

[0345] DMF: N,N-dimethylformamide

[0346] THF: Tetrahydrofuran

[0347] tert-:uncle

[0348] CDCl3: deuterated chloroform

[0349] DMSO-d6: deuterated dimethyl sulfoxide

[0350] Proton nuclear magnetic resonance spectra were measured using an FT-NMR spectrometer (300 MHz or 400 MHz, JEOL). Chemical shifts are expressed as δ values ​​(ppm). The symbols used in NMR have the following meanings: s is singlet, d is doublet, dd is doublet of doublets, dt is doublet of triplet, t is triplet, q is quartet, m is multiplet, br is broad, brs is broad singlet, and J is the coupling constant.

[0351] Example 1

[0352] 7-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0353]

[0354] To a solution of 6,7-dihydro-1,7-naphthyridin-8(5H)-one (240 mg) in toluene (5.0 mL) was added the compound of Reference Example 1 (452 ​​mg), potassium hydroxide (136 mg) and tetrabutylammonium bromide (172 mg) at room temperature. After stirring at reflux temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (377 mg).

[0355] 1 H-NMR (400 MHz, CDCl3) δ : 2.71 (6H, m), 3.03 (2H, t, J = 6.6 Hz), 3.55 (4H, t, J = 6.6 Hz), 3.68 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.3 Hz),7.19 (1H, m), 7.31 (1H, dd, J = 7.7, 4.8 Hz), 7.41-7.50 (2H, m), 7.52-7.56(1H, m), 7.66 (1H, d, J = 8.0 Hz), 8.67 (1H, dd, J = 4.6, 1.7 Hz).

[0356] Example 2

[0357] 2-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0358]

[0359] To a solution of the compound of Reference Example 10 (99.0 mg) in toluene (3.7 mL) was 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 at reflux for 15 hours, water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and recrystallized from 2-propanol to obtain the title compound (160 mg).

[0360] 1 H-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).

[0361] Example 3

[0362] 2-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0363]

[0364] To a solution of the compound of Reference Example 19 (684 mg) in toluene (8.4 mL) was added the compound of Reference Example 1 (1.18 g), potassium hydroxide (355 mg) and tetrabutylammonium bromide (449 mg) at room temperature. After stirring at reflux for 2 hours, brine was added to the reaction mixture at room temperature, and the reaction mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.20 g).

[0365] 1 H-NMR (400 MHz, CDCl3) δ : 2.56 (3H, s), 2.65-2.85 (6H, m), 2.96 (2H,t, J = 6.7 Hz), 3.60-3.66 (4H, m), 3.65 (2H, t, J = 6.7 Hz), 3.70-3.85 (2H,m), 6.97 (1H, s), 7.21 (1H, dd, J = 7.3, 7.3 Hz), 7.42-7.49 (2H, m), 7.65(1H, d, J = 7.9 Hz), 9.05 (1H, s).

[0366] Example 4-21

[0367] According to the method of Example 3, the compounds of Examples 4 to 21 were prepared from the corresponding compounds of Reference Examples.

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374] Example 22

[0375] 7-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0376]

[0377] To a solution of 3-(piperidin-4-yl)benzo[d]isoxazole (1.44 g) in dichloromethane (20 mL) was added the compound of Reference Example 22 (1.58 g) and sodium triacetoxyborohydride (1.96 g), and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.30 g).

[0378] 1 H-NMR (300 MHz, CDCl3) δ : 1.96-2.16 (4H, m), 2.27 (2H, td, J = 11.4,2.9 Hz), 2.72 (2H, t, J = 6.3 Hz), 3.00-3.17 (5H, m), 3.72 (2H, t, J = 6.6Hz), 3.79 (2H, t, J = 6.3 Hz), 7.28-7.37 (2H, m), 7.49-7.60 (3H, m), 7.69-7.74 (1H, m), 8.70 (1H, dd, J = 4.7, 1.6 Hz).

[0379] Examples 23-31

[0380] According to the method of Example 22, the compounds of Examples 23 to 31 were prepared from the corresponding compounds of Reference Example.

[0381]

[0382]

[0383]

[0384] Example 32

[0385] 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

[0386]

[0387] 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. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) and further purified by preparative thin layer chromatography (chloroform / methanol) to give the title compound (10.0 mg).

[0388] 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).

[0389] Examples 33-34

[0390] According to the method of Example 32, the compounds of Examples 33-34 were prepared from the corresponding compounds of Reference Example.

[0391]

[0392] Example 35

[0393] 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

[0394]

[0395] To a suspension of 55% sodium hydride (34.4 mg) in N,N-dimethylformamide (1.0 mL) was added the compound of Reference Example 26 (100 mg). After stirring at room temperature for 30 minutes, the compound of Reference Example 3 (209 mg) and potassium iodide (54.6 mg) were added thereto, and the reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol), and further purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (160 mg).

[0396] 1H-NMR (400 MHz, CDCl3) δ : 1.97-2.11 (4H, m), 2.19-2.28 (2H, m), 2.52(3H, s), 2.61 (2H, t, J = 6.4 Hz), 2.88 (2H, t, J = 7.1 Hz), 3.03-3.13 (3H,m), 3.62 (2H, t, J = 6.4 Hz), 3.72 (2H, t, J = 7.1 Hz), 7.24-7.29 (1H, m), 7.48-7.56 (2H, m), 7.70 (1H, d, J = 7.8 Hz).

[0397] Example 36

[0398] 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

[0399]

[0400] To a suspension of 55% sodium hydride (61.9 mg) in N,N-dimethylformamide (8.0 mL) was added the compound of Reference Example 13 (156 mg). After the mixture was stirred at room temperature for 30 minutes, the compound of Reference Example 2 (349 mg) and potassium iodide (86.0 mg) were added thereto, and the mixture was stirred at 50°C for 16 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (205 mg).

[0401] 1H-NMR (400 MHz, CDCl3) δ : 2.77 (2H, t, J = 6.6 Hz), 2.85-2.87 (4H,br m), 2.95 (2H, t, J = 6.4 Hz), 3.59-3.60 (4H, m), 3.66-3.73 (4H, m), 3.89(3H, s), 7.36 (1H, ddd, J = 8.3, 8.3, 0.8 Hz), 7.47 (1H, ddd, J = 8.3, 8.3,0.8 Hz), 7.75 (1H, s), 7.81 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.3 Hz).

[0402] Example 37

[0403] 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

[0404]

[0405] To a suspension of 55% sodium hydride (23.2 mg) in N,N-dimethylformamide (1.6 mL) was added the compound of Reference Example 38 (80.0 mg) at ice temperature. After stirring at room temperature for 30 minutes, the compound of Reference Example 3 (141 mg) and potassium iodide (40.2 mg) were added thereto, and the reaction mixture was stirred at 50°C for 15 hours. Water 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 purified by silica gel column chromatography (chloroform / methanol) and further purified by amino silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (87.0 mg).

[0406] 1H-NMR (400 MHz, CDCl3) δ : 2.04-2.10 (4H, m), 2.22-2.29 (2H, m), 2.53(3H, s), 2.64 (2H, t, J = 6.9 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.04-3.16 (3H,m), 3.61-3.67 (4H, m), 3.75 (3H, s), 7.26-7.29 (1H, m), 7.50-7.57 (2H, m), 7.73 (1H, d, J = 7.8 Hz).

[0407] Examples 38-87

[0408] According to the method of Example 37, the compounds of Examples 38 to 87 were prepared from the corresponding compounds of Reference Examples.

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] Example 88

[0424] 6-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

[0425]

[0426] 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. Water (5.0 mL) was added to the reaction mixture, and the reaction mixture was extracted with chloroform / methanol (90 / 10), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting N,N-dimethylformamide was azeotroped with toluene, and the residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethanol (12 mL) to obtain the title compound (710 mg).

[0427] 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).

[0428] Examples 89-92

[0429] According to the method of Example 88, the compounds of Examples 89 to 92 were prepared from the corresponding compounds of Reference Example.

[0430]

[0431] Example 93

[0432] 6-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-2-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

[0433]

[0434] To a solution of the compound of Reference Example 43 (100 mg) in dimethyl sulfoxide (1.0 mL) were added potassium hydroxide (38.0 mg) and the compound of Reference Example 2 (159 mg) in this order, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (chloroform / methanol) and further purified by amino silica gel column chromatography (hexane / ethyl acetate) to give the title compound (92.7 mg).

[0435] 1 H-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 = 4.8Hz), 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).

[0436] Examples 94-95

[0437] According to the method of Example 93, the compounds of Examples 94-95 were prepared from the corresponding compounds of Reference Example.

[0438]

[0439] Example 96

[0440] 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

[0441]

[0442] To a suspension of the compound of Reference Example 45 (100 mg) in dichloromethane (2.1 mL) was added N,N-diisopropylethylamine (0.110 mL), and the mixture was stirred at room temperature for 5 minutes. After the compound of Reference Example 46 (38.3 mg) and acetic acid (0.0241 mL) were added to the mixture, sodium triacetoxyborohydride (89.0 mg) was added thereto, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium bicarbonate 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 purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (4.60 mg).

[0443] 1 H-NMR (400 MHz, CDCl3) δ : 2.01-2.15 (4H, m), 2.23-2.33 (2H, m), 2.66(2H, t, J = 6.9 Hz), 2.83 (2H, t, J = 6.6 Hz), 3.05-3.16 (3H, m), 3.64-3.71(4H, m), 4.18 (3H, s), 7.27-7.32 (2H, m), 7.51-7.59 (2H, m), 7.71 (1H, d, J =7.8 Hz).

[0444] Example 97

[0445] 5-{2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-4(1H)-one

[0446]

[0447] A mixture of the compound of Reference Example 47 (0.102 g), triethylamine (0.145 mL), N,N-dimethylformamide dimethyl acetal (0.0700 mL) and dichloromethane (5.0 mL) was stirred at room temperature for 60 hours. N,N-dimethylformamide dimethyl acetal (0.100 mL) was added thereto, and the mixture was heated under reflux for 3 hours. Additional N,N-dimethylformamide dimethyl acetal (0.250 mL) was added thereto, and the mixture was heated under reflux for 2.5 hours. Toluene (30 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hydrazine monohydrate (14.3 mg) was added to a solution of the concentrated residue in ethanol (10 mL). After heating under reflux for 24 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (chloroform / methanol) to obtain the title compound (13.0 mg).

[0448] 1 H-NMR (400 MHz, CDCl3) δ : 2.01-2.20 (6H, m), 2.22-2.34 (2H, m), 2.66(2H, t, J = 6.6 Hz), 2.99 (2H, t, J = 6.9 Hz), 3.05-3.20 (3H, m), 3.52 (2H,t, J = 4.8 Hz), 3.73 (2H, t, J = 6.6 Hz), 7.26-7.31 (1H, m), 7.50-7.58 (2H,m), 7.70-7.73 (1H, m), 8.07 (1H, s).

[0449] Example 98

[0450] 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

[0451]

[0452] A solution of the compound of reference example 50 (9.00 mg) in trifluoroacetic acid (1.0 mL) was heated under reflux for 2 hours. The reaction mixture was concentrated, and tetrahydrofuran (1.0 mL) and triethylamine (0.50 mL) were added thereto. After heating under reflux for 78 hours, the reaction mixture was concentrated, purified by silica gel column chromatography (chloroform / methanol), and further purified to obtain title compound (2.30 mg) by preparative thin layer column chromatography (chloroform / methanol).

[0453] 1 H-NMR (400 MHz, CDCl3) δ : 2.03-2.16 (4H, m), 2.20-2.34 (2H, m), 2.62-2.73 (2H, m), 2.87 (2H, t, J = 6.8 Hz), 3.03-3.19 (3H, m), 3.67-3.75(4H, m), 7.27-7.31 (1H, m), 7.46 (1H, s), 7.51-7.58 (2H, m), 7.71 (1H, d, J =8.0 Hz).

[0454] Example 99

[0455] 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

[0456]

[0457] To the compound (103 mg) of Reference Example 48 was added 48% hydrobromic acid (1.50 mL). After stirring at room temperature for 2 hours, a 4 mol / L sodium hydroxide aqueous solution was added to the reaction mixture. The reaction mixture was adjusted to pH 7 and extracted with chloroform / methanol (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Pyridine (0.0401 mL), magnesium chloride (23.6 mg), and acetic anhydride (0.0257 mL) were added to a solution of the obtained concentrated residue (84.7 mg) in dichloromethane (1.2 mL) 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. A solution of hydrazine (10.7 mg) in water (0.355 ml) was added to a solution of the obtained concentrated residue (81.7 mg) in ethanol (0.71 mL) 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).

[0458] 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).

[0459] Example 100

[0460] 5-{2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydroimidazo[4,5-c]azepine-4(3H)-one

[0461]

[0462] A mixture of the compound of Reference Example 51 (401 mg), 20% palladium hydroxide on carbon (1.25 g) and methanol (4.5 mL) was stirred at 60 ° C for 1.5 hours under a hydrogen atmosphere (1 atmosphere). The reaction mixture was filtered and 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 purified by silica gel column chromatography (chloroform / methanol). To a solution of the obtained purified product (10.5 mg) in N,N-dimethylformamide (0.37 mL) was added 55% sodium hydride (2.98 mg) at ice temperature. After stirring at ice temperature for 30 minutes, the compound of Reference Example 2 (11.0 mg) and potassium iodide (3.10 mg) were added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol). The purified product obtained is dissolved in dichloromethane (0.37 mL), and trifluoroacetic acid (0.37 mL) is added thereto. The mixture is stirred at room temperature for 1 hour, and concentrated. The reaction mixture is purified by reversed-phase liquid chromatography (water / acetonitrile) to obtain the title compound (0.87 mg).

[0463] 1H-NMR (400 MHz, CDCl3) δ : 2.11-2.18 (2H, m), 2.63-2.84 (6H, m), 2.95(2H, t, J = 6.6 Hz), 3.40-3.62 (6H, m), 3.73 (2H, t, J = 6.4 Hz), 7.36 (1H,dd, J = 7.1, 7.1 Hz), 7.47 (1H, dd, J = 7.6, 7.6 Hz), 7.64 (1H, s), 7.81 (1H,d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz).

[0464] Example 101

[0465] 5-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepine-4(1H)-one

[0466]

[0467] A mixture of the compound (697 mg) of Reference Example 51, 20% carbon-supported palladium hydroxide (3310 mg) and methanol (7.9 mL) was stirred at 60 ° C for 1.5 hours under a hydrogen atmosphere (1 atmosphere). The reaction mixture was filtered and concentrated under reduced pressure. A mixture of the obtained residue (492 mg), triethylamine (2.18 mL) and ethanol (7.9 mL) was heated under reflux for 72 hours. The reaction mixture was concentrated, and the residue was 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 thereto. The mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated, the residue was dissolved in N, N-dimethylformamide (0.42 mL), and 8 mol / L potassium hydroxide aqueous solution (2.88 μL) and iodomethane (3.27 mg) were added thereto at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and concentrated. To a solution of the obtained residue (3.47 mg) in N,N-dimethylformamide (0.21 mL) was added 55% sodium hydride (1.68 mg) at ice temperature. After stirring at ice temperature for 30 minutes, the compound of Reference Example 3 (5.84 mg) and potassium iodide (1.74 mg) were added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.64 mg).

[0468] 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).

[0469] Example 102

[0470] 7-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-8-oxo-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carbonitrile

[0471]

[0472] To a solution of the compound of Reference Example 62 (24.0 mg) in N,N-dimethylformamide (0.25 mL) was added zinc cyanide (25.1 mg) and tetrakis(triphenylphosphine)palladium (11.7 mg) at room temperature. After stirring at 100° C. for 1.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (9.5 mg).

[0473] 1 H-NMR (400 MHz, CDCl3) δ : 2.66-2.71 (6H, m), 3.01 (2H, t, J = 6.6Hz), 3.44-3.48 (4H, m), 3.65-3.74 (4H, m), 7.29 (1H, dd, J = 8.0, 7.1 Hz), 7.40 (1H, dd, J = 8.0, 7.1 Hz), 7.49 (1H, s), 7.74 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 9.19 (1H, s).

[0474] Example 103

[0475] 5-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

[0476]

[0477] To a solution of the compound of Reference Example 47 (75.0 mg) in N-methylpyrrolidone (0.53 mL) were added 2,2-dimethoxy-N-methylethane-1-amine (251 mg), methanesulfonic acid (27.4 μL) and magnesium sulfate (152 mg), and the mixture was stirred at 110 ° C for 1 hour. The mixture was stirred at 150 ° C for 2 hours, and a 10% aqueous sodium hydroxide solution was added thereto to adjust the pH to 9 or higher. The mixture was extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl acetate / hexane (2 / 1) was added to the residue, and the mixture was washed with water. The combined aqueous layer was extracted with ethyl acetate / hexane (2 / 1). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by amino silica gel column chromatography (hexane / ethyl acetate). Ethyl acetate (0.91 mL) was added to the obtained solid. After confirming that all solids dissolved at 70°C, the mixture was gradually cooled to room temperature. After confirming that solids precipitated, the mixture was stirred at ice temperature for 2 hours, and the solids were collected by filtration. The solids were washed with ethyl acetate cooled to 0°C and dried under reduced pressure to obtain the title compound (46.0 mg).

[0478] 1 H-NMR (400 MHz, CDCl3) δ : 1.98-2.18 (6H, m), 2.18-2.29 (2H, m), 2.61(2H, t, J = 6.7 Hz), 2.77 (2H, t, J = 7.0 Hz), 3.01-3.14 (3H, m), 3.43-3.51(5H, m), 3.69 (2H, t, J = 6.7 Hz), 6.54 (1H, d, J = 2.4 Hz), 6.67 (1H, d, J =2.4 Hz), 7.24-7.30 (1H, m), 7.47-7.56 (2H, m), 7.71 (1H, d, J = 7.9 Hz).

[0479] Example 104

[0480] 2-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-ethyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0481]

[0482] To a solution of the compound of Example 62 (114 mg) in tetrahydrofuran (6.0 mL) was added 1.1 mol / L diethylzinc-hexane aqueous solution (0.329 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane addition compound (17.7 mg) at room temperature. After stirring at 70°C for 2 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (62.3 mg).

[0483] 1 H-NMR (400 MHz, CDCl3) δ : 1.24 (3H, t, J = 7.6 Hz), 2.66 (3H, t, J =6.4 Hz), 2.67-2.71 (4H, m), 2.77 (2H, q, J = 7.6 Hz), 2.90 (2H, t, J = 6.6Hz), 3.44-3.47 (4H, m), 3.60 (2H, t, J = 6.6 Hz), 3.67 (2H, t, J = 6.6 Hz), 6.91 (1H, s), 7.28 (1H, dd, J = 8.3, 8.3 Hz), 7.39 (1H, dd, J = 8.3, 8.3 Hz),7.73 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 8.3 Hz), 9.04 (1H, s).

[0484] Example 105

[0485] 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

[0486]

[0487] To a solution of the compound of Example 69 (62.0 mg) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (54.1 mg), trimethylboroxine (0.0500 mL) and tetrakis(triphenylphosphine)palladium (15.1 mg) at room temperature. After stirring at 150°C under microwave irradiation, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase liquid chromatography (acetonitrile / water, including 0.05% trifluoroacetic acid) to give the title compound (12.3 mg).

[0488] 1 H-NMR (400 MHz, CDCl3) δ : 2.44 (3H, s), 2.65 (2H, t, J = 6.6 Hz), 2.74 (4H, t, J = 5.0 Hz), 2.85 (2H, t, J = 6.9 Hz), 3.51 (4H, t, J = 5.0 Hz), 3.63 (2H, t, J = 6.6 Hz), 3.68 (2H, d J = 6.9 Hz), 3.70 (3H, s), 7.31-7.35 (1H, ddd, J = 8.3, 7.8 0.9 Hz), 7.44 (1H, ddd, J =7.8, 7.8, 0.9 Hz), 7.79(1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 8.3 Hz).

[0489] Example 106

[0490] 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

[0491]

[0492] To a solution of the compound of Example 73 (14.0 mg) in methanol (1.0 mL) was added sodium methoxide (15.9 mg) at room temperature. After stirring at 120° C. for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.1 mg).

[0493] 1H-NMR (400 MHz, CDCl3) δ : 2.67 (2H, t, J = 6.6 Hz), 2.76 (4H, t, J =4.8 Hz), 2.83 (2H, t, J = 6.6 Hz), 3.54 (4H, t, J = 4.8 Hz), 3.61 (3H, s), 3.62 (2H, J = 6.6 Hz), 3.67 (2H, J = 6.6 Hz), 4.34 (3H, s), 7.35 (1H, dd, J =7.6, 7.6 Hz), 7.46 (1H, dd, J = 7.6, 7.6 Hz), 7.81 (1H, d, J = 7.6 Hz), 7.90(1H, d, J = 7.6 Hz).

[0494] Example 107

[0495] 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

[0496]

[0497] To a solution of the compound of Example 62 (60.0 mg) in deuterated methanol (0.50 mL) was added 55% sodium hydride (16.6 mg) at ice temperature. After stirring at 80°C for 4 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (32.2 mg).

[0498] 1H-NMR (400 MHz, CDCl3) δ : 2.70 (2H, t, J = 6.4 Hz), 2.75 (4H, t, J =4.8 Hz), 3.51 (4H, t, J = 4.8 Hz), 3.60 (2H, s), 3.71 (2H, t, J = 6.4 Hz), 6.49 (1H, s), 7.33 (1H, 1H, dd, J = 8.3, 8.3 Hz), 7.44 (1H, dd, J = 8.3, 8.3Hz), 7.78 (1H, d, J = 8.3 Hz), 7.88 (1H, d, J = 8.3 Hz), 8.79 (1H, s).

[0499] Example 108

[0500] 2-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0501]

[0502] To a solution of the compound of Example 62 (84.0 mg) in 1,2-dimethoxyethane (1.6 mL) was 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 obtain the title compound (7.0 mg).

[0503] 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 = 8.3Hz), 9.06 (1H, s).

[0504] Example 109

[0505] 5-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

[0506]

[0507] The compound of Reference Example 49 (0.790 g), sodium sulfate (8.00 g), and p-toluenesulfonic acid monohydrate (0.422 g) were dissolved in 2,2-dimethoxy-N-methylethylamine (25 mL), and the mixture was stirred at 150°C for 12 hours. The reaction mixture was filtered through Celite and washed with chloroform. Saturated aqueous sodium bicarbonate solution was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) and reverse phase purification to obtain the title compound (0.161 g).

[0508] 1H-NMR (400 MHz, CDCl3) δ : 2.15-2.16 (2H, m), 2.66 (2H, t, J = 6.6Hz), 2.74 (4H, t, J = 5.0 Hz), 2.79 (2H, t, J = 6.9 Hz), 3.48-3.49 (2H, m),3.50 (3H, s), 3.56 (4H, t, J = 5.0 Hz), 3.72 (2H, t, J = 6.6 Hz), 6.56 (1H,d, J = 3.2 Hz), 6.68 (1H, d, J = 2.8 Hz), 7.21 (1H, ddd, J = 8.3, 8.0, 0.9Hz), 7.43-7.48 (2H, m), 7.69 (1H, d, J = 8.3 Hz).

[0509] Example 110

[0510] 2-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-(trifluoromethyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0511]

[0512] 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) was added sodium triacetoxyborohydride (78.0 mg), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.20 mg).

[0513] 1H-NMR (400 MHz, CDCl3) δ : 2.72-2.81 (6H, m), 3.11 (2H, t, J = 6.4Hz), 3.53 (4H, t, J = 4.6 Hz), 3.72-3.81 (4H, m), 7.36 (1H, dd, J = 7.3, 7.3Hz), 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).

[0514] Example 111

[0515] 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

[0516]

[0517] To oxetane-3-ol (83.0 mg) in N,N-dimethylformamide (0.21 mL) was added 55% sodium hydride (36.9 mg) at ice temperature. After stirring at room temperature for 15 minutes, the compound of Example 62 (50.0 mg) was added to the reaction mixture. After stirring at 80 ° C for 1 hour, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (11.4 mg).

[0518] 1H-NMR (400 MHz, CDCl3) δ : 2.72 (2H, t, J = 6.6 Hz), 2.77 (4H, t, J =4.6 Hz), 2.96 (2H, t, J = 6.6 Hz), 3.53 (4H, t, J = 4.6 Hz), 3.64 (2H, t, J =6.6 Hz), 3.73 (2H, t, J = 6.6 Hz), 4.71 (2H, dd, J = 8.0, 5.3 Hz), 5.00 (2H,t, J = 7.3 Hz), 5.63-5.69 (1H, m), 6.58 (1H, s), 7.36 (1H, dd, J = 8.3, 8.3Hz), 7.47 (1H, ddd, J = 8.3, 8.3, 0.9 Hz), 7.81 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz), 8.71 (1H, s).

[0519] Example 112

[0520] 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

[0521]

[0522] To the solution of the compound (286 mg) of embodiment 61 in methanol (3.6 mL), fumaric acid (84.0 mg) is added, and the mixture is stirred at room temperature for 2 hours.Precipitated solid is filtered to obtain solid (300 mg).The mixture of the solid (300 mg), N-fluorobenzenesulfonimide (370 mg) and acetonitrile (2.9 mL) obtained is stirred at room temperature for 1.5 hours.Reactant mixture is concentrated, and the residue obtained is passed through silica gel column chromatography (chloroform / methanol) purification, and is further purified to obtain title compound (3.7 mg) by preparative thin layer chromatography (chloroform / methanol).

[0523] 1H-NMR (400 MHz, CDCl3) δ : 2.67 (2H, t, J = 6.6 Hz), 2.72-2.79 (6H,m), 3.41 (3H, s), 3.54 (4H, t, J = 4.8 Hz), 3.61-3.74 (4H, m), 5.86 (1H, d, J = 4.1 Hz), 7.36 (1H, dd, J = 7.6, 7.6 Hz), 7.47 (1H, dd, J = 7.3, 7.3 Hz), 7.81 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 8.3 Hz).

[0524] Example 113

[0525] 2-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-6-methyl-2,7-naphthyridin-1(2H)-one

[0526]

[0527] To a solution of the compound of Example 3 (104 mg) in 1,4-dioxane (1.0 mL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (60.3 mg). After stirring at 100 ° C for 1 hour, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was filtered, extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) and further purified by amino silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (10.5 mg).

[0528] 1 H-NMR (400 MHz, CDCl3) δ : 2.64 (3H, s), 2.73 (4H, t, J = 4.9 Hz), 2.81 (2H, t, J = 6.4 Hz), 3.54 (4H, t, J = 4.9 Hz), 4.13 (2H, t, J = 6.4 Hz), 6.34 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.17-7.22 (1H, m), 7.27 (1H, d, J =7.3 Hz), 7.41-7.50 (2H, m), 7.64 (1H, d, J = 7.9 Hz), 9.49 (1H, s).

[0529] Example 114

[0530] 6-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2,4-dimethylpyrido[4,3-d]pyrimidin-5(6H)-one

[0531]

[0532] The title compound was prepared according to a similar method to Example 1 from the compound of Reference Example 3 and 2,4-dimethyl-pyrido[4,3-d]pyrimidin-5(6H)-one.

[0533] 1 H-NMR (400 MHz, CDCl3) δ : 1.95-2.08 (4H, m), 2.25-2.35 (2H, m), 2.69(3H, s), 2.72 (2H, t, J = 6.1 Hz), 2.98 (3H, s), 2.99-3.10 (3H, m), 4.05 (2H,t, J = 6.4 Hz), 6.48 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (3H,m), 7.63 (1H, d, J = 7.9 Hz).

[0534] Examples 115-139

[0535] According to the method of Example 3, the compounds of Examples 115 to 139 were prepared from the corresponding compounds of Reference Examples.

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543] Examples 140-152

[0544] According to the method of Example 22, the compounds of Examples 140 to 152 were prepared from the corresponding compounds of Reference Example.

[0545]

[0546]

[0547]

[0548]

[0549] Example 153

[0550] 6-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0551]

[0552] According to the method of Example 32, the title compound was prepared from the corresponding Reference Example.

[0553] LC-MS: RT = 1.22 min, ObsMS = 379 [M+1].

[0554] Examples 154-175

[0555] According to the method of Example 37, the compounds of Examples 154 to 175 were prepared from the corresponding compounds of Reference Example.

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] Examples 176-179

[0564] According to the method of Example 88, the compounds of Examples 176 to 179 were prepared from the corresponding compounds of Reference Example.

[0565]

[0566] Examples 180-182

[0567] According to the method of Example 93, the compounds of Examples 180 to 182 were prepared from the corresponding compounds of Reference Example.

[0568]

[0569] Examples 183-185

[0570] According to the method of Example 108, the compounds of Examples 183-185 were prepared from the corresponding compounds of Example 144 or Example 146.

[0571]

[0572] Examples 186-187

[0573] According to the method of Example 106, the compounds of Examples 186-187 were prepared from the corresponding compounds of Example 144 or Example 146.

[0574]

[0575] Example 188

[0576] 7-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-fluoro-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0577]

[0578] To a solution of the compound of Example 146 (10.0 mg) in N,N-dimethylformamide (0.5 mL) was added cesium fluoride (18.5 mg). After stirring at 200 ° C for 2 hours under microwave irradiation, water was added to the reaction mixture. The mixture was extracted with chloroform, and the combined organic layer was concentrated. The concentrated residue was purified by preparative thin layer chromatography (chloroform / methanol) to obtain the title compound (1.6 mg).

[0579] 1H-NMR (400 MHz, CDCl3) δ : 1.99-2.16 (4H, m), 2.29 (2H, t, J = 11.5Hz), 2.73 (2H, t, J = 6.2 Hz), 3.05 (2H, t, J = 6.6 Hz), 3.09-3.18 (3H, m),3.73 (2H, t, J = 6.6 Hz), 3.78 (2H, t, J = 6.2 Hz), 7.02 (1H, dd, J = 8.3,3.2 Hz), 7.28-7.33 (1H, m), 7.51-7.59 (2H, m), 7.66-7.74 (2H,m).

[0580] Example 189

[0581] 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

[0582]

[0583] To the solution of the compound (210 mg) of reference example 54 in tetrahydrofuran (6.0 mL), 5 mol / L hydrochloric acid (1.2 mL) is added, and the mixture is stirred at room temperature for 6 hours.Then, saturated sodium bicarbonate aqueous solution is added in reaction mixture, and mixture chloroform is extracted, through anhydrous sodium sulfate drying, filtered, and concentrated.Concentrated residue is passed through amino silica gel column chromatography (chloroform / methanol) purifying, and is further purified to obtain title compound (96.0 mg) by reversed-phase liquid chromatography (acetonitrile / water, including 0.05% trifluoroacetic acid).

[0584] 1 H-NMR (400 MHz, CDCl3) δ : 1.99-2.12 (4H, m), 2.19-2.31 (2H, m), 2.65(2H, t, J = 6.6 Hz), 2.98 (2H, t, J = 6.7 Hz), 3.04-3.18 (3H, m), 3.64-3.73(4H, m), 7.24-7.28 (1H, m), 7.48-7.56 (2H, m), 7.69 (1H, d, J = 8.0 Hz), 7.95(1H, s).

[0585] Example 190

[0586] 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

[0587]

[0588] According to the similar method to Example 110 and Reference Example 52, the title compound was obtained from 3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride.

[0589] 1 H-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 = 7.8Hz), 7.77 (1H, s).

[0590] Example 191

[0591] 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

[0592]

[0593] To a solution of 6,7-dihydro-3H-imidazo[4,5-c]pyridin-4(5H)-one (78.5 mg) in tetrahydrofuran (2.0 mL) was added di-tert-butyl dicarbonate (187 mg). After stirring at room temperature for 24 hours, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography (chloroform / methanol). Tetrabutylammonium bromide (7.62 mg) and potassium hydroxide (6.03 mg) were added to a solution of the solid (17.0 mg) and the compound (19.9 mg) of Reference Example 3 in toluene (0.4 mL), and the mixture was stirred at room temperature for 6 hours. Then, 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added thereto. After stirring at room temperature for 24 hours, the reaction mixture was purified by amino silica gel column chromatography and silica gel column chromatography (chloroform / methanol) to obtain the title compound (14.4 mg).

[0594] 1 H-NMR (300 MHz, CDCl3) δ : 2.01-2.13 (4H, m), 2.25-2.37 (2H, m), 2.80(2H, t, J = 6.4 Hz), 2.94 (2H, t, J = 7.0 Hz), 3.00-3.16 (3H, m), 3.61 (2H,td, J = 7.1, 2.6 Hz), 4.44 (2H, t, J = 6.3 Hz), 5.23 (1H, s), 7.26-7.32 (1H,m), 7.50-7.59 (2H, m), 7.63 (1H, s), 7.73 (1H, d, J = 7.9 Hz).

[0595] Example 192

[0596] 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

[0597]

[0598] To a suspension of 55% sodium hydride (31.6 mg) in N,N-dimethylformamide (1.3 mL) was added 3-bromo-1-(4-methoxybenzyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (177 mg) at ice temperature. After stirring for 1 hour at ice temperature, potassium iodide (43.7 mg) and the compound of Reference Example 3 (146 mg) were added thereto, and the mixture was stirred at room temperature for 72 hours. Then, water (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate). Trifluoroacetic acid (1.0 mL) was added to the product obtained, and the mixture was stirred at 75 ° C for 2 hours. Then, the reaction mixture was purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (47.8 mg).

[0599] 1H-NMR (400 MHz, CDCl3) δ : 1.99-2.14 (4H, m), 2.24-2.32 (2H, m), 2.68(2H, t, J = 6.4 Hz), 3.02 (2H, t, J = 6.6 Hz), 3.06-3.14 (1H, m), 3.14-3.21(2H, m), 3.65-3.73 (4H, m), 7.27-7.31 (1H, m), 7.50-7.58 (2H, m), 7.70 (1H,d, J = 7.8 Hz).

[0600] Example 193

[0601] 6-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0602]

[0603] To the solution of the compound of Example 179 (100 mg) in 1,4-dioxane (0.7 mL) was added dimethyldioxirane (37.8 mg). After stirring at 100 ° C for 2 hours, a saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) and further purified by preparative thin layer column chromatography (ethyl acetate / methanol) to obtain the title compound (8.10 mg).

[0604] 1 H-NMR (400 MHz, CDCl3) δ : 2.67 (4H, t, J = 4.9 Hz), 2.74 (2H, t, J =6.1 Hz), 2.77 (3H, s), 3.49 (4H, t, J = 4.9 Hz), 4.08 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 7.12-7.17 (1H, m), 7.36-7.44 (2H, m), 7.47 (1H, d,J = 7.3 Hz), 7.60 (1H, d, J = 8.5 Hz), 9.49 (1H, s).

[0605] Example 194

[0606] 6-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one

[0607]

[0608] The title compound was prepared from the compound of Example 150 according to a procedure analogous to Example 193.

[0609] 1 H-NMR (400 MHz, CDCl3) δ: 1.91-2.08 (4H, m), 2.22-2.32 (2H, m), 2.71(2H, t, J = 6.1 Hz), 2.77 (3H, s), 2.95-3.08 (3H, m), 4.06 (2H, t, J) = 6.1Hz), 6.52 (1H, d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.44-7.52 (3H, m), 7.62(1H, d, J = 7.9 Hz), 9.49 (1H, s).

[0610] Reference Example 1

[0611] 3-[4-(2-chloroethyl)piperazin-1-yl]-1,2-benzisoxazole

[0612]

[0613] A mixture of 3-(piperazine-1-yl)benzo[d]isoxazole hydrochloride (5.44 g), potassium hydroxide (3.82 g), 1-bromo-2-chloroethane (9.41 mL), tetrahydrofuran (100 mL) and water (100 mL) was stirred at room temperature for 24 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.45 g).

[0614] 1 H-NMR (400 MHz, CDCl3) δ: 2.56-2.92 (6H, m), 3.42-3.76 (6H, m), 7.17-7.23 (1H, m), 7.42-7.50 (2H, m), 7.66 (1H, d, J = 7.9 Hz).

[0615] Reference Example 2

[0616] 3-[4-(2-chloroethyl)piperazin-1-yl]-1,2-benzisothiazole

[0617]

[0618] To a mixture of 3-(piperazine-1-yl)benzo[d]isothiazole (25.0 g), potassium hydroxide (12.8 g), tetrahydrofuran (60 mL) and water (7.5 mL) was added 1-bromo-2-chloroethane (37.8 mL), and the mixture was stirred at room temperature for 72 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (22.3 g).

[0619] 1 H-NMR (400 MHz, CDCl3) δ : 2.76 (4H, t, J = 5.0 Hz), 2.84 (2H, t, J =7.1 Hz), 3.58 (4H, t, J = 4.8 Hz), 3.65 (2H, t, J = 6.9 Hz), 7.33-7.39 (1H, m), 7.44-7.50 (1H, m), 7.79-7.83 (1H, m), 7.88-7.92 (1H, m).

[0620] Reference Example 3

[0621] 3-[1-(2-chloroethyl)piperidin-4-yl]-1,2-benzisoxazole

[0622]

[0623] To a mixture of 3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (2.01 g), tetrahydrofuran (4.0 mL), water (2.4 mL) was added potassium hydroxide (1.42 g), and the mixture was stirred at room temperature for 30 minutes. Then, 1-bromo-2-chloroethane (2.79 mL) was added thereto, and the mixture was stirred at room temperature for 24 hours. 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 purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (1.10 g).

[0624] 1H-NMR (400 MHz, CDCl3) δ : 2.04-2.20 (4H, m), 2.27-2.36 (2H, m), 2.80(2H, t, J = 7.1 Hz), 3.04-3.15 (3H, m), 3.64 (2H, t, J = 7.1 Hz), 7.27-7.32 (1H, m), 7.51-7.59 (2H, m), 7.74-7.78 (1H, m).

[0625] Reference Examples 4-5

[0626] According to the method of Reference Example 3, the compounds of Reference Examples 4-5 were prepared from the corresponding starting materials.

[0627]

[0628] Reference Example 6

[0629] 3-[1-(2-chloroethyl)piperidin-4-yl]-6-fluoro-5-methyl-1,2-benzisoxazole

[0630]

[0631] a) Preparation of tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (Compound IN-1-1)

[0632] 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, a saturated aqueous 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 a saturated aqueous ammonium chloride solution, washed with a saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (4.52 g).

[0633] 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).

[0634] b) Preparation of tert-butyl 4-(2,4-difluoro-5-methylbenzoyl)piperidine-1-carboxylate (Compound IN-1-2)

[0635] 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 for 3 minutes. After stirring at -78 ° C for 1 hour, compound IN-1-1 (1.50 g) was added thereto, and the mixture was stirred at -78 ° C for 2.5 hours. Then, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.01 g).

[0636] 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).

[0637] c) Preparation of tert-butyl 4-(6-fluoro-5-methyl-1,2-benzisoxazol-3-yl)piperidine-1-carboxylate (Compound IN-1-3)

[0638] The mixture of compound IN-1-2 (731 mg), hydroxylamine hydrochloride (599 mg), sodium acetate (707 mg) and ethanol (10 mL) was stirred at 60 DEG C for 4 hours.Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was passed through silica gel column chromatography (hexane / ethyl acetate) purification. The mixture of the product (335 mg), cesium carbonate (615 mg) and acetonitrile (9.0 mL) obtained was stirred at 130 DEG C for 3.5 hours in a closed tube.Then, the reaction mixture was filtered, concentrated, and purified to obtain title compound (90.8 mg) by silica gel column chromatography (hexane / ethyl acetate).

[0639] 1H-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).

[0640] d) Preparation of 3-[1-(2-chloroethyl)piperidin-4-yl]-6-fluoro-5-methyl-1,2-benzisoxazole (Reference Example 6)

[0641] To the solution of compound IN-1-3 (131 mg) in dichloromethane (1.0 mL), 4 mol / L hydrochloric acid / ethyl acetate (1.0 mL) is added, and the mixture is stirred at room temperature for 1.5 hours.Then, reaction mixture is concentrated to obtain solid (114 mg).The mixture of the solid (114 mg), potassium carbonate (232 mg), 1-bromo-2-chloroethane (301 mg), tetrahydrofuran (1.7 mL) and water (0.42 mL) obtained is stirred at room temperature overnight.Then, reaction mixture is concentrated, and residue is passed through silica gel chromatography (hexane / ethyl acetate) purifying to obtain title compound (41.8 mg).

[0642] 1 H-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).

[0643] Reference Example 7

[0644] 3-[1-(2-chloroethyl)piperidin-4-yl]-5-methyl-1,2-benzisoxazole

[0645]

[0646] The title compound was prepared according to a similar method to Reference Example 6 from 1-fluoro-2-iodo-4-methylbenzene.

[0647] 1H-NMR (400 MHz, CDCl3) δ : 1.97-2.25 (4H, m), 2.27-2.42 (2H, m), 2.45(3H, s), 2.71-2.97 (2H, m), 2.99-3.22 (3H, m), 3.58-3.80 (2H, m), 7.24-7.27(1H, m), 7.33 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz).

[0648] Reference Example 8

[0649] 3-(Piperidin-4-yl)-1,2-benzisothiazole

[0650]

[0651] a) Preparation of tert-butyl 4-[2-(benzylsulfanyl)benzoyl]piperidine-1-carboxylate (Compound IN-2-1)

[0652] To a solution of tert-butyl 4-(2-fluorobenzoyl)piperidine-1-formate (664 mg) in dimethyl sulfoxide (5.0 mL) was added anhydrous sodium sulfide (554 mg), and the mixture was stirred at 80 ° C for 2 hours. Then, another anhydrous sodium sulfide (560 mg) was added thereto, and the mixture was stirred at 110 ° C for 3 hours. Potassium carbonate (895 mg) and benzyl bromide (0.270 mL) were added to the reaction mixture. After stirring at room temperature for 5 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (391 mg).

[0653] LC-MS: RT = 2.12 min ObsMS = 412 [M+1]

[0654] b) Preparation of tert-butyl 4-(1,2-benzisothiazol-3-yl)piperidine-1-carboxylate (Compound IN-2-2)

[0655] To the solution of compound IN-2-1 (391 mg) in dichloromethane (5.0 mL) at ice temperature, sulfuryl chloride (0.081 mL) is added, and the mixture is stirred at ice temperature for 1 hour.Then, the reaction mixture is concentrated, and 2 mol / L ammonia-ethanol (4.75 mL) is added to the solution of the residue obtained in tetrahydrofuran (5.0 mL), and the mixture is stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After washing with salt water, the mixture is dried over anhydrous sodium sulfate, filtered, and concentrated. Residue is passed through silica gel column chromatography (hexane / ethyl acetate) purifying to obtain title compound (187 mg).

[0656] 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).

[0657] c) Preparation of 3-(piperidin-4-yl)-1,2-benzisothiazole (Reference Example 8)

[0658] To a solution of compound IN-2-2 (173 mg) in chloroform (5.0 mL) was added 4 mol / L hydrochloric acid-ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was then concentrated to give the title compound (119 mg).

[0659] LC-MS: RT = 1.28 min ObsMS = 219 [M+1].

[0660] Reference Example 9

[0661] 6-Fluoro-3-(piperazin-1-yl)-1,2-benzisothiazole

[0662]

[0663] a) Preparation of tert-butyl 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperazine-1-carboxylate (Compound IN-3-1)

[0664] To 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 bromotris(pyrrolidin-1-yl)phosphonium(V) hexafluorophosphate (6.06 g). After stirring at room temperature for 1 hour, tert-butylpiperazine-1-carboxylate (6.61 g) was added to the reaction mixture, and the reaction mixture was stirred at 80°C for 48 hours. Water was then added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.260 g).

[0665] 1 H-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).

[0666] b) Preparation of 6-fluoro-3-(piperazin-1-yl)-1,2-benzisothiazole (Reference Example 9)

[0667] To a solution of compound IN-3-1 (912 mg) in dichloromethane (6.8 mL) was added trifluoroacetic acid (6.8 mL), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was then concentrated, saturated sodium bicarbonate was added thereto, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain title compound (639 mg).

[0668] 1 H-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, 1.8Hz), 7.85 (1H, dd, J = 8.9, 4.8 Hz).

[0669] Reference Example 10

[0670] 6-Methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0671]

[0672] To a 28% sodium methoxide-methanol solution (50.0 mL) at room temperature was added 6-bromo-3,4-dihydro-2,7-naphthyridin-1(2H)-one (5.00 g). After stirring at 70°C for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.68 g).

[0673] 1 H-NMR (400 MHz, CDCl3) δ : 2.92 (2H, t, J = 6.4 Hz), 3.53 (2H, td, J= 6.5, 3.1 Hz), 3.96 (3H, s), 6.06 (1H, br s), 6.53 (1H, d, J = 0.9 Hz), 8.80(1H, s).

[0674] Reference Example 11

[0675] 5-Methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0676]

[0677] a) Preparation of methyl 3-(cyanomethyl)pyridine-2-carboxylate (compound IN-4-1)

[0678] To a solution of methyl 3-picolinate (1.00 g) in chloroform (27 mL) 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). Sodium cyanide (0.0712 g) was added to a solution of the obtained product (0.304 g) in N,N-dimethylformamide (3.3 mL) at room temperature. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.0440 g).

[0679] 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, 1.4Hz).

[0680] b) Preparation of methyl 3-(1-cyanoethyl)pyridine-2-carboxylate (compound IN-4-2)

[0681] To a solution of compound IN-4-1 (63.0 mg) in tetrahydrofuran (1.2 mL) was added 55% sodium hydride (15.6 mg) at ice temperature. After stirring at 0 ° C for 30 minutes, a solution of iodomethane (0.0291 mL) in tetrahydrofuran (0.30 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).

[0682] 1 H-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).

[0683] c) Preparation of 5-methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Reference Example 11)

[0684] To a solution of compound IN-4-2 (35.0 mg) in ethanol (2.17 mL) was added Raney nickel (15.8 mg) at ice temperature. After stirring at 50 ° C for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered through diatomaceous earth (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).

[0685] 1H-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).

[0686] Reference Example 12

[0687] 1-Methyl-1,5,6,7-tetrahydro-4H-imidazo[4,5-c]pyridin-4-one

[0688]

[0689] a) Preparation of 1-methyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (Compound IN-5-1)

[0690] 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. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (127 mg).

[0691] 1 H-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).

[0692] b) Preparation of 1-methyl-1,5,6,7-tetrahydro-4H-imidazo[4,5-c]pyridin-4-one (Reference Example 12)

[0693] A mixture of compound IN-5-1 (0.106 g), 20% palladium hydroxide on carbon (1.25 g) and acetic acid (7.1 mL) was stirred at 70 ° C for 8 hours under a hydrogen atmosphere (1 atmosphere). Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (13.9 mg).

[0694] 1 H-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).

[0695] Reference Example 13

[0696] 2-Methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0697]

[0698] To a mixture of piperidine-2,4-dione (19.0 g), acetic acid (1.01 g), and N,N-dimethylformamide (80 mL) was added methylhydrazine (7.74 g) at 0°C, and the mixture was stirred for 20 minutes. After stirring at room temperature for 1 hour, N,N-dimethylformamide dimethyl acetal (44.0 g) was added. After stirring at 60°C for 2 hours, the reaction mixture was cooled to room temperature, diethyl ether (100 mL) was added, and the mixture was stirred at 0°C for 30 minutes. The precipitated solid was collected by filtration to obtain the title compound (14.4 g).

[0699] 1 H-NMR (400 MHz, CDCl3) δ : 2.91 (2H, t, J = 6.6 Hz), 3.57 (2H, td, J= 6.6, 2.6 Hz), 3.90 (3H, s), 5.85 (1H, s), 7.78 (1H, s).

[0700] Reference Example 14

[0701] 2-Cyclopropyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0702]

[0703] According to a similar method to Reference Example 13, the title compound was purified by cyclopropylhydrazine monohydrochloride.

[0704] 1 H-NMR (400 MHz, CDCl3) δ: 1.03-1.15 (4H, m), 2.91 (2H, t, J = 6.6Hz), 3.55-3.60 (2H, m), 5.56 (1H, brs), 7.87 (1H, s).

[0705] Reference Example 15

[0706] 1-Methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0707]

[0708] To a solution of piperidine-2,4-dione (500 mg) in ethanol (9.0 mL) was added N,N-dimethylformamide dimethyl acetal (632 mg), and the mixture was heated under reflux for 2 hours. Then, methyl hydrazine (224 mg) was added dropwise at ice temperature, and the mixture was stirred at room temperature for 2 hours. After stirring at 80 ° C for 1 hour, ether (15 mL) was added thereto. The mixture was ground, and the solid was collected by filtration to obtain the title compound (565 mg).

[0709] 1 H-NMR (400 MHz, CDCl3) δ : 2.91 (2H, t, J = 6.6 Hz), 3.63 (2H, td, J= 6.8, 2.4 Hz), 3.84 (3H, s), 6.10 (1H, s), 7.87 (1H, s).

[0710] Reference Example 16

[0711] 1,7-Dimethyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0712]

[0713] The title compound was prepared according to a similar method to Reference Example 15 from 5-methyl-2,4-piperidinedione.

[0714] 1 H-NMR (400 MHz, CDCl3) δ : 1.33 (3H, d, J = 6.9 Hz), 3.06-3.14 (1H,m), 3.29 (1H, dq, J = 12.5, 2.2 Hz), 3.79 (1H, dd, J = 12.4, 5.0 Hz), 3.85 (3H, s), 5.29 (1H, brs), 7.86 (1H, s).

[0715] Reference Example 17

[0716] 1-Methyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-4(1H)-one

[0717]

[0718] a) Preparation of N-(1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-ylidene)hydroxylamine (Compound IN-6-1)

[0719] 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 hours. The reaction mixture was then filtered and concentrated. The concentrated residue was triturated with hexane:ethyl acetate (1:1), collected by filtration, and dried to give the title compound (635 mg).

[0720] 1 H-NMR (400 MHz, CDCl3) δ: 2.00-2.08 (2H, m), 2.48 (2H, t, J = 6.2Hz), 2.73 (2H, t, J = 6.2 Hz), 3.81 (3H, s), 8.19 (1H, s).

[0721] b) Preparation of 1-methyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-4(1H)-one (Reference Example 17)

[0722] To the mixture of compound IN-6-1 (7.86 g), triethylamine (9.95 mL) and dichloromethane (95 mL), p-toluenesulfonyl chloride (10.4 g) was added, and the mixture was heated under reflux for 30 minutes. Then, saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl acetate (18 mL) was added to the residue, and the mixture was heated to 80°C. After confirming that all solids had dissolved, the mixture was gradually cooled to room temperature, and hexane (18 mL) and ethyl acetate (3.0 mL) were added in succession. 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 under reflux for 30 minutes. The product of 4-nitro-1-oxo-2-oxo-4-oxo-1-oxo-4-oxo-2 ...

[0723] 1 H-NMR (400 MHz, CDCl3) δ : 2.13-2.20 (2H, m), 2.91 (2H, t, J = 6.4Hz), 3.38 (2H, td, J = 5.0, 5.0 Hz), 3.79 (3H, s), 6.10 (1H, brs), 7.99 (1H,s).

[0724] Reference Example 18

[0725] 1,3-Dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-4(1H)-one

[0726]

[0727] According to a similar method to Reference Example 17, the title compound was obtained from 1,3-dimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one.

[0728] 1H-NMR (400 MHz, CDCl3) δ: 2.06-2.13 (2H, m), 2.44 (3H, s), 2.86 (2H,t, J = 6.7 Hz), 3.26-3.33 (2H, m), 3.69 (3H, s), 6.18 (1H, brs).

[0729] Reference Example 19

[0730] 6-Methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0731]

[0732] a) Preparation of methyl 4-chloro-6-methylpyridine-3-carboxylate (compound IN-7-1)

[0733] To a solution of 4-hydroxy-6-methylnicotinate (1.00 g) in toluene (6.5 mL) was added N, N-dimethylformamide (0.0200 mL), and then oxalyl chloride (3.00 mL) was added dropwise at room temperature. 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 sodium bicarbonate aqueous 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).

[0734] 1 H-NMR (400 MHz, CDCl3) δ: 2.57 (3H, s), 3.93 (3H, s), 7.27 (1H, s), 8.92 (1H, s).

[0735] b) Preparation of methyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-methylpyridine-3-carboxylate (Compound IN-7-2)

[0736] To a mixture of compound IN-7-1 (5.03 g) and toluene / water (3:1, 54 mL) were added tert-butyl N-[2-(trifluoroborylethyl]carbamate potassium salt (10.2 g), cesium carbonate (22.1 g), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane addition compound (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. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.84 g).

[0737] 1 H-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).

[0738] c) Preparation of 6-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one (Reference Example 19)

[0739] In room temperature, 4 mol / L hydrochloric acid-ethyl acetate (21.2 mL, 85.0 mmol) is added to a solution of compound IN-7-2 (1.25 g) in ethyl acetate / methanol (1: 1, 4.2 mL). After stirring at room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in methanol (5.0 mL), and 28% sodium methoxide-methanol solution (3.27 g) is added thereto at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture is concentrated under reduced pressure. 2 mol / L hydrochloric acid (10.0 ml) is added to the residue, and the water layer is washed with ethyl acetate. 1 mol / L sodium hydroxide aqueous solution is added to the water layer to neutralize, and the mixture is extracted with chloroform / methanol (4: 1). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is ground together with ethanol / hexane to obtain the title compound (519 mg).

[0740] 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).

[0741] Reference Example 20

[0742] 6'-Methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridine]-1'-one

[0743]

[0744] a) Preparation of methyl 6-chloro-4-(cyanomethyl)pyridine-3-carboxylate (compound IN-8-1)

[0745] To a solution of methyl 4,6-dichloronicotinate (5.00 g) in N,N-dimethylformamide (49 mL) was added potassium carbonate (6.71 g) and tert-butyl cyanoacetate (3.77 g) at room temperature. After stirring at 100°C for 2 hours, water (100 mL) was added to the reaction mixture, and the mixture was neutralized with 2 mol / L hydrochloric acid (35 mL) and extracted with toluene (100 mL x 4). After washing the organic layer with 0.1 mol / L hydrochloric acid (50 mL), the mixture was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure until the solvent was reduced to 300 mL, and p-toluenesulfonic acid monohydrate (0.462 g) was added thereto. After stirring at 100°C for 1 hour, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.35 g).

[0746] 1 H-NMR (400 MHz, CDCl3) δ: 3.97 (3H, s), 4.28 (2H, s), 7.65 (1H, s), 9.02 (1H, s).

[0747] b) Preparation of methyl 4-(cyanomethyl)-6-methylpyridine-3-carboxylate (compound IN-8-2)

[0748] To a solution of compound IN-8-1 (2.55 g) in 1,2-dimethoxyethane (17 mL) was added potassium carbonate (2.51 g), trimethylcyclotriboroxane (5.08 mL), 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).

[0749] 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).

[0750] c) Preparation of methyl 4-(1-cyanocyclopropyl)-6-methylpyridine-3-carboxylate (compound IN-8-3)

[0751] To a solution of compound IN-8-2 (101 mg) in acetonitrile (1.8 mL) was 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).

[0752] 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).

[0753] d) Preparation of 6'-methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-1'-one (Reference Example 20)

[0754] 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) at ice temperature. After stirring at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered through diatomaceous earth (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).

[0755] 1 H-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).

[0756] Reference Example 21

[0757] 4,4,6-Trimethyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one

[0758]

[0759] The title compound was prepared from compound IN-8-2 according to a similar method to Reference Example 20 using iodomethane.

[0760] 1 H-NMR (400 MHz, CDCl3) δ: 1.36 (6H, s), 2.62 (3H, s), 3.34 (2H, d, J= 0.8 Hz), 6.52 (1H, brs), 7.09 (1H, s), 9.09 (1H, s).

[0761] Reference Example 22

[0762] 7-(2-Hydroxy-2-methoxyethyl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0763]

[0764] a) Preparation of 7-(prop-2-en-1-yl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Compound IN-9-1)

[0765] To a solution of 6,7-dihydro-1,7-naphthyridine-8 (5H) -one (1.29 g) in DMF (20 mL) was added 55% sodium hydride (0.456 g) at ice temperature, and the mixture was stirred for 1 hour. Then, allyl iodide (0.949 mL) was added thereto at ice temperature, 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 the mixture was concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.97 g).

[0766] 1 H-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).

[0767] b) Preparation of 7-(2-hydroxy-2-methoxyethyl)-6,7-dihydro-1,7-naphthyridin-8(5H)-one (Reference Example 22)

[0768] To a mixture of compound IN-9-1 (1.69 g), tetrahydrofuran (44 mL) and water (22 mL) was added sodium periodate (4.80 g) and osmium tetroxide (0.183 g) at ice temperature. After stirring for 6 hours at ice temperature, the reaction mixture was filtered through diatomaceous earth (Celite) and washed with chloroform / methanol (4 / 1). Saturated aqueous sodium thiosulfate solution was added to the filtrate, and the mixture was extracted with chloroform / methanol (4 / 1, 50 mL x 12), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.65 g).

[0769] 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).

[0770] Reference Examples 23-25

[0771] According to the method of Reference Example 22, the compounds of Reference Examples 23-25 ​​were prepared from the corresponding starting materials.

[0772]

[0773] Reference Example 26

[0774] 2-Methyl-6,7-dihydro[1,3]oxazolo[5,4-c]pyridin-4(5H)-one

[0775]

[0776] a) Preparation of ethyl 5-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate (Compound IN-10-1)

[0777] 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 thereto. After stirring at room temperature for 1.5 hours, ethyl malonate potassium salt (9.91 g) was added, and then magnesium chloride (5.54 g) was slowly added. After stirring for 15 minutes, the mixture was 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (8.58 g).

[0778] 1H-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).

[0779] b) Preparation of ethyl 5-{[(benzyloxy)carbonyl]amino}-2-chloro-3-oxopentanoate (Compound IN-10-2)

[0780] Compound IN-10-1 (8.58 g) was dissolved in dichloromethane (150 mL) and sulfuryl chloride (2.38 mL) was added dropwise at 0°C. After stirring at 0°C for 2 hours, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (9.47 g).

[0781] 1 H-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).

[0782] c) Preparation of ethyl 2-(acetyloxy)-5-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate (Compound IN-10-3)

[0783] Compound IN-10-2 (1.50 g) is dissolved in acetonitrile (5.0 mL), and acetic acid (0.786 mL) and triethylamine (3.19 mL) are added thereto, and the mixture is stirred at room temperature overnight. Then, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer combined is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain title compound (1.57 g).

[0784] 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).

[0785] d) Preparation of ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-4)

[0786] Compound IN-10-3 (9.11 g) and ammonium acetate (4.00 g) were dissolved in acetic acid (40 mL), and the mixture was heated at 120 ° C for 1 hour. After cooling to room temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (8.74 g).

[0787] 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).

[0788] e) Preparation of ethyl 4-(2-aminoethyl)-2-methyl-1,3-oxazole-5-carboxylate (Compound IN-10-5)

[0789] Compound IN-10-4 (3.44 g) and 5% Pd-C (2.00 g) were dissolved in ethanol (25 mL). The mixture was then stirred at room temperature for 20 hours under a hydrogen atmosphere and filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (1.78 g).

[0790] 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).

[0791] f) Preparation of 2-methyl-6,7-dihydro[1,3]oxazolo[5,4-c]pyridin-4(5H)-one (Reference Example 26)

[0792] 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 the solvent was removed. The residue was then purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.322 g).

[0793] 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).

[0794] Reference Examples 27-30

[0795] According to the method of Reference Example 26, the compounds of Reference Examples 27-30 were prepared from the corresponding starting materials.

[0796]

[0797] Reference Example 31

[0798] 2-Methyl-6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-4(5H)-one

[0799]

[0800] a) Preparation of ethyl 5-(2-{[(benzyloxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylate (Compound IN-11-1)

[0801] To a solution of 3-([(benzyloxy)carbonyl]amino)propanoic 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 isocyanatoethyl acetate (3.20 mL) were added thereto. 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).

[0802] 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).

[0803] b) Preparation of ethyl 5-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-iodo-1,3-oxazole-4-carboxylate (Compound IN-11-2)

[0804] To the solution of compound IN-11-1 (446 mg) in tetrahydrofuran (2.1 mL), 1.0 mol / L bis (trimethylsilyl) lithium amide-tetrahydrofuran solution (3.08 mL) was added at -40 ° C. After stirring for 15 minutes at -40 ° C, 0.5 mol / L zinc chloride-tetrahydrofuran solution (6.17 mL) was added thereto, and the mixture was warmed to 0 ° C and kept for 45 minutes, and iodine (462 mg) was added. After stirring at room temperature for 1 hour, saturated sodium thiosulfate aqueous 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. Residue was passed through silica gel column chromatography (hexane / ethyl acetate) to obtain title compound (510 mg).

[0805] 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).

[0806] c) Preparation of ethyl 5-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-1,3-oxazole-4-carboxylate (Compound IN-11-3)

[0807] To a solution of compound IN-11-2 (265 mg) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (247 mg), trimethylcyclotriboroxine (97.0 mg) and tetrakis(triphenylphosphine)palladium (68.9 mg) at room temperature. After reacting at 120 ° C. for 1.5 hours under microwave irradiation, the reaction mixture was filtered through diatomaceous earth (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).

[0808] 1 H-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).

[0809] d) Preparation of 2-methyl-6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-4(5H)-one (Reference Example 31)

[0810] To a solution of compound IN-11-3 (710 mg) in ethanol (11 mL) was added palladium on carbon (227 mg) at room temperature. After stirring at room temperature under a hydrogen atmosphere for 15 hours, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure.

[0811] To the solution of the obtained residue (423 mg) in 1,2-dimethoxyethane / water (1 / 1, 1.9 mL) 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 obtain the title compound (209 mg).

[0812] 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).

[0813] Reference Example 32

[0814] 2-Methyl-5,6,7,8-tetrahydro-4H-[1,3]oxazolo[4,5-c]azepine-4-one

[0815]

[0816] The title compound was prepared according to a similar method to Reference Example 31 from 4-([(benzyloxy)carbonyl]amino)butyric acid.

[0817] 1 H-NMR (400 MHz, CDCl3) δ: 2.07-2.13 (2H, m), 2.44 (3H, s), 2.94 (2H,t, J = 6.7 Hz), 3.37 (2H, dd, J = 9.8, 5.4 Hz), 6.12 (1H, brs).

[0818] Reference Example 33

[0819] 1-Methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepine-8(1H)-one

[0820]

[0821] a) Preparation of methyl 4-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-methyl-1H-pyrazole-5-carboxylate (Compound IN-12-1)

[0822] To a solution of 4-iodo-1-methyl-1H-pyrazole-5-formic acid methyl ester (600 mg) in N,N-dimethylformamide (5.0 mL) was added benzyl propane-2-yn-1-ylcarbamate (640 mg), triethylamine (2.20 mL), bis(triphenylphosphine)palladium dichloride (II) (158 mg) and cuprous iodide (I) (43.0 mg), and the mixture was stirred at 90 ° C for 3 hours. After this, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate / toluene (1 / 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (610 mg).

[0823] 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).

[0824] b) Preparation of 1-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepine-8(1H)-one (Reference Example 33)

[0825] To a solution of compound IN-12-1 (610 mg) in methanol (10 mL) 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 diatomaceous earth (Celite) and concentrated. To a solution of the obtained residue in ethanol (10 mL) was added triethylamine (0.519 mL), and the mixture was heated under reflux for 140 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (130 mg).

[0826] 1 H-NMR (400 MHz, CDCl3) δ: 1.99-2.07 (2H, m), 2.86 (2H, t, J = 7.1Hz), 3.28-3.34 (2H, m), 4.14 (3H, s), 5.93 (1H, brs), 7.31 (1H, s).

[0827] Reference Example 34

[0828] 2-Methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]azepine-8(2H)-one

[0829]

[0830] According to a similar method to Reference Example 33, the title compound was obtained from methyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate.

[0831] 1 H-NMR (400 MHz, CDCl3) δ: 2.00-2.09 (2H, m), 2.83 (2H, t, J = 6.8Hz), 3.33-3.40 (2H, m), 3.95 (3H, s), 6.11 (1H, brs), 7.23 (1H, s).

[0832] Reference Example 35

[0833] 3-Methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepine-4(3H)-one

[0834]

[0835] a) Preparation of methyl 4-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-methyl-1H-imidazole-5-carboxylate (Compound IN-13-1)

[0836] The mixture of 4-imidazolecarboxylic acid methyl ester (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 passed through silica gel column chromatography (chloroform / methanol) purification. Under ice temperature, 55% sodium hydride (0.0680 g) was added to a solution of the purified product (0.267 g) obtained in N, N-dimethylformamide (6.5 mL). After stirring at ice temperature for 30 minutes, iodomethane (0.277 g) was added thereto, and the mixture was stirred at room temperature for 4 hours. Methanol was added to the reaction mixture, and the mixture was concentrated. The residue was passed through silica gel column chromatography (chloroform / methanol) purification. The mixture of the purified product (176 mg), N-(tert-butoxycarbonyl) propargylamine (228 mg), cuprous iodide (I) (15.3 mg), triethylamine (0.569 g), bis(triphenylphosphine) palladium dichloride (II) (56.4 mg) and N,N-dimethylformamide (15 mL) was stirred at 100 ° C for 1.5 hours under microwave irradiation. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (101 mg).

[0837] 1 H-NMR (400 MHz, CDCl3) δ: 3.79-3.91 (5H, m), 4.27 (2H, d, J = 5.1Hz), 5.13 (3H, s), 7.28-7.42 (5H, m), 7.49-7.61 (1H, m).

[0838] b) Preparation of 3-methyl-5,6,7,8-tetrahydroimidazo[4,5-c]azepine-4(3H)-one (Reference Example 35)

[0839] The mixture of compound IN-13-1 (101 mg), 20% carbon-supported palladium hydroxide (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 mixture of the residue (60.9 mg), triethylamine (125 mg) and ethanol (1.6 mL) obtained was stirred at 100 DEG C for 72 hours. The reaction mixture was concentrated, and the residue was passed through into silica gel column chromatography (chloroform / methanol) purification to obtain title compound (6.6 mg).

[0840] 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).

[0841] Reference Example 36

[0842] 1-Methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0843]

[0844] The mixture of 2,4-piperidinedione (200 mg), methylaminoacetaldehyde dimethyl acetal (253 mg), p-toluenesulfonic acid monohydrate (33.6 mg) and toluene (8.8 mL) was stirred at 140 ° C for 1 hour with Dean-Stark equipment. Then, the reaction mixture was concentrated under reduced pressure, and trifluoroacetic acid (1.6 mL) was added thereto at room temperature. After stirring at room temperature for 24 hours, toluene was added, and the solvent azeotropic was removed. Residue was passed through amino silica gel column chromatography (chloroform / methanol) purification to obtain title compound (194 mg).

[0845] 1 H-NMR (400 MHz, CDCl3) δ : 2.81 (2H, t, J = 6.9 Hz), 3.55-3.62 (5H,m), 5.34 (1H, brs), 6.54 (1H, d, J = 5.0 Hz), 6.55 (1H, d, J = 4.6 Hz).

[0846] Reference Example 37

[0847] 1,7-Dimethyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0848]

[0849] The title compound was prepared according to a similar method to Reference Example 36 from 5-methyl-2,4-piperidinedione.

[0850] 1H-NMR (400 MHz, CDCl3) δ : 1.25 (3H, d, J = 7.3 Hz), 3.01-3.09 (1H,m), 3.39-3.46 (1H, m), 3.62 (3H, s), 3.82 (1H, dd, J = 13.1, 5.3 Hz), 6.52 (1H, d, J = 3.2 Hz), 6.57 (1H, d, J = 3.2 Hz), 8.82 (1H, brs).

[0851] Reference Example 38

[0852] 2,3-Dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0853]

[0854] To a solution of piperidine-2,4-dione (10.0 g, 88.0 mmol) in N,N-dimethylformamide (44 mL) was added methylhydrazine (4.70 mL, 88.0 mmol) at ice temperature. After stirring at room temperature for 1 hour, N,N-dimethylacetamide dimethyl acetal (65.4 mL, 442 mmol) was added to the reaction mixture. After stirring at 130°C for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain the title compound (11.2 g).

[0855] 1 H-NMR (400 MHz, CDCl3) δ: 2.51 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.51 (2H, td, J = 6.6, 2.8 Hz), 3.74 (3H, s), 5.34 (1H, s).

[0856] Reference Examples 39 and 40

[0857] 3-Bromo-1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 39)

[0858] 3-Bromo-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Reference Example 40)

[0859]

[0860] a) Preparation of 3-bromo-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound IN-14-1)

[0861] 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) was added bromine (0.451 mL) at ice temperature. After stirring at ice temperature for 2 hours, additional sodium acetate (1.44 g) and bromine (0.451 mL) were added. After stirring at ice temperature for another 2 hours, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in methanol, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (1.02 g).

[0862] 1 H-NMR (400 MHz, CD3OD) δ: 2.96 (2H, t, J = 6.9 Hz), 3.54 (2H, t, J =6.9 Hz).

[0863] 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)

[0864] To a solution of compound IN-14-1 (1.02 g) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.31 g) and iodomethane (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).

[0865] 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).

[0866] Reference Example 40: 1H-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).

[0867] Reference Example 41

[0868] 2-Methyl-3-(trifluoromethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0869]

[0870] To a mixture of the compound of Reference Example 13 (100 mg), bis(((trifluoromethyl)sulfinyl)oxy)zinc (439 mg), dichloromethane (3.0 mL) and water (1.2 mL) was added dropwise 70% 2-hydroperoxide-2-methylpropane aqueous solution (0.362 mL) at ice temperature. After stirring at room temperature for 16 hours, a 10% aqueous sodium thiosulfate solution was added to the reaction mixture. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.0400 g).

[0871] 1 H-NMR (400 MHz, CDCl3) δ : 2.92 (2H, t, J = 6.6 Hz), 3.56 (2H, td, J = 6.6, 3.2 Hz), 4.04 (3H, q, J = 1.4 Hz), 5.79 (1H, brs).

[0872] Reference Example 42

[0873] 2-Methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one

[0874]

[0875] a) Preparation of (3E)-3-[(dimethylamino)methoxy]piperidine-2,4-dione (Compound IN-15-1)

[0876] To a solution of piperidine-2,4-dione (2.50 g) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamide dimethyl acetal (3.52 mL), and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was then concentrated to give the title compound (3.72 g).

[0877] 1 H-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).

[0878] b) Preparation of 2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (Reference Example 42)

[0879] 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 purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (87.9 mg).

[0880] 1 H-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).

[0881] Reference Examples 43-44

[0882] According to the method of Reference Example 42, the compounds of Reference Examples 43-44 were prepared using corresponding reagents.

[0883]

[0884] Reference Example 45

[0885] 2-[4-(1,2-Benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine dihydrochloride

[0886]

[0887] a) Preparation of tert-butyl {2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}carbamate (Compound IN-16-1)

[0888] 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 layer was washed with water and salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain title compound (5.70 g).

[0889] 1 H-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).

[0890] b) Preparation of 2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethan-1-amine dihydrochloride (Reference Example 45)

[0891] The title compound was prepared from compound IN-16-1 according to a similar method to Reference Example 8.

[0892] 1H-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).

[0893] Reference Example 46

[0894] 1-Methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxylic acid methyl ester

[0895]

[0896] a) Preparation of methyl 4-[(Z)-2-ethoxyvinyl]-1-methyl-1H-pyrazole-5-carboxylate (Compound IN-17-1)

[0897] The title compound was prepared from methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate according to a similar method to compound IN-12-1.

[0898] 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).

[0899] b) Preparation of methyl 1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxylate (Reference Example 46)

[0900] 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) at ice temperature, and the mixture was stirred at 40° C. for 3 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (79.2 mg).

[0901] 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).

[0902] Reference Example 47

[0903] 1-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}azepane-2,4-dione

[0904]

[0905] a) Preparation of 1,4-dioxa-8-azaspiro[4.6]undecan-7-one (Compound IN-18-1)

[0906] To a solution of azepane-2,4-dione (1.07 g) in toluene (15 mL), ethane-1,2-diol (0.570 mL) and methanesulfonic acid (0.0270 mL) were added, and the mixture was heated under reflux for 4 hours with a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, and hexane (15 mL) was added thereto. After stirring at room temperature for 30 minutes, the precipitated solid was collected by filtration, washed with toluene / hexane = 1 / 1 (2.0 mL) to obtain the title compound (1.37 g).

[0907] 1 H-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).

[0908] b) Preparation of 1-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}azepane-2,4-dione (Reference Example 47)

[0909] To a solution of compound IN-18-1 (375 mg) in N,N-dimethylformamide (4.4 mL) was added 55% sodium hydride (96.0 mg) at ice temperature. After stirring at ice temperature for 20 minutes, 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 remove the remaining N,N-dimethylformamide, toluene was added to the residue and concentrated, and these operations were repeated twice. Tetrahydrofuran (7.3 mL) and 6 mol / L hydrochloric acid (7.30 mL) were added to the concentrated residue obtained, and the mixture was stirred at 60 ° C for 1 hour. Then, a 2 mol / L sodium hydroxide aqueous solution was added to the reaction mixture, and the pH was adjusted to 7 or higher. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (630 mg).

[0910] 1 H-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).

[0911] Reference Example 48

[0912] 8-{2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-1,4-dioxa-8-azaspiro[4.5]decan-7-one

[0913]

[0914] The title compound was prepared according to a method similar to Example 47 using piperidine-2,4-dione.

[0915] 1H-NMR (400 MHz, CDCl3) δ: 1.89-1.97 (2H, m), 2.01-2.08 (4H, m), 2.18-2.25 (2H, m), 2.55-2.60 (2H, m), 2.59 (2H, s), 3.04-3.08 (3H, m), 3.45(2H, t, J = 6.4 Hz), 3.52 (2H, t, J = 6.4 Hz), 3.92-4.00 (4H, m), 7.24-7.28(2H, m), 7.48-7.55 (2H, m), 7.69-7.73 (1H, m).

[0916] Reference Example 49

[0917] 1-{2-[4-(1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}azepane-2,4-dione

[0918]

[0919] To a solution of compound IN-18-1 (1.20 g) in N,N-dimethylformamide (20 mL) was added 55% sodium hydride (0.421 g) at ice temperature. After stirring for 30 minutes at ice temperature, the compound (1.86 g) and potassium iodide (0.582 g) of Reference Example 1 were added thereto, and the mixture was stirred at 60 ° C for 4 hours. Then, 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was stirred at 90 ° C for 1 hour. Then, 4 mol / L sodium hydroxide was added to the reaction mixture to adjust the pH to 9 or higher. The mixture was extracted with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.17 g).

[0920] 1 H-NMR (400 MHz, CDCl3) δ : 2.06-2.11 (1H, m), 2.62-2.73 (7H, m), 3.54(4H, t, J = 10.3 Hz), 3.64 (4H, tt, J = 8.3, 4.8 Hz), 4.81 (4H, s), 7.22 (1H, dd, J = 8.3, 8.0, 0.9 Hz), 7.44-7.51 (2H, m), 7.68 (1H, dd, J = 8.3, 0.9 Hz).

[0921] Reference Example 50

[0922] 4-[2-({2-[4-(1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}amino)ethyl]-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3-carboxylic acid methyl ester

[0923]

[0924] a) Preparation of methyl 4-iodo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3-carboxylate (Compound IN-19-1)

[0925] To a mixture of 4-iodo-1H-pyrazole-5-carboxylic acid methyl ester (413 mg) and acetonitrile (8.2 mL) was added potassium carbonate (339 mg) and 4-methoxybenzyl chloride (0.268 mL), and the mixture was stirred at 50 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (467 mg).

[0926] 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).

[0927] b) Preparation of methyl 1-[(4-methoxyphenyl)methyl]-4-(2-oxoethyl)-1H-pyrazole-3-carboxylate (Compound IN-19-2)

[0928] The title compound was prepared from compound IN-19-1 according to a similar method to Reference Example 46.

[0929] 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 = 8.7Hz), 7.33 (1H, s), 9.72 (1H, t, J = 1.4 Hz).

[0930] 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)

[0931] To the solution of the compound (105 mg) of reference example 45 in dichloromethane (1.7 mL), N, N-diisopropylethylamine (0.144 mL) was added, 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 thereto, and the mixture was stirred at room temperature for 10 minutes. Then, sodium triacetoxyborohydride (70.0 mg) was added thereto, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. Residue was passed through silica gel column chromatography (chloroform / methanol) purified to obtain title compound (26.2 mg).

[0932] 1 H-NMR (400 MHz, CDCl3) δ : 1.99-2.23 (6H, m), 2.52 (2H, t, J = 6.2Hz), 2.75 (2H, t, J = 10.0 Hz), 2.84 (2H, t, J = 6.9 Hz), 2.93 (2H, t, J = 6.9 Hz) =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).

[0933] Reference Example 51

[0934] 4-(3-{[(Benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-5-carboxylic acid methyl ester

[0935]

[0936] The mixture of 4-bromo-1H-imidazole-5-methyl formates (450 mg), 2-(trimethylsilyl)ethoxymethyl chloride (5.49 g), triethylamine (3.33 g) and acetonitrile (11 mL) was stirred at room temperature for 3 hours.Then, the reaction mixture was concentrated under reduced pressure, and the residue was passed through silica gel column chromatography (hexane / ethyl acetate) purification. The mixture of the purified product (528 mg) obtained, N-(benzyloxycarbonyl) propargylamine (596 mg), cuprous iodide (I) (60.0 mg), triethylamine (1.59 g), bis(triphenylphosphine) palladium dichloride (II) (221 mg) and DMF (7.9 mL) was stirred at 130 ° C for 1.5 hours under microwave radiation.Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was passed through silica gel column chromatography (hexane / ethyl acetate) purification to obtain the title compound (401 mg).

[0937] 1 H-NMR (400 MHz, CDCl3) δ: -0.08-0.01 (9H, m), 0.81-0.99 (2H, m), 1.99-2.08 (3H, m), 3.42-3.65 (2H, m), 3.77-3.96 (2H, m), 4.04-4.18 (2H, m), 4.96-5.22 (2H, m), 7.28-7.42 (5H, m), 7.72 (1H, s).

[0938] Reference Example 52

[0939] [4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]acetaldehyde

[0940]

[0941] a) Preparation of 3-[4-(2,2-diethoxyethyl)piperazin-1-yl]-1,2-benzisothiazole (Compound IN-20-1)

[0942] To a solution of 3-(piperazine-1-yl)benzo[d]isothiazole (2.00 g) in acetonitrile (9.1 mL) was added 2-bromo-1,1-diethoxyethane (2.16 g), potassium carbonate (2.52 g) and potassium iodide (0.151 g). After heating at reflux for 13 hours, ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.04 g).

[0943] 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).

[0944] b) Preparation of [4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]acetaldehyde (Reference Example 52)

[0945] 47% hydrobromic acid (15.0 mL) was added to compound IN-20-1 (3.04 g) at room temperature for 1 hour. The reaction mixture was then poured into ice water (40 mL), 20% aqueous sodium hydroxide solution (27 mL) was added thereto, 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).

[0946] 1 H-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).

[0947] Reference Example 53

[0948] Methyl 4-(2-aminoethyl)-6-(trifluoromethyl)pyridine-3-carboxylate monohydrochloride

[0949]

[0950] a) Preparation of methyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-(trifluoromethyl)pyridine-3-carboxylate (Compound IN-21-1)

[0951] The title compound was obtained from methyl 4-iodo-6-trifluoromethylpyridine-3-carboxylate according to a similar method to compound IN-7-2.

[0952] LC-MS: RT = 1.693 min ObsMS = 249 [M+1]

[0953] b) Preparation of methyl 4-(2-aminoethyl)-6-(trifluoromethyl)pyridine-3-carboxylate monohydrochloride (Reference Example 53)

[0954] 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. The reaction mixture was then concentrated to give the title compound (0.942 g).

[0955] LC-MS: RT = 1.002 min ObsMS = 249 [M+1].

[0956] Reference Example 54

[0957] 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

[0958]

[0959] a) Preparation of 2-(triphenylmethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (Compound IN-22-1)

[0960] To a solution of 6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (0.500 g) in triethylamine (0.762 mL) was 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. The precipitated solid was collected by filtration to give the title compound (0.796 g).

[0961] 1 H-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).

[0962] 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)

[0963] According to a similar method to Reference Example 3, the title compound was obtained from the compound of Reference Example 3 and compound IN-21-1.

[0964] 1 H-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 = 6.8Hz), 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).

[0965] Experiment 1: Human 5-HT 1A Receptor, human 5-HT 2A Evaluation of the binding activity of D2 receptors to human D2 receptors

[0966] The effects of the compounds of the present invention on human 5-HT were measured by the following procedure. 1A Receptor, human 5-HT 2A Binding affinity of the receptor to the human D2 receptor.

[0967] In which human 5-HT is expressed 1A Receptor, human 5-HT 2A CHO cell membrane fractions of 5-HT receptor and human D2 receptor were purchased from PerkinElmer, Inc. In the assays for evaluating binding affinity, test compounds were dissolved in dimethyl sulfoxide (DMSO) and lysed for 5-HT 1A receptors, 5-HT 2A receptors and D2 receptors, each receptor membrane sample diluted in buffer was mixed with [ 3 H]8-OH-DPAT, [ 3[H]ketanserin or [3H]spiperone (both available from PerkinElmer, Inc.) were mixed. Each mixture was incubated at room temperature for 60 minutes. The mixture was then quickly added to a glass fiber filter plate (Multiscreen FB, Millipore, Inc.) coated with a 0.3% aqueous polyethyleneimine solution and vacuum filtered. The radioactivity remaining on the filter was measured using a liquid scintillation counter (PerkinElmer, Inc.). The binding inhibition rate was calculated from the following formula.

[0968] 5-HT 1A Receptor binding inhibition rate (%) = 100 -100 x {(in the presence of test compound [ 3 H]8-OH-DPAT binding amount)} -(In the presence of 10 μmol / L 8-OH-DPAT [ 3 H]8-OH-DPAT binding)} / {(in the absence of test compound [ 3 H]8-OH-DPAT binding amount)} -(In the presence of 10 μmol / L 8-OH-DPAT [ 3 H]8-OH-DPAT binding amount)}

[0969] 5-HT 2A Receptor binding inhibition rate (%) = 100 -100 x {(in the presence of test compound [ 3 H] ketanserin binding)} -(in the presence of 10 μmol / L mianserin [ 3 H] ketanserin bound)} / {(in the absence of test compound [ 3 H] ketanserin binding)} -(in the presence of 10 μmol / L mianserin [ 3 H]ketanserin bound)}

[0970] D2 receptor binding inhibition rate (%) = 100 -100 x {(in the presence of test compound [ 3 H]Spiperone binding amount)} -(In the presence of 10 μmol / L spiperone [ 3 H]Spiperone bound)} / {(in the absence of test compound [ 3 H]Spiperone binding amount)} -(In the presence of 10 μmol / L spiperone [ 3 H]Spiperone bound)}

[0971] Calculation of IC by Hill analysis 50The Ki of each compound was calculated from the following formula.

[0972] Binding inhibition constant (Ki) = IC 50 / (1 + S / Kd)

[0973] Where S is the concentration of the ligand; Kd is the dissociation constant of the ligand binding to the membrane, which is calculated from a saturation binding experiment with the same cell membrane. A small Ki value means strong binding ability to the receptor.

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980] Experiment 2: Human 5-HT 1A Evaluation of receptor agonist activity

[0981] Purchase CHO cell membrane fraction, in which human 5-HT is expressed, as used in Experiment 1 1A Receptor. To a buffer containing guanosine diphosphate, a test compound dissolved in DMSO, each receptor membrane sample diluted with buffer and [ 35 S]guanosine 5'-O-[γ-thio]triphosphate (GTPγS). The mixture was incubated at room temperature for 60 minutes. The mixture was then quickly added to a glass fiber filter plate (Multiscreen FB, Millipore, Inc.) and vacuum filtered. The radioactivity remaining on the receptor was measured using a liquid scintillation counter. The agonist activity was calculated using the following formula.

[0982] 5-HT 1A Agonist activity of receptor (%) = 100 x {(in the presence of test compound [ 35 S] GTPγS binding)} -(In the presence of 20 μmol / L GTPγS [ 35 S] GTPγS binding)} / {(In the presence of 100 μmol / L 5-HT [ 35 S] GTPγS binding) -(In the presence of 20 μmol / L GTPγS [ 35 S] GTPγS binding amount)}

[0983] The agonist activity in the presence of 10 μM of each compound is shown as the maximal activity (E max ), and will get E max The concentration at which the activity reaches half of its target is calculated as EC 50 .

[0984]

[0985]

[0986]

[0987] Experiment 3: Human 5-HT 2A Evaluation of receptor antagonist activity

[0988] Aequorin, Gα16 protein, and each receptor were transiently expressed in CHO-K1 cells (Chinese Hamster Ovary). The cells were cultured overnight at 37°C in a CO2 incubator, seeded in 384-well plates, and left at room temperature for 2 or more hours. Each compound dissolved in DMSO was added, and changes in luminescence were measured using the FDSS / μCELL Functional Drug Screening System (Hamamatsu Photonics KK). Antagonist activity was calculated using the following formula.

[0989] Antagonist activity (%) = 100 x {(luminescence of wells in the presence of 1 nmol / L 5-HT - luminescence of wells containing solvent) - (luminescence of wells in the presence of test compound and 1 nmol / L 5-HT - luminescence of wells containing solvent)} / (luminescence of wells in the presence of 1 nmol / L 5-HT - luminescence of wells containing solvent)

[0990] The concentration of the test compound that yielded 50% of the antagonist activity was calculated as IC 50 The results are shown below.

[0991]

[0992]

[0993]

[0994] Experiment 4: Metabolic stability test in human liver microsomes

[0995] The stability of the compounds of the present invention in human liver microsomal metabolism was evaluated as follows. Human liver microsomes were obtained from Xenontech. Human liver microsomes, NADPH, and each test compound were mixed in 25 mmol / L phosphate buffer (pH 7.4) to achieve the following concentrations as shown below, and the mixture was incubated at 37°C for 30 minutes.

[0996] -Human liver microsomes: 0.1 mg / mL

[0997] -NAPDH: 3.2 mmol / L

[0998] -Test compound: 0.1 μmol / L

[0999] The residual ratio of the test compound in each sample after 30 minutes was measured by LC-MS, and the metabolic stability in human liver microsomes was calculated from the following formula.

[1000] Metabolic stability in human liver microsomes (mL / min / mg protein) = -LN (residual ratio) / 30 / 0.1

[1001] The results are shown in the table below.

[1002]

[1003]

[1004]

[1005] Experiment 5: Prediction of human half-life

[1006] The disappearance half-life of the compound of the present invention in humans is predicted in the following manner.

[1007] The compound of the invention was administered intravenously to cynomolgus monkeys as an aqueous solution in 0.01 mol / L hydrochloric acid. Blood was collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration. Plasma was obtained from the collected blood, and drug concentrations in plasma were measured by LC-MS. The monkeys' volume of distribution was calculated from the concentration changes.

[1008] The unbound fraction rate of the compound of the present invention in human or monkey serum was measured by equilibrium dialysis.

[1009] Using the results of the volume of distribution in monkeys, the unbound fraction ratio in human or monkey serum, and the metabolic stability in human liver microsomes obtained in Experiment 3, the half-life in humans was calculated according to the following formula.

[1010] Volume of distribution in humans = Volume of distribution in monkeys x Unbound fraction ratio in human serum / Unbound fraction ratio in monkey serum

[1011] Human liver clearance = (human liver blood flow x ratio of unbound fraction in human serum x 56.7 x metabolic stability in human liver microsomes) / (human liver blood flow + ratio of unbound fraction in human serum x 56.7 x metabolic stability in human liver microsomes)

[1012] Half-life in humans = 0.693 x human volume of distribution / human hepatic clearance

[1013] The results are shown in the table below.

[1014]

[1015] Test 6-1: Evaluation of inhibitory activity on hERG channels

[1016] CHO cells were used in which the expression of a protein involved in the human rapidly activating delayed rectifier potassium current (I Kr ) hERG channel) The inhibitory activity of the compounds of the present invention on the hERG channel was measured by the whole-cell patch clamp method using an automated patch clamp system.

[1017] (Preparation of Cell Suspension)

[1018] hERG-CHO cells purchased from ChanTest Cop. were cultured in a CO 2 incubator at 37° C. and dissociated from the flask with trypsin shortly before the measurement of hERG current to prepare a cell suspension.

[1019] (Solution Preparation)

[1020] Extracellular and intracellular fluids used in the measurements were prepared as follows.

[1021] 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

[1022] 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

[1023] Test compound solution: The test compound was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test compound solution. The test compound solution was further diluted 200-fold with extracellular fluid and serially diluted with extracellular fluid to calculate the IC value of hERG inhibition. 50 Test compound solutions were prepared at each concentration necessary for the desired value.

[1024] (Current measurement and data analysis)

[1025] The cell suspension, extracellular fluid, intracellular fluid and measuring plate are set in an automatic patch clamp system, and hERG current is measured by the whole-cell patch clamp method. The voltage scheme is as follows: the holding potential is adjusted to -80 mV, a depolarizing pulse is provided at -50 mV to +20 mV for 5 seconds, a repolarizing pulse is provided at -50 mV for 5 seconds, and then the potential is restored to the holding potential. Each pulse interval is 15 seconds. Data analysis is performed using Qpatch Assay Software (Biolin Scientific). The test is performed by incrementally applying 4 concentrations of each test compound, and the average value of the maximum peak tail current obtained from the last 3 stimulations of each concentration is determined as the data for evaluation. Based on the current inhibition rate of the pre-applied current at each concentration of each test compound, the IC is calculated using the Hill equation using software. 50 The results are shown below.

[1026]

[1027]

[1028]

[1029]

[1030] Test 6-2: Evaluation of hERG channel inhibitory activity

[1031] CHO cells were used in which the expression of a protein involved in the human rapidly activating delayed rectifier potassium current (I Kr ) hERG channel) The inhibitory activity of the compounds of the present invention on the hERG channel was measured by the whole-cell patch clamp method using an automated patch clamp system.

[1032] (Preparation of Cell Suspension)

[1033] hERG-CHO cells obtained from ChanTest were incubated at 37° C. in a CO 2 incubator and dissociated from the flask with trypsin shortly before measuring hERG current to prepare a cell suspension.

[1034] (Solution Preparation)

[1035] The extracellular and intracellular fluids used in the measurements were prepared as follows:

[1036] 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

[1037] Intracellular fluid: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF

[1038] Test compound solution: The test compound was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare each test compound solution. The test compound solution was further diluted 200-fold with extracellular fluid and serially diluted with extracellular fluid to calculate the IC value of hERG inhibition. 50 Test compound solutions were prepared at each concentration necessary for the desired value.

[1039] (Current measurement and data analysis)

[1040] The cell suspension, extracellular fluid, intracellular fluid and measuring plate are set in the automatic patch clamp system, and the hERG current is measured by the whole-cell patch clamp method. The voltage scheme is as follows: the holding potential is adjusted to -80 mV, the depolarization pulse is provided at -50 mV to +20 mV for 5 seconds, the repolarization pulse is provided at -50 mV for 5 seconds, and then the potential is restored to the holding potential. Each pulse interval is 15 seconds. Data analysis is performed using Qube's analysis software (Sophion Sophion). The test is performed by incrementally applying 4 concentrations of each test compound, and the average value of the maximum peak tail current obtained from the last 3 stimulations of each concentration is determined as the data for evaluation. Based on the current inhibition rate of the pre-applied current at each concentration of each test compound, IC is calculated using the software by the Hill equation 50 value.

[1041] The results are shown in the table below.

[1042]

[1043] Experiment 7: Evaluation of MK-801-induced suppression of hyperactivity

[1044] 7-week-old SD male rats were used. The test compound administration liquid was prepared by suspending them in a 0.5% methylcellulose solvent, and the MK-801 administration liquid was prepared by dissolving it in a saline solvent.

[1045] The MK-801-induced hyperactivity inhibition test was performed using Supermex, the data collection program CompACT AMS, and transparent plastic cages from Muromachi Kikai Co., Ltd. as follows.

[1046] Animal is housed in a cage, and the amount of movement is measured. After 45 minutes, take out the cage with rat gently, and respectively orally or subcutaneously administer the application liquid (solvent or test compound suspension) or the application liquid (solvent or MK-801 solution) of compound. Cage is returned to the measurement ground. After starting to measure 2 hours and 30 minutes, finish the measurement of movement amount. After starting to measure 1 hour (administer compound or MK-801 after 15 minutes) to 2 hours and 30 minutes between 90 minutes, the data obtained are used as result of the test to summarize the movement amount of each individual in 90 minutes.

[1047] The test results were analyzed as follows.

[1048] Parametric Dunnett's multiple comparisons (significance level: two-sided 5%) were performed between the test compound-administered group and the solvent-administered group. When the test compound-administered group showed a significant decrease in motor activity compared to the solvent-administered group, the compound was determined to have antipsychotic activity. The results of the above test were shown in Figure 1 and 2 middle.

[1049] Test 8: Evaluation of binding activity to side effect-related receptors

[1050] The binding affinity of the compounds of the present invention for side effect-related receptors (eg, adrenergic alpha receptors, histamine receptors, and muscarinic receptors) can be measured by the following methods.

[1051] The evaluation test of binding was carried out as follows using CHO cell membrane fractions expressing human target receptors therein. The test compound dissolved in dimethyl sulfoxide (DMSO), each receptor membrane sample diluted with buffer and a [3H]-labeled ligand with strong binding affinity for each target receptor were mixed. Each mixture was incubated at room temperature, quickly added to a glass fiber filter plate (Multiscreen FB, Millipore, Inc.) and vacuum filtered. The radioactivity remaining on the filter was measured with a liquid scintillation counter (PerkinElmer, Inc.). The binding inhibition rate was calculated from the following formula. A control compound (rather than a test compound) with strong binding affinity for the target receptor was used to calculate the nonspecific binding amount to the receptor membrane sample.

[1052] Inhibition rate of target receptor binding (%) = 100 -100 x {(in the presence of test compound [ 3 H]-labeled ligand binding)} -(in the presence of 10 μmol / L control compound [ 3 H]-labeled ligand bound)} / {(in the absence of test compound [ 3 H]-labeled ligand binding)} -(in the presence of 10 μmol / L control compound [ 3 H]-labeled ligand bound)}.

[1053] Test 9: Evaluation of P-gp substrate properties

[1054] Can calculate NFR (net flux ratio) as follows, it is the index of P-gp substrate properties.MDCKII (Madin-Darby canine kidney strain II) cell and the MDR1-MDCKII cell of overexpression MDR1 (multidrug resistance protein 1) therein are used to measure the apparent permeability coefficient (Papp AB) of MDCKII cell and MDR1-MDCKII cell from lumen (A) to basement membrane (B) and the apparent permeability coefficient (Papp BA) from basement membrane (B) to lumen (A).NFR (net flux ratio) is calculated from the ratio of the ratio (Papp BA / Papp AB) of the apparent permeability coefficient of MDR1-MDCKII cell and the ratio of the apparent permeability coefficient of MDCKII cell.

[1055] The results of Experiment 9 are shown in the table below.

[1056]

[1057] Study 10: Evaluation of brain transferability (Study on brain transferability in rats)

[1058] In this study, the brain transferability of the compounds of the present invention was evaluated by the following method. The compounds of the present invention were administered subcutaneously as a solution in saline or orally as a suspension in methylcellulose to 7-week-old SD or WKY rats. Plasma and brain were collected 0.5 hours, 1 hour, or 2 hours after administration to measure drug concentrations in plasma and brain by LC-MS.

[1059] The binding of the compounds of the present invention to plasma and brain proteins was measured by equilibrium dialysis.

[1060] Kp,uu,brain (ratio of unbound drug concentration between brain and plasma) can be calculated by applying the compound concentrations in plasma and brain and the binding rates to plasma and brain proteins obtained from the above experiments to the following formula.

[1061] Kp,uu,brain = (Compound concentration in brain x (100 – Binding rate to brain proteins (%)) / 100) / (Compound concentration in plasma x (100 – Binding rate to plasma proteins (%)) / 100)

[1062] The results of Test 10 are shown in the table below.

[1063]

[1064] Study 11: Evaluation of Hepatotoxicity Risk (Dansylglutathione (dGSH) Trapping Assay)

[1065] The compounds of the present invention are metabolized in liver microsomes, and the active metabolites that react with dansylglutathione (dGSH) are detected and quantified from the resulting metabolites. Measurements were performed using a screening robot (Tecan) for metabolic reactions and a fluorescence detection UPLC system (Waters) for metabolite-dGSH binding concentrations.

[1066] (Solution Preparation)

[1067] Dissolve the compound of the present invention in DMSO to prepare a 10 mmol / L test compound solution. Mix 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (Xenotech, 20 mg protein / mL), and 1.27 mL of purified water to prepare a microsomal solution. Add 0.67 mL of purified water to 3.78 mL of the microsomal solution to prepare a microsomal (dGSH(-)) solution. Add 1.14 mL of dGSH solution (20 mmol / L) to 6.48 mL of the microsomal solution to prepare a microsomal (dGSH(+)) solution. Dissolve 80.9 mg of NADPH in 30 mL of purified water to prepare a cofactor solution. Dissolve 33 mg of tris(2-carboxyethyl)phosphine (TECP) in 115 mL of methanol to prepare a reaction stop solution.

[1068] (reaction)

[1069] 12 μL of the test compound solution was mixed with 388 μL of pure water, and 50 μL of the mixture was dispensed into 6 wells of a 96-well plate. The 6 wells were divided into 3 groups of 2 wells each, and each was named "reaction group," "unreaction group," and "no dGSH group." 50 μL of the microsomal (dGSH(+)) solution was added to the "reaction group" and "unreaction group," and the microsomal (dGSH(-)) solution was added to the "no dGSH group." 50 μL of the cofactor solution was added to the "reaction group" and "no dGSH group," and pure water was added to the "unreaction group." After incubation at 37°C for 60 minutes, 450 μL of the reaction stop solution was added to stop the reaction. 50 μL of pure water was added to the "reaction group" and "no dGSH group," and the cofactor solution was added to the "unreaction group." The plate was cooled at -20°C for 1 hour and the solution was centrifuged (4000 rpm, 10 minutes). The supernatant was collected into another plate and analyzed.

[1070] (analyze)

[1071] The metabolite-dGSH bound concentration was measured using a fluorescence detection UPLC system (Waters) by the following method.

[1072] Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 x 10 mm

[1073] Eluent: A, 0.2% formic acid in water; B, 0.2% formic acid / acetonitrile

[1074] Gradient: B, 20%(0 min) -> 70%(9.33 min) -> 90%(10.63 min) -> 20%(11 min)-> 20%(14 min)

[1075] The fluorescence intensity was corrected with the composition of the organic solvent at the time of elution because the fluorescence intensity varies with the composition of the organic solvent.

[1076] The results of Test 11 are shown in the table below.

[1077]

[1078]

[1079]

[1080] Test 12: Evaluation of enzyme induction activity

[1081] The enzyme inducing activity of the compounds of the present invention was measured by the following method.

[1082] -Preparation of induction medium

[1083] A DMSO solution (10 mmol / L) of the test compound was diluted with HepaRG serum-free induction medium to prepare a 1 μmol / L or 10 μmol / L induction medium (containing 0.1% DMSO).

[1084] -Cell culture

[1085] After thawing the HepaRG cells, dilute the cells to 1.25 x 10 6 viable cells / mL and at 1.0 x 10 5 Cells were plated per well of a collagen I-coated 96-well plate. The cells were incubated at 37°C under 5% CO₂ for 6 hours. After confirming cell adhesion, the culture medium was replaced with fresh HepaRG thawed culture medium, and the cells were incubated at 37°C under 5% CO₂ for 3 days. The HepaRG thawed culture medium was then removed and induction culture medium containing each concentration of the test compound was added, and the cells were incubated for 48 hours. The induction culture medium was replaced every 24 hours.

[1086] - Analysis of mRNA expression variation

[1087] RNA was purified using RNeasy 96, and cDNA was synthesized using SuperScript IV VILO Master Mix. mRNA expression was measured by real-time PCR using TaqMan Gene Expression Assays and TaqMan Fast Advanced Master Mix.

[1088] -Calculation of induction fold

[1089] The fold induction of each CYP molecule was calculated as follows.

[1090] Induction fold = 2^(-ΔΔCt)

[1091] ΔΔCt = ΔCt(test compound treatment) - ΔCt(solvent control treatment)

[1092] ΔCt = Ct(target gene) -Ct(endogenous control gene)

[1093] Ct: Cycle number at a certain fluorescence intensity (threshold cycle)

[1094] The results of Test 12 are shown in the table below.

[1095]

[1096] Industrial Applicability

[1097] The compounds of the present invention show the effect of serotonin 5-HT 2A 5-HT receptor antagonist activity and serotonin 1A The compounds of the present invention have agonist activity at the agonist receptors and, therefore, are useful as drugs for the treatment of neuropsychiatric disorders.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: Where V is CR A R B ; n is 1 or 2; Z is a nitrogen atom, a carbon atom or -CR J -, provided that when bond (a) is a single bond, Z is a nitrogen atom, or -CR J And R J is a hydrogen atom, when bond (a) is a double bond, Z is a carbon atom, t is 1 or 2; The bond (a) accompanied by a dashed line is either a single bond or a double bond; R A and R B are independent of each other, wherein when each symbol exists in plural, each symbol may be independently the same or different, and is a hydrogen atom, or C 1-6 alkyl; R 1a , R 1b , R 1c and R 1d each independently a hydrogen atom; Ring Q 1 is any one of the following formulas (4a), (4b), (4c), (4d), (4e) or (4f): Where R 3a and R 3b are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, or C 1-6 Alkoxy, where R 3a and R 3b C 1-6 The alkyl group may be independently and optionally substituted by the same or different 1 to 3 halogen atoms. 2 is a group of the following formula (3a) or (3b): Where R 2a , R 2b , R 2c and R 2d are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl, or C 1-6 Alkoxy, R J It is a hydrogen atom; The prerequisite is that When ring Q 1 When it is any one of formula (4c), (4d), (4e) or (4f), then R 2a , R 2b , R 2c and R 2d It's a hydrogen atom.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1) is formula (1a): Where Q 1 , Q 2 ,V,Z,n,R 1a , R 1b , R 1c , R 1d and the bond (a) accompanied by a dashed line is as defined in claim 1.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R A and R B They are all hydrogen atoms.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 2. 5 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the bond (a) accompanied by a dotted line is a single bond.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1) is represented by the following formula (1b): Where Q 1 , Q 2 and Z as defined in claim 1.

7. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein Z is a nitrogen atom.

8. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein Z is -CH-.

9. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is any one of the following formulas (5a), (5b), (5c), (5d), (5e) or (5g): Where R 4a It is C 1-6 Alkyl or C 1-6 Alkoxy, R 4b is a hydrogen atom or C 1-6 alkyl.

10. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein ring Q 2 It is a group of formula (3a).

11. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein ring Q 2 It is a group of formula (3b).

12. The compound according to any one of claims 1, 2 and 6, or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 2c and R 2d It's a hydrogen atom.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by one of the following formulae:

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

19. A medicament comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

20. A medicament for treating mental disorders or central nervous system diseases, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

21. The medicament of claim 20, wherein the mental illness or central nervous system disease is organic, including symptomatic mental disorders; mental and behavioral disorders caused by the use of psychoactive substances; schizophrenia, schizotypal disorders and delusional disorders; mood [affective] disorders; neurotic disorders, stress-related disorders and somatic disorders; non-organic sleep disorders; sexual dysfunction not caused by organic disorders or diseases; general developmental delay; behavioral and emotional disorders that often occur in childhood and adolescence; extrapyramidal and movement disorders; other degenerative diseases of the nervous system; or sleep disorders.

22. The medicament of claim 20, wherein the psychiatric 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 dementia with Lewy bodies, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or irritation, agitation or aggression associated with Alzheimer's disease.

23. The medicament of claim 20, wherein the psychiatric disorder or central nervous system disorder is schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, or irritation, agitation or aggression associated with Alzheimer's disease.

24. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating mental illness or a central nervous system disease.

25. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for use in treating a mental disorder or a central nervous system disease.

26. A medicament for treating mental illness or central nervous system disease, comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and at least one medicament selected from the group consisting of antidepressants, antianxiety drugs, anti-schizophrenia agents, dopamine supplements, dopamine receptor agonists, anti-Parkinson's disease drugs, anti-epileptic drugs, analgesics, hormone preparations, anti-migraine drugs, adrenergic beta receptor antagonists, anti-dementia drugs, drugs for treating mood disorders, antiemetic drugs, sleep-inducing drugs and anticonvulsants.

27. A medicament for treating mental illness or central nervous system disease, comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient, for use in combination with at least one medicament selected from the group consisting of antidepressants, antianxiety drugs, anti-schizophrenia agents, dopamine supplements, dopamine receptor agonists, anti-Parkinson's disease drugs, anti-epileptic drugs, analgesics, hormone preparations, anti-migraine drugs, adrenergic beta receptor antagonists, anti-dementia drugs, drugs for treating mood disorders, antiemetic drugs, sleep-inducing drugs and anticonvulsants.

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