Nitrogen-containing aromatic heterocyclic and aromatic carbocyclic derivative having serotonin receptor binding activity

Abstract

The present invention provides a compound having a serotonin 5-HT2A receptor antagonistic and / or inverse agonistic action as well as a serotonin 5-HT2C receptor antagonistic and / or inverse agonistic action, or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition containing the same.　Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In the formula: R1 is a substituted or unsubstituted 6-membered aromatic heterocyclic group or the like; A1 is CR2 or the like; A2 is CR3 or the like; A3 is N or the like; R2 and R3 are each independently a hydrogen atom or the like; the ring B is a substituted or unsubstituted pyrazole or the like; R15 and R16 are each independently a hydrogen atom or the like; and R17 and R18 are each independently a hydrogen atom or the like.

Description

Nitrogen-containing aromatic heterocyclic and aromatic carbocyclic derivatives with serotonin receptor binding activity

[0001] The present invention relates to a compound or a pharmaceutically acceptable salt thereof that has serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. The present invention also relates to a compound or a pharmaceutically acceptable salt thereof that is useful in the treatment and / or prevention of diseases caused by serotonin 5-HT2A receptor and / or serotonin 5-HT2C receptor, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0002] Neurodegenerative disorders (NDs) are a group of related human diseases that share a common pathophysiological feature: the progressive degeneration of selective neuronal populations over time. These neurodegenerative disorders include, but are not limited to, Alzheimer's disease and related dementias, Parkinson's disease, Huntington's disease, Lewy body disease and related movement disorders. Each of these disorders has unique clinical aspects, including age of onset, time course of progression, neurological signs and symptoms, neuropsychiatric symptoms, and sensitivity to known therapeutic agents. Furthermore, the pathophysiological basis of each of these disorders is caused by genetic mechanisms unique to each disorder (Non-Patent Document 1).

[0003] Despite considerable progress in understanding the genetic causes underlying these disparate disorders, relatively little is known about the biochemical mechanisms underlying the selective neuronal degeneration common to all of them. Furthermore, while genetic factors have been identified that cause rare familial forms of the most common of these disorders, including Parkinson's disease and Alzheimer's disease, the pathophysiological basis of the majority of sporadic cases remains unknown. Consequently, there are currently no specific therapeutic agents that can directly alter disease progression or completely prevent its onset. Instead, clinicians rely on a variety of existing medications to achieve symptomatic relief of the motor, cognitive, and neuropsychiatric manifestations that characterize these disorders (Non-Patent Documents 2, 3).

[0004] Among the various neurological symptoms that characterize ND, the occurrence of motor abnormalities, including bradykinesia, dyskinesia, and chorea, as well as neuropsychiatric symptoms, including psychosis and emotional symptoms such as anxiety and depression, are common symptoms and seriously affect the functional status and quality of life of patients (Non-Patent Documents 4, 5). Most existing treatments, including antipsychotics and antidepressants, are often effective in these patients, but are significantly poorly tolerated (Non-Patent Document 6). Furthermore, available Parkinson's disease treatments, including L-dopa and dopamine agonists, are generally effective, but cause severe treatment-limiting side effects that cannot currently be addressed by pharmacological therapy.

[0005] For a long time, there were no approved drugs specifically for ND, but in 2016, the 5-HT2A receptor inverse agonist pimavanserin was approved in the United States for the first time for the treatment of hallucinations and delusions associated with Parkinson's disease (Non-Patent Document 7). Unlike existing antipsychotics, this drug has not been reported to cause side effects such as worsening of motor symptoms or decreased cognitive function. Pimavanserin's primary pharmacological action is serotonin 5-HT2A receptor inverse agonism / antagonism, but it also has serotonin 5-HT2C receptor inverse agonism / antagonism (Non-Patent Document 8). The results of 5-HT2A occupancy measured in a PET study of pimavanserin in humans and the results of clinical trials of pimavanserin suggest that pimavanserin exerts its therapeutic effects via 5-HT2A and 2C receptors (Non-Patent Document 9). Furthermore, the results of efficacy evaluation of pimavanserin on MK801-induced hyperactivity in rats, 5-HT2A occupancy measurement, and 5-HT2C inhibitory activity confirmation experiments also suggest that pimavanserin exerts its pharmacological effects via 5-HT2A and 2C (Non-Patent Document 14). Furthermore, pimavanserin has significant adverse effects on the cardiovascular system, and its use dose is limited.

[0006] These findings highlight the need to develop novel therapeutic agents specifically designed to be not only effective against these specific disabling conditions, but also well-tolerated in these specific patient populations. This can be achieved by improving the selectivity of drug-target interactions of new therapeutic agents, specifically by having potent activity and selectivity for the 5-HT2A and 2C targets, and reducing adverse cardiovascular effects.

[0007] Compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity are described in Patent Documents 1 to 16 and 21 and Non-Patent Documents 10 to 14, but none of these documents describe or suggest compounds related to the present invention. Patent Document 17 discloses a benzamide derivative having interleukin-6 inhibitory activity, but does not describe or suggest serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity or therapeutic effects for hallucinations and delusions, nor does it describe or suggest compounds related to the present invention. Patent Documents 18 to 20 disclose pyrimidine derivatives having protein kinase C inhibitory activity, but does not describe or suggest serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity or therapeutic effects for hallucinations and delusions, nor does it describe or suggest compounds related to the present invention.

[0008] International Publication No. WO 2005 / 012254 International Publication No. WO 2006 / 078610 International Publication No. WO 2007 / 136703 International Publication No. WO 2007 / 136680 International Publication No. WO 2022 / 093850 International Publication No. WO 2022 / 093849 International Publication No. WO 2007 / 120600 International Publication No. WO 2006 / 055734 International Publication No. WO 2004 / 058722 International Publication No. WO 2004 / 028450 International Publication No. 01 / 29008 International Publication No. 2013 / 171641 International Publication No. 2008 / 027483 International Publication No. 2007 / 136875 International Publication No. 99 / 52927 International Publication No. 03 / 062206 International Publication No. 2019 / 165158 International Publication No. 2013 / 152198 International Publication No. 2014 / 089112 International Publication No. 2014 / 151900 International Publication No. 2024 / 122617

[0009] Nature Reviews Neurology, Vol. 10, pp. 620-633, 2014; Progress in Neurology and Psychiatry, Vol. 22, No. 1, pp. 30-35, 2018; Movement Disorders, Vol. 24, No. 11, pp. 1641-1649, 2009; Parkisonism and Related Disorders, Vol. 15, Supplement 3, pp. S105-S109, 2009; Neurology, 2004; Vol. 63, No. 2, pp. 293-300, 2004; JAMA Neurology, Vol. 73, No. 5, pp. 535-541, 2016 The Lancet, Vol. 383, pp. 533-540, 2014 Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 2, pp. 910-918, 2006 CNS Spectrum, Vol. 21, pp. 271-275, 2016 Bioorganic & Medicinal Chemistry Letters, Volume 19, Pages 5486-5489, 2009 Journal of Medicinal Chemistry, Vol. 53, pp. 4412-4421, 2010 Journal of Medicinal Chemistry, Vol. 53, pp. 1923-1936, 2010 Journal of Medicinal Chemistry, Vol. 53, pp. 5696-5706, 2010 Journal of Medicinal Chemistry, Vol. 67, pp. 14478-14492, 2024

[0010] An object of the present invention is to provide a novel compound having serotonin 5-HT2A receptor antagonistic and / or inverse agonist activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonist activity. More preferably, the present invention provides a novel compound or a pharmaceutically acceptable salt thereof, which has serotonin 5-HT2A receptor antagonistic and / or inverse agonist activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonist activity and is thereby effective against diseases involving serotonin, including hallucinations and delusions associated with Parkinson's disease and / or dementia, as well as a pharmaceutical containing the same.

[0011] The present invention relates to the following items (1) to (23), (5′) and (14′): (1) Formula (I): (In the formula, R １ is a substituted or unsubstituted 6-membered aromatic heterocyclic group, a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a substituted or unsubstituted 6-membered aromatic carbocyclic group; １ is CR ２ or N; A ２ is CR ３ or N; A ３ is CR ４ or N; R ２ , R ３ and R ４ are each independently a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; Ring B is a substituted or unsubstituted pyrazole or a substituted or unsubstituted pyrazolopyridine; R １５ and R １６ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R １７ and R １８ (2) R is a compound represented by the formula (1), or a pharmaceutically acceptable salt thereof. １５ and R １６ is a hydrogen atom, and R １７ and R １８(3) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R １５ , R １６ , R １７ and R １８ (4) The compound according to the above (1) or (2), or a pharmaceutically acceptable salt thereof, wherein R １ But the formula: (In the formula, R ６ and R ７ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a cyano (provided that R ６ When is a hydrogen atom, R ７ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or cyano; R ８ and R ９ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a cyano, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ (5) The compound according to any one of (1) to (3) above, wherein R is a group represented by the formula: １ But the formula: (In the formula, R ６ , R ７ are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano; R ８is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ (5') R is a group represented by the formula (1), or a pharmaceutically acceptable salt thereof. １ But the formula: (6) A compound according to any one of (1) to (4) above, which is a group represented by the formula: (wherein each symbol has the same meaning as in (5) above), or a pharmaceutically acceptable salt thereof. １ But, CR ２ or N; R ２ is a hydrogen atom; ２ But, CR ３ or N; R ３ is the same as (1) above; A ３ But, CR ４ or N; R ４ (7) The compound according to any one of (1) to (5) and (5′) above, wherein A is a hydrogen atom, or a pharmaceutically acceptable salt thereof. １ But, CR ２ or N; R ２ is the same as (1) above; A ２ But, CR ３ or N; R ３ is a hydrogen atom or a halogen; ３ But, CR ４ or N; R ４ is the same as defined in (1) above, or a pharmaceutically acceptable salt thereof. １ is CH, and A ２ is N and A ３ is CH; or (ii) A １ is CH, and A ２ is CR ３ and R ３ is a hydrogen atom or a halogen, and A３ (9) The compound according to any one of the above (1) to (7) and (5′), or a pharmaceutically acceptable salt thereof, wherein ring B is a group represented by the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R １２ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R １３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２５ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ (10) The compound according to any one of (1) to (8) and (5') above, wherein R is a ring represented by the formula: １２ , R １４ and R ２７ (11) The compound according to the above (9) or a pharmaceutically acceptable salt thereof, wherein ring B is a group represented by the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom; R ２６is halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom; and n is an integer of 0 to 2), or a pharmaceutically acceptable salt thereof. (12) The compound according to any one of the above (1) to (10) and (5'), wherein ring B is a ring represented by the formula: (In the formula, R １０ , R １１ and R １２ (13) The compound according to the above (11), wherein R is a ring represented by the formula (11) or a pharmaceutically acceptable salt thereof. １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (14) The compound according to (1) above, which is selected from the group consisting of compounds I-027, I-028, I-071, I-114, I-144, I-145, I-155, I-158, I-166, I-257, I-262, I-266, and I-267, or a pharmaceutically acceptable salt thereof. (14') The following compound: (15) A pharmaceutical composition comprising the compound according to any one of (1) to (14), (5') and (14') above or a pharmaceutically acceptable salt thereof. (16) The pharmaceutical composition according to (15), which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist. (17) The pharmaceutical composition according to (15), which is an antagonist and / or inverse agonist of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor. (18) A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor, comprising administering the compound according to any one of (1) to (14), (5') and (14') above or a pharmaceutically acceptable salt thereof. (19) A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor, comprising administering a compound according to any one of (1) to (14), (5') and (14') above, or a pharmaceutically acceptable salt thereof. (20) A compound according to any one of (1) to (14), (5') and (14') above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A receptor. (21) A compound according to any one of (1) to (14), (5') and (14') above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor. (22) Use of the compound according to any one of the above (1) to (14), (5') and (14'), or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing diseases involving the serotonin 5-HT2A receptor. (23) Use of the compound according to any one of the above (1) to (14), (5') and (14'), or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing diseases involving the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor.

[0012] The compound according to the present invention has serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity, and is useful as a therapeutic and / or preventive agent for hallucinations and delusions associated with Parkinson's disease and / or dementia.

[0013] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0014] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred. R ７ As the "halogen" in the formula (I), a chlorine atom and a bromine atom are preferred.

[0015] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0016] "C1-C3 alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

[0017] "Haloalkyl" refers to the above alkyl substituted with one or more halogens. When substituted with two or more halogens, the halogens may be the same or different. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl, 3,3,3-trifluoro-2-trifluoromethylpropyl, and the like. Preferred embodiments of "haloalkyl" include difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, and 2,2,3,3,3-pentafluoropropyl. More preferred embodiments include difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0018] "Alkyloxy" refers to a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc. Preferred embodiments of "alkyloxy" include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy. More preferred embodiments include methyloxy, ethyloxy, n-propyloxy, and isopropyloxy.

[0019] "Haloalkyloxy" refers to a group in which the above-mentioned "haloalkyl" is bonded to an oxygen atom. Examples include difluoromethyloxy, 2-monofluoroethyloxy, 3-monofluoropropyloxy, 2,2,3,3,3-pentafluoropropyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy, 2,2,2-trichloroethyloxy, 2,2,2-trifluoroethyloxy, 2,2-difluoroethyloxy, 3,3,3-trifluoropropyloxy, 2,2,3,3,3-pentafluoropropyloxy, and 2,2,3,3,4,4,4-heptafluorobutyloxy. Preferred embodiments of "haloalkyloxy" include difluoromethyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy, 2,2-difluoroethyloxy, and 3,3,3-trifluoropropyloxy. More preferred embodiments include difluoromethyloxy, trifluoromethyloxy, and 2,2,2-trifluoroethyloxy.

[0020] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.

[0021] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0022] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0023] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group." An example of a "6-membered aromatic carbocyclic group" is phenyl.

[0024] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. A bicyclic or multicyclic "non-aromatic carbocyclic group" also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group" is fused. Furthermore, the term "non-aromatic carbocyclic group" also includes bridged groups or groups that form spiro rings as shown below. The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0025] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0026] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, oxazolopyridyl, and thiazolopyridyl.Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, and pyrazinopyridazinyl. Examples of aromatic heterocyclic groups having three or more rings include 13- to 15-membered groups. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0027] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0028] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Examples of 8-membered non-aromatic heterocyclic groups include azocane, thiocane, and oxocane. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, and more preferably have 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0029] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0030] "Trialkylsilyl" refers to a group in which three of the above-mentioned "alkyl" groups are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0031] In this specification, the phrase "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, and γ'.

[0032] Examples of substituents such as "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyloxy," "substituted alkenylcarbonyloxy," "substituted alkynylcarbonyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," "substituted alkynylcarbonyl," "substituted alkyloxycarbonyl," "substituted alkenyloxycarbonyl," "substituted alkynyloxycarbonyl," "substituted alkylsulfanyl," "substituted alkenylsulfanyl," "substituted alkynylsulfanyl," "substituted alkylsulfinyl," "substituted alkenylsulfinyl," "substituted alkynylsulfinyl," "substituted alkylsulfonyl," "substituted alkenylsulfonyl," and "substituted alkynylsulfonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α,alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted by substituent group γ', aromatic heterocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted by substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted by substituent group γ,Non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0033] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, alkyloxy substituted with alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, non-aromatic carbocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic group substituted with alkyloxy, aromatic carbocyclic group substituted with halogen, aromatic carbocyclic group substituted with haloalkyl, non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted with halogen, sulfanyl, and cyano.

[0034] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0035] Substituent group γ: Substituent group α, alkyl, alkyl substituted with alkyloxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0036] Substituent group γ': Substituent group γ and oxo.

[0037] Substituents on the ring of an "aromatic carbocycle" and an "aromatic heterocycle", such as a "substituted aromatic carbocyclic group", a "substituted 6-membered aromatic carbocyclic group", a "substituted aromatic heterocyclic group", a "substituted 6-membered aromatic heterocyclic group", a "substituted 5-membered aromatic heterocyclic group", a "substituted pyrazole", a "substituted pyrazolopyridine", a "substituted aromatic carbocycleoxy", a "substituted aromatic heterocycleoxy", a "substituted aromatic carbocyclecarbonyloxy", a "substituted aromatic heterocyclecarbonyloxy", a "substituted aromatic carbocyclecarbonyl", a "substituted aromatic heterocyclecarbonyl", a "substituted aromatic carbocycleoxycarbonyl", a "substituted aromatic heterocycleoxycarbonyl", a "substituted aromatic carbocyclesulfanyl", a "substituted aromatic heterocyclesulfanyl", a "substituted aromatic carbocyclesulfinyl", a "substituted aromatic heterocyclesulfinyl", a "substituted aromatic carbocyclesulfonyl", and a "substituted aromatic heterocyclesulfonyl", include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α,alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, An aromatic carbocyclic group optionally substituted with a substituent group γ, a non-aromatic carbocyclic group optionally substituted with a substituent group γ', an aromatic heterocyclic group optionally substituted with a substituent group γ, a non-aromatic heterocyclic group optionally substituted with a substituent group γ', an aromatic carbocyclic oxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic oxy optionally substituted with a substituent group γ', an aromatic heterocyclic oxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic oxy optionally substituted with a substituent group γ', an aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ', an aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ, and a non-aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ'. carbonyloxy, aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ,Non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic oxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic oxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, Non-aromatic carbocyclic alkyloxyalkyl optionally substituted with γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0038] "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "R ２ and R３ "a substituted non-aromatic carbocyclic ring formed together with the carbon to which R is attached," "R ２ and R ３ ", together with the carbon to which it is bonded, forms a "substituted non-aromatic heterocycle," "substituted non-aromatic carbocycleoxy," "substituted non-aromatic heterocycleoxy," "substituted non-aromatic carbocyclecarbonyloxy," "substituted non-aromatic heterocyclecarbonyloxy," "substituted non-aromatic carbocyclecarbonyl," "substituted non-aromatic heterocyclecarbonyl," "substituted non-aromatic carbocycleoxycarbonyl," "substituted non-aromatic heterocycleoxycarbonyl," "substituted non-aromatic carbocyclecarbonyl," "substituted non-aromatic heterocyclecarbonyl," "substituted non-aromatic carbocycleoxycarbonyl," "substituted non-aromatic carbocyclesulfanyl," "substituted non-aromatic heterocyclesulfanyl," "substituted non-aromatic carbocyclesulfinyl," "substituted non-aromatic heterocyclesulfinyl," "substituted non-aromatic carbocyclesulfonyl," and "substituted non-aromatic heterocyclesulfonyl." Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" include the following Substituent Group C. An atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group C. Substituent Group C: Substituent Group B and oxo.

[0039] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows:

[0040] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following Substituent Group D. Each group may be substituted with 1 or 2 groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0041] R １Examples of the substituents on the ring of the "substituted 6-membered aromatic heterocyclic group", "substituted 5-membered aromatic heterocyclic group" and "substituted 6-membered aromatic carbocyclic group" in the above formula include unsubstituted alkyl, haloalkyl, alkyl substituted with unsubstituted alkyloxy, alkyl substituted with alkyloxy substituted with unsubstituted alkyloxy, alkyl substituted with haloalkyloxy, alkyl substituted with unsubstituted non-aromatic heterocyclic oxy, alkyl substituted with unsubstituted non-aromatic carbocyclic oxy, unsubstituted alkyloxy, haloalkyloxy, alkyloxy substituted with unsubstituted alkyloxy, haloalkyloxy substituted with unsubstituted alkyloxy, unsubstituted Examples of the alkyloxy group substituted with non-aromatic heterocyclic group include alkyloxy group substituted with non-aromatic heterocyclic group, alkyloxy group substituted with non-aromatic carbocyclic group, alkyloxy group substituted with non-aromatic carbocyclic group, non-substituted non-aromatic heterocyclic group, non-aromatic heterocyclic group substituted with halogen, non-substituted non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted with halogen, non-substituted non-aromatic heterocyclic group, non-aromatic heterocyclic group substituted with halogen, non-substituted non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted with halogen, halogen, cyano, alkenyl, alkynyl. Any atom on the ring may be substituted with one or more groups selected from these.

[0042] R ６ and R ７ In the above, examples of the substituents of "substituted alkyl", "substituted alkyloxy", "substituted alkenyl" and "substituted alkynyl" include halogen.

[0043] R ８ and R ９In the above, examples of the substituents of "substituted alkyl" and "substituted alkyloxy" include halogen, unsubstituted alkyloxy, haloalkyloxy, alkyloxy substituted with alkyloxy, unsubstituted non-aromatic heterocyclic oxy, unsubstituted non-aromatic carbocyclic oxy, unsubstituted non-aromatic heterocyclic group, non-aromatic heterocyclic group substituted with halogen, unsubstituted non-aromatic carbocyclic group, and non-aromatic carbocyclic group substituted with halogen. Carbon atoms at any position may be substituted with one or more groups selected from these.

[0044] R ８ and R ９ In the above, examples of the substituents on the ring of the "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "substituted non-aromatic carbocyclic group" and "substituted non-aromatic heterocyclic group" include halogen.

[0045] R ３１ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0046] R ２ , R ３ and R ４ In the above, examples of the substituents of "substituted alkyl" and "substituted alkyloxy" include halogen.

[0047] Examples of the substituents on the ring B of the "substituted pyrazole" and "substituted pyrazolopyridine" include unsubstituted alkyl, haloalkyl, alkyl substituted with haloalkyloxy, alkyl substituted with an aromatic carbocyclic group substituted with a halogen, alkyl substituted with an aromatic carbocyclic group substituted with a haloalkyl, alkyl substituted with a non-aromatic carbocyclic group substituted with a halogen, haloalkyl substituted with an unsubstituted non-aromatic carbocyclic group, haloalkyl substituted with a non-aromatic carbocyclic group substituted with a halogen, aromatic carbocyclic group substituted with a halogen, Alkenyl substituted with a group, unsubstituted alkyloxy, haloalkyloxy, unsubstituted aromatic carbocyclic groups, aromatic carbocyclic groups substituted with alkyl substituted with unsubstituted alkyloxy, aromatic carbocyclic groups substituted with unsubstituted alkyl, aromatic carbocyclic groups substituted with halogen, aromatic carbocyclic groups substituted with haloalkyl, aromatic carbocyclic groups substituted with unsubstituted alkyloxy, aromatic carbocyclic groups substituted with haloalkyloxy, aromatic carbocyclic groups substituted with unsubstituted non-aromatic carbocyclic groups, aromatic carbocyclic groups substituted with cyano, cyano and halo aromatic carbocyclic groups substituted with aryl, aromatic carbocyclic groups substituted with cyano and haloalkyl, aromatic carbocyclic groups substituted with halogen and unsubstituted alkyl, aromatic carbocyclic groups substituted with halogen and haloalkyl, aromatic carbocyclic groups substituted with halogen and alkyloxy, unsubstituted non-aromatic carbocyclic groups, non-aromatic carbocyclic groups substituted with halogen, non-aromatic carbocyclic groups substituted with unsubstituted alkyl, non-aromatic carbocyclic groups substituted with haloalkyl, unsubstituted aromatic heterocyclic groups, alkyl substituted with unsubstituted alkyloxy aromatic heterocyclic groups substituted with unsubstituted alkyl, aromatic heterocyclic groups substituted with halogen, aromatic heterocyclic groups substituted with haloalkyl, aromatic heterocyclic groups substituted with unsubstituted alkyloxy, aromatic heterocyclic groups substituted with haloalkyloxy, aromatic heterocyclic groups substituted with unsubstituted non-aromatic carbocyclic groups, aromatic heterocyclic groups substituted with unsubstituted non-aromatic carbocyclicoxy, aromatic heterocyclic groups substituted with cyano, aromatic heterocyclic groups substituted with cyano and halogen, aromatic heterocyclic groups substituted with cyano and haloalkyl,Examples of the heterocyclic group include aromatic heterocyclic groups substituted with cyano and unsubstituted alkyl, aromatic heterocyclic groups substituted with cyano and unsubstituted alkyloxy, aromatic heterocyclic groups substituted with halogen and unsubstituted alkyl, aromatic heterocyclic groups substituted with alkyl and haloalkyl, aromatic heterocyclic groups substituted with halogen and haloalkyl, aromatic heterocyclic groups substituted with halogen and unsubstituted alkyloxy, aromatic heterocyclic groups substituted with haloalkyl and unsubstituted alkyloxy, aromatic heterocyclic groups substituted with alkyl and alkyl substituted with alkyloxy, aromatic heterocyclic groups substituted with alkyl and halogen substituted with alkyloxy, aromatic heterocyclic groups substituted with alkyl and unsubstituted non-aromatic carbocyclic groups substituted with alkyloxy, halogen, and cyano. Any atom on the ring may be substituted with one or more groups selected from these.

[0048] R １０ and R １３ Examples of the substituent of "substituted alkyl" in the formula (I) include halogen, haloalkyloxy, aromatic carbocyclic group substituted with halogen, aromatic carbocyclic group substituted with haloalkyl, non-aromatic carbocyclic group substituted with halogen, unsubstituted non-aromatic carbocyclic group, and non-aromatic carbocyclic group substituted with halogen. Carbon atoms at any position may be substituted with one or more groups selected from these.

[0049] R １０ and R １３ In the above, examples of the substituents of the "substituted aromatic carbocyclic group", "substituted phenyl" and "substituted aromatic heterocyclic group" include alkyl substituted with unsubstituted alkyloxy, unsubstituted alkyl, halogen, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, unsubstituted non-aromatic carbocyclic group, unsubstituted non-aromatic carbocyclic oxy and cyano. Carbon atoms at any position may be substituted with one or more groups selected from these.

[0050] R １０ and R １３ Examples of the substituents of the "substituted non-aromatic carbocyclic group" in the above formula include halogen.

[0051] R １１ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0052] R １１ In the above, examples of the substituents of the "substituted aromatic carbocyclic group" and "substituted aromatic heterocyclic group" include alkyl, halogen, alkyloxy, haloalkyl, and haloalkyloxy. Carbon atoms at any position may be substituted with one or more groups selected from these.

[0053] R １１ Examples of the substituents of the "substituted non-aromatic carbocyclic group" in the above formula include halogen.

[0054] R １２ , R １４ and R ２７ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0055] R ２５ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0056] R ２６ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0057] R ２７ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0058] R １５ and R １６ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0059] R １７ and R １８ The substituents of the "substituted alkyl" in the above formula include, for example, halogen.

[0060] In the compound of formula (I), R １ , R ６ , R ７ , R ８ , R ９ , R ３１ , A １ , A２ , A ３ , R ２ , R ３ , R ４ , ring B, R １０ , R １１ , R １２ , R １３ , R １４ , R ２５ , R ２６ , R ２７ , n, R １５ , R １６ , R １７ and R １８ Preferred embodiments of the compound represented by formula (I) are shown below. Examples of the compound represented by formula (I) include all combinations of the specific examples shown below. １ R may be a substituted or unsubstituted 6-membered aromatic heterocyclic group, a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a substituted or unsubstituted 6-membered aromatic carbocyclic group (hereinafter referred to as A-1). １ is the formula: (wherein each symbol has the same meaning as in (4) above) (hereinafter referred to as A-2). １ is the formula: (wherein each symbol has the same meaning as in (5) above) (hereinafter referred to as A-3). １ is the formula: (wherein each symbol has the same meaning as in (5') above) (hereinafter referred to as A-4). １ is the formula: (wherein each symbol has the same meaning as in (5') above) (hereinafter referred to as A-5). １ is the formula: (wherein each symbol has the same meaning as in (5) above) (hereinafter referred to as A-6). １ is the formula: (In the formula, R ７ is halogen or unsubstituted alkyl, and R ３１ is unsubstituted alkyl, and R ６ is unsubstituted alkyl, and R ８is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocyclic oxy) (hereinafter referred to as A-6'). １ is the formula: (wherein each symbol has the same meaning as in (5) above) (hereinafter referred to as A-7). １ is the formula: (In the formula, R ７ is halogen, unsubstituted alkyl or cyano, R ３１ is an unsubstituted alkyl) (hereinafter referred to as A-8). １ is the formula: (wherein each symbol has the same meaning as in (5) above) (hereinafter referred to as A-9). １ is the formula: (In the formula, R ６ is unsubstituted alkyl, and R ７ is unsubstituted alkyl, and R ８ is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocyclic oxy) (hereinafter referred to as A-10).

[0061] R ６ R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a cyano (hereinafter referred to as B-1). ６ R is exemplified by halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and cyano (hereinafter referred to as B-2). ６ R is substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (hereinafter referred to as B-3). ６ R is an unsubstituted alkyl or unsubstituted alkyloxy (hereinafter referred to as B-4). ６ R is methyl or methyloxy (hereinafter referred to as B-5). ６Examples of the alkyl group include methyl (hereinafter referred to as B-6).

[0062] R ７ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a cyano (provided that R ６ When is a hydrogen atom, R ７ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano (hereinafter referred to as C-1). ７ R is a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group (hereinafter referred to as C-2). ７ R is a halogen atom, a substituted or unsubstituted alkyl group, or a cyano group (hereinafter referred to as C-3). ７ R is halogen, unsubstituted alkyl, haloalkyl, or cyano (hereinafter referred to as C-4). ７ R is a halogen atom, an unsubstituted alkyl group, or a cyano group (hereinafter referred to as C-5). ７ R is halogen, methyl, ethyl, isopropyl, or cyano (hereinafter referred to as C-6). ７ R is halogen, methyl, or cyano (hereinafter referred to as C-7). ７ R is a halogen or unsubstituted alkyl (hereinafter referred to as C-8). ７ R is halogen or methyl (hereinafter referred to as C-9). ７ is an unsubstituted alkyl (hereinafter referred to as C-10). ７ Examples of R include methyl (hereinafter referred to as C-11). ７ Examples of C-12 include halogens (hereinafter referred to as C-12).

[0063] R ８R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a cyano, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as D-1). ８ R is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as D-2). ８ R is a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as D-3). ８ R is substituted or unsubstituted alkyl (hereinafter referred to as D-4). ８ R is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as D-5). ８ R is methyl, methyl substituted with unsubstituted alkyloxy, or methyl substituted with unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as D-6). ８ R includes methyl substituted with methyloxy, methyl substituted with oxetanyloxy, and methyl (hereinafter referred to as D-7). ８ is methyl substituted with methyloxy, or methyl (hereinafter referred to as D-8).

[0064] R ９ R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a cyano, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as E-1). ９ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as E-2).９ R is a hydrogen atom, a halogen atom, or an unsubstituted alkyl (hereinafter referred to as E-3). ９ represents a hydrogen atom or a halogen (hereinafter referred to as E-4).

[0065] R ３１ is substituted or unsubstituted alkyl (hereinafter referred to as E'-1). ３１ is an unsubstituted alkyl (hereinafter referred to as E'-2). ３１ R is methyl, ethyl, propyl, or isopropyl (hereinafter referred to as E'-3). ３１ Examples of the alkyl group include methyl (hereinafter referred to as E'-4).

[0066] A １ is CR ２ Or N (hereinafter referred to as F-1). １ is CR ２ (hereinafter referred to as F-2). １ Examples of the compound include N (hereinafter referred to as F-3).

[0067] R ２ R is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as G-1). ２ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as G-2). ２ is a hydrogen atom, a halogen atom, or an unsubstituted alkyl (hereinafter referred to as G-3). ２ is a hydrogen atom or a halogen atom (hereinafter referred to as G-4). ２ is a hydrogen atom (hereinafter referred to as G-5).

[0068] A ２ is CR ３ Or N (hereinafter referred to as H-1). ２ is CR ３ (hereinafter referred to as H-2). ２ Examples of the hydroxyl group include N (hereinafter referred to as H-3).

[0069] R３ R is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as J-1). ３ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as J-2). ３ R is a halogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as J-3). ３ R is a halogen or an unsubstituted alkyl (hereinafter referred to as J-4). ３ is a hydrogen atom or a halogen (hereinafter referred to as J-5). ３ is a hydrogen atom (hereinafter referred to as J-6). ３ Examples of the halogen include halogen (hereinafter referred to as J-7).

[0070] A ３ is CR ４ Or N (hereinafter referred to as K-1). ３ is CR ４ (hereinafter referred to as K-2). ３ Examples of the compound include N (hereinafter referred to as K-3).

[0071] R ４ R is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as L-1). ４ R is a hydrogen atom, halogen, cyano, unsubstituted alkyl, or unsubstituted alkyloxy (hereinafter referred to as L-2). ４ is a hydrogen atom or a halogen (hereinafter referred to as L-3). ４ is a hydrogen atom (hereinafter referred to as L-4).

[0072] Ring B may be a substituted or unsubstituted pyrazole or a substituted or unsubstituted pyrazolopyridine (hereinafter referred to as M-1). Ring B may be a group represented by the formula: (wherein each symbol has the same meaning as in (9) above) (hereinafter referred to as M-2). Ring B is a ring represented by the formula: (wherein each symbol has the same meaning as in (11) above) (hereinafter referred to as M-3). Ring B is a ring represented by the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω′ (substituent group ω′: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R １１ is a hydrogen atom; R １２ is a hydrogen atom; R ２６ is haloalkyl; R ２７ is a hydrogen atom; and n is 0 or 1) (hereinafter referred to as M-4). Ring B includes a substituted or unsubstituted pyrazole (hereinafter referred to as M-5). Ring B includes a ring represented by the formula: (wherein each symbol has the same meaning as in (9) above) (hereinafter referred to as M-6). Ring B is a ring represented by the formula: (wherein each symbol has the same meaning as in (11) above) (hereinafter referred to as M-7). Ring B is a ring represented by the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω′ (substituent group ω′: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom) (hereinafter referred to as M-8). Ring B is a ring represented by the formula: (In the formula, R １０is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω′ (substituent group ω′: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R １１ is a hydrogen atom; R １２ is a hydrogen atom) (hereinafter referred to as M-9). Ring B is a ring represented by the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω″, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω″ (substituent group ω″: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy); R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom) (hereinafter referred to as M-9'). Ring B is a ring represented by the formula: (In the formula, R １０ is a phenyl substituted with one or more groups selected from the substituent group ω″ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω″ (substituent group ω″: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy); R １１ is a hydrogen atom; R １２ is a hydrogen atom) (hereinafter referred to as M-10).

[0073] R １０ R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as N-1). １０ R is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as N-2). １０R is a substituted or unsubstituted alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as N-3). １０ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω, unsubstituted phenyl, a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω, or an unsubstituted 6-membered aromatic heterocyclic group (substituent group ω: halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-4). １０ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω, and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω (substituent group ω: halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-5). １０ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω', and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω' (substituent group ω': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-6). １０ is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ω'', or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω'' (substituent group ω': halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-6'). R １０ N-7 includes phenyl substituted with one or more groups selected from the substituent group ω″ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω″ (substituent group ω″: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy) (hereinafter referred to as N-7).

[0074] R １３R may be a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as O-1). １３ R may be a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as O-2). １３ R is a substituted or unsubstituted alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as O-3). １３ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω, unsubstituted phenyl, a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω, or an unsubstituted 6-membered aromatic heterocyclic group (substituent group ω: halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as O-4). １３ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω, and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω (substituent group ω: halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as O-5). １３ R includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω', and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω' (substituent group ω': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as O-6). １３ includes phenyl substituted with one or more groups selected from the substituent group ω″ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω″ (substituent group ω″: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy) (hereinafter referred to as O-7).

[0075] R １１R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as P-1). １１ is a hydrogen atom or a halogen (hereinafter referred to as P-2). １１ is a hydrogen atom (hereinafter referred to as P-3). １１ Examples of the halogen include halogen (hereinafter referred to as P-4).

[0076] R １２ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as Q-1). １２ is a hydrogen atom or a halogen (hereinafter referred to as Q-2). １２ is a hydrogen atom (hereinafter referred to as Q-3). １２ Examples of the halogen include halogen (hereinafter referred to as Q-4).

[0077] R １４ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as R-1). １４ is a hydrogen atom or a halogen atom (hereinafter referred to as R-2). １４ is a hydrogen atom (hereinafter referred to as R-3). １４ Examples of R include halogen (hereinafter referred to as R-4).

[0078] R ２７ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as S-1). ２７ is a hydrogen atom or a halogen (hereinafter referred to as S-2). ２７ is a hydrogen atom (hereinafter referred to as S-3). ２７ Examples of the halogen include halogen (hereinafter referred to as S-4).

[0079] R ２５ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as T-1). ２５R is a hydrogen atom, a halogen atom, or an alkyl group (hereinafter referred to as T-2). ２５ is a hydrogen atom, halogen, or C1-C3 alkyl (hereinafter referred to as T-3). ２５ R is a hydrogen atom or a halogen atom (hereinafter referred to as T-4). ２５ is a hydrogen atom (hereinafter referred to as T-5). ２５ Examples of the halogen include halogen (hereinafter referred to as T-6).

[0080] R ２６ Each of R is independently a halogen or a substituted or unsubstituted alkyl (hereinafter referred to as U-1). ２６ R is independently halogen, unsubstituted alkyl, or haloalkyl (hereinafter referred to as U-2). ２６ are each independently a halogen or haloalkyl (hereinafter referred to as U-3). ２６ is a halogen (hereinafter referred to as U-4). ２６ Examples of U-5 include haloalkyl (hereinafter referred to as U-5).

[0081] n can be an integer of 0 to 4 (hereinafter referred to as V-1). n can be an integer of 0 to 2 (hereinafter referred to as V-2). n can be 1 or 2 (hereinafter referred to as V-3). n can be 1 (hereinafter referred to as V-4). n can be 0 or 1 (hereinafter referred to as V-5).

[0082] R １５ is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as W-1). １５ is a hydrogen atom or an unsubstituted alkyl (hereinafter referred to as W-2). １５ is a hydrogen atom (hereinafter referred to as W-3).

[0083] R １６ is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as X-1). １６ is a hydrogen atom or an unsubstituted alkyl (hereinafter referred to as X-2).１６ is a hydrogen atom (hereinafter referred to as X-3).

[0084] R １７ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as Y-1). １７ is a hydrogen atom, a halogen atom, or an unsubstituted alkyl (hereinafter referred to as Y-2). １７ is a hydrogen atom (hereinafter referred to as Y-3).

[0085] R １８ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as Z-1). １８ is a hydrogen atom, a halogen atom, or an unsubstituted alkyl (hereinafter referred to as Z-2). １８ is a hydrogen atom (hereinafter referred to as Z-3).

[0086] One embodiment is as follows: (i) Formula (I): (In the formula, R １ is the formula: (In the formula, R ６ , R ７ are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano; R ８ and R ９ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a cyano, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ is a substituted or unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH,N,CH) or (CH,CR ３ , N); R ３ is a hydrogen atom or a halogen; Ring B is a group of the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R １２ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R １３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２５ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; n is an integer of 0 to 4; R １５ , R １６ , R １７ and R １８ (ii) a compound represented by formula (I): or a pharmaceutically acceptable salt thereof. (In the formula, R １ is the formula: (In the formula, R ６ , R ７ are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano; R ８is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ is a substituted or unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH,N,CH) or (CH,CR ３ , N); R ３ is a hydrogen atom or a halogen; Ring B is a group of the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R １２ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R １３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２５ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; n is an integer of 0 to 4; R １５ , R １６ , R １７ and R １８ (iii) A compound represented by formula (I): or a pharmaceutically acceptable salt thereof. (In the formula, R １ is the formula: (In the formula, R ６ , R ７ are each independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ８ is substituted or unsubstituted alkyl; R ３１ is a substituted or unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH,N,CH) or (CH,CR ３ , N); R ３ is a hydrogen atom or a halogen; Ring B is a group of the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom; R １３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １４ is a hydrogen atom; R ２５ is a hydrogen atom or halogen; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom; n is an integer of 0 to 2; R １５ , R １６ , R １７ and R １８ is a hydrogen atom) or a pharmaceutically acceptable salt thereof. (In the formula, R １ is the formula: (In the formula, R ６ is unsubstituted alkyl or unsubstituted alkyloxy; R７ is halogen, unsubstituted alkyl or unsubstituted alkyloxy; R ８ is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocycleoxy; R ３１ is an unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH,N,CH) or (CH,CR ３ , N); R ３ is a hydrogen atom or a halogen; Ring B is a group of the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω (substituent group ω: halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom); １５ , R １６ , R １７ and R １８ is a hydrogen atom) or a pharmaceutically acceptable salt thereof. (In the formula, R １ is the formula: (In the formula, R ６ is unsubstituted alkyl or unsubstituted alkyloxy; R ７ is halogen, unsubstituted alkyl or unsubstituted alkyloxy; R ８ is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocycleoxy; R ３１ is an unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH,N,CH) or (CH,CR ３ , N); R ３is a hydrogen atom or a halogen; Ring B is a group of the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω′ (substituent group ω′: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom); １５ , R １６ , R １７ and R １８ is a hydrogen atom) or a pharmaceutically acceptable salt thereof. (In the formula, R １ is the formula: (In the formula, R ６ is unsubstituted alkyl; R ７ is halogen or unsubstituted alkyl; R ８ is an unsubstituted alkyl, an alkyl substituted with an unsubstituted alkyloxy, or an alkyl substituted with an unsubstituted non-aromatic heterocycleoxy; R ３１ is an unsubstituted alkyl); １ , A ２ , A ３ ) combination is (CH, CR ３ , N); R ３ is a halogen; Ring B is a group of the formula: (In the formula, R １０ is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ω″, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ω″ (substituent group ω″: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy); R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom); １５ , R１６ , R １７ and R １８ is a hydrogen atom), or a pharmaceutically acceptable salt thereof.

[0087] The compound represented by formula (I) is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0088] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include: ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. 123 I and ３６ The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals. The compounds of formula (I) include all radiolabeled compounds of the compounds of formula (I) substituted with radioactive isotopes contained in the isotopes. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compound," and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0089] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0090] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts of the compound represented by formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picolinic acid, methylparaben ... Examples of suitable salts include salts with carboxylic acids (e.g., carboxylic acids such as carboxylic acids, ...

[0091] The present invention includes the following forms: (i-A) The compound represented by formula (I) of the present invention may form a salt or a co-crystal. (i-B) The compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (i-C) Pharmaceutically acceptable salts of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (i-D) Co-crystals of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (i-E) A "solvate" may be coordinated with the compound represented by formula (I) with any number of solvent molecules (e.g., water molecules, etc.). (i-F) When a compound represented by formula (I), a pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention, or a cocrystal of a compound represented by formula (I) of the present invention is left in the atmosphere, it may absorb moisture, resulting in the formation of adsorbed water or the formation of a hydrate. (i-G) A compound represented by formula (I), a pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention, or a cocrystal of a compound represented by formula (I) of the present invention may be mutually converted by recrystallization. (i-H) A pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention refers to a compound composed of a compound represented by formula (I) and a counter molecule or counter ion, the two being bonded via an ionic bond. (i-I) A cocrystal of a compound represented by formula (I) of the present invention means that the compound represented by formula (I) and a counter molecule exist in the same crystal lattice, and may contain any number of counter molecules. (i-J) A cocrystal is distinguished from a salt in that the compound represented by formula (I) remains essentially uncharged or neutral. (i-K) Cocrystals are distinguished from solvates (e.g., hydrates) in that the counter molecule is not water or a solvent. In general, salts are considered to be those in which proton transfer occurs between a compound and a counter molecule, but it is known that in some cases, proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer may change continuously depending on the temperature.Therefore, as used herein, "a pharmaceutically acceptable salt of a compound represented by formula (I)" includes a cocrystal and refers to a pharmaceutically acceptable salt or cocrystal of a compound represented by formula (I). (i-L) The compound represented by formula (I) of the present invention may be amorphous. (i-M) The pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention may be amorphous.

[0092] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0093] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO ３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are listed.

[0094] The compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity, and are therefore useful as therapeutic and / or preventive agents for diseases associated with the serotonin 5-HT2A receptor and / or the serotonin 5-HT2C receptor. Examples of diseases associated with the serotonin 5-HT2A receptor and / or the serotonin 5-HT2C receptor include serotonin-mediated diseases such as hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, hallucinations and delusions associated with schizophrenia, hallucinations and delusions associated with depression, hallucinations and delusions associated with neurodegenerative diseases, depression, schizophrenia, autism, addiction, dyskinesia, sleep disorders, obstructive sleep apnea syndrome, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, and sexual dysfunction. Preferred examples include hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, hallucinations and delusions associated with schizophrenia, hallucinations and delusions associated with depression, sleep disorders, obstructive sleep apnea syndrome, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, etc. More preferred examples include hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, obstructive sleep apnea syndrome, etc.

[0095] (Method for Producing the Compound of the Present Invention) The compound of formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments performed in ordinary organic chemistry experiments. The compound of the present invention can be synthesized by referring to methods known in the art.

[0096] General synthesis method 1 (Method A) (In the formula, X １ , X ２ and X ３are each independently a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, PG is a protecting group such as TBS, and other symbols are as defined in (1) above.) Step 1: Compound (a-2) can be obtained by reacting compound (a-1) with compound (a-6) in the presence of a base. The reaction temperature is 0°C to reflux temperature, preferably 60°C to 80°C. The reaction time is 0.5 hours to 12 hours, preferably 1 hour to 6 hours. Examples of bases include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound (a-1). Examples of reaction solvents include dichloromethane, acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, etc., and these can be used alone or in combination. Step 2: Compound (a-3) can be obtained by reacting compound (a-2) with compound (a-7) in the presence of a metal catalyst and a base. Examples of the metal catalyst include palladium acetate, [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, and XPhos Pd G3. These metal catalysts can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound (a-2). Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, and can be used in an amount of 1 to 5 molar equivalents relative to compound (a-2). Compound (a-7) can be used in an amount of 1 to 5 molar equivalents relative to compound (a-2). The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination. Step 3: Compound (a-4) can be obtained by reacting compound (a-3) with compound (a-8) in the presence of a metal catalyst, a ligand, and a base. Examples of metal catalysts include (dibenzylideneacetone)palladium, palladium acetate, and palladium chloride. Examples of ligands to be combined with these catalysts include Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, and 1,1'-bis(diphenylphosphinoferrocene), each of which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound (a-3). Alternatively, examples of metal catalysts include tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphinoferrocene)palladium(II) dichloride, and PdCl. ２Examples of suitable bases include bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, Xantphos Pd G3, XPhos Pd G3, and Brettphos Pd G3, and these can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound (a-3). Examples of suitable bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, and these can be used in an amount of 1 to 5 molar equivalents relative to compound (a-3). Compound (a-8) can be used in an amount of 1 to 5 molar equivalents relative to compound (a-3). The reaction is carried out at a temperature of 50°C to the reflux temperature of the solvent, and optionally under microwave irradiation. The reaction time is 1 to 48 hours, preferably 1 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, dioxane, etc., and these can be used alone or in combination. Step 4: Compound (a-5) can be obtained by reacting compound (a-4) with a deprotecting agent. Examples of deprotecting agents include tetrabutylammonium fluoride, hydrogen fluoride pyridine, trifluoroacetic acid, and hydrochloric acid, and these can be used in an amount of 0.2 to 10 molar equivalents relative to compound (a-4). The reaction temperature is 0°C to 60°C, preferably 20°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 0.5 to 2 hours. Examples of reaction solvents include tetrahydrofuran, dichloromethane, dichloroethane, and methanol, and these can be used alone or in combination.

[0097] General synthesis method 2 (Method B) (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ４is a leaving group such as a fluorine atom, a chlorine atom, or a bromine atom, PG is a protecting group such as TBS, and the other symbols are as defined above in (1) and (9). Step 1: Compound (b-2) can be obtained by reacting compound (b-1) with compound (b-5) in the presence of a base. The reaction temperature is 0°C to 150°C, preferably room temperature to 100°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 6 hours. Examples of bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, pyridine, triethylamine, DBU, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound (b-1). Examples of reaction solvents include acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, NMP, etc., and these can be used alone or in combination. Step 2: Compound (b-3) can be obtained from compound (a-3) and compound (b-2) by the method described in step 3 of the above-mentioned Method A. Step 3: Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of the above-mentioned Method A.

[0098] General synthesis method 3 (C method) (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ５is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom; PG is a protecting group such as TBS; and the other symbols are as defined in (1) and (9) above. Step 1: Compound (b-2) can be obtained by reacting compound (b-1) with compound (c-1) in the presence of a base and a metal catalyst. The reaction temperature is room temperature to 150°C, preferably 60 to 120°C. The reaction time is 0.5 to 24 hours, preferably 1 to 6 hours. Examples of bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, and DBU, and can be used in an amount of 1 to 5 molar equivalents relative to compound (b-1). Examples of metal catalysts that can be used include copper chloride, copper bromide, and copper iodide. N,N,N',N'-tetramethylethylenediamine and N,N,N',N'-tetramethylcyclohexanediamine can be added as catalyst ligands. Examples of reaction solvents include acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, and NMP, and these can be used alone or in combination. Step 2: Compound (b-3) can be obtained from compound (a-3) and compound (b-2) by the method described in step 3 of Method A above. Step 3: Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of Method A above.

[0099] General synthesis method 4 (D method) (In the formula, X １is a leaving group such as a chlorine atom, bromine atom, or iodine atom, PG is a protecting group such as TBS, and the other symbols are as defined above in (1) and (9). Step 1: Compound (b-2) can be obtained by reacting compound (d-1) with compound (b-1) in the presence of a base and a metal catalyst under air or an oxygen atmosphere. The reaction temperature is 0°C to 100°C, preferably room temperature to 50°C. The reaction time is 0.5 hours to 72 hours, preferably 12 hours to 24 hours. Examples of bases include pyridine, triethylamine, DBU, etc., and can be used in an amount of 1 molar equivalent to the solvent amount relative to compound (b-1). Examples of metal catalysts that can be used include copper acetate, copper chloride, copper bromide, etc. Reaction solvents include acetonitrile, toluene, methanol, dichloromethane, DMF, DMA, etc. In addition, bases such as pyridine and triethylamine can also be used as solvents, and these can be used alone or in combination. Step 2: Compound (b-3) can be obtained from compound (a-3) and compound (b-2) by the method described in step 3 of the above-mentioned Method A. Step 3: Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of the above-mentioned Method A.

[0100] General synthesis method 5 (E method) (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ４is a leaving group such as a fluorine atom, chlorine atom, bromine atom, iodine atom, or trifluoromethanesulfonyloxy group; PG is a protecting group such as TBS; and other symbols are as defined above in (1) and (9). Step 1: Compound (e-2) can be obtained by reacting compound (e-1) with compound (e-3) in the presence of a base. The reaction temperature is 0°C to 150°C, preferably room temperature to 100°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 6 hours. Examples of bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, pyridine, triethylamine, DBU, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound (e-1). Examples of reaction solvents include acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, NMP, etc., and these can be used alone or in combination. Step 2: Compound (b-2) can be obtained by reacting compound (e-2) with a reducing agent. The reaction temperature is room temperature to 100°C, preferably room temperature to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 6 hours. Examples of reducing agents that can be used include metal salts such as iron powder and tin chloride, and hydrogen gas in the presence of palladium on carbon. Examples of reaction solvents include methanol, ethanol, tetrahydrofuran, ethyl acetate, and water, which can be used alone or in a mixture in an appropriate combination with the reducing agent. Step 3: Compound (b-3) can be obtained from compound (a-3) and compound (b-2) by the method described in Step 3 of Method A above. Step 4: Compound (b-4) can be obtained from compound (b-3) by the method described in Step 4 of Method A above.

[0101] The compounds of the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity, and are therefore useful as therapeutic and / or preventive agents for hallucinations and delusions associated with Parkinson's disease and / or dementia. Furthermore, the compounds of the present invention are useful as pharmaceuticals and preferably have one or more of the following excellent characteristics: a) weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics, such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory activity against CYP enzymes (e.g., CYP3A4) within the concentration ranges measured under the conditions described herein; e) no mutagenicity; f) low cardiovascular risk; and g) high solubility. h) Has high serotonin 5-HT2A receptor binding ability. i) Has high serotonin 5-HT2C receptor binding ability. j) Has high brain penetration. k) Has low P-gp substrate. l) Has low BCRP (breast cancer resistance protein) substrate. m) Does not have phototoxicity.

[0102] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0103] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0104] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0105] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0106] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage can be administered once or in divided doses several times a day.

[0107] The compound of the present invention can be used in combination with an anti-Parkinson's drug, an anti-Alzheimer's drug, an antipsychotic drug, or an antidepressant drug (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing these active ingredients.

[0108] The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0109] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0110] The abbreviations used in this specification have the following meanings: BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3: [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate CDCl3: deuterated chloroform DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DMSO-d ６ : Deuterated dimethyl sulfoxide DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMA: N,N-dimethylacetamide DMAP: 4-(dimethylamino)pyridine NMP: N-methyl-2-pyrrolidone PdCl ２(dtbpf): 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) THF: tetrahydrofuran TBS: tert-butyldimethylsilyl X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xantphos Pd G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate HPLC: High performance liquid chromatography ESI: Electrospray ionization nM: nmol / L μM: μmol / L

[0111] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ Measurement was performed using the method described above. When NMR data is presented, not all measured peaks may be listed. "MS (m / z)" indicates the mass of the molecule observed by LC / MS (liquid chromatography / mass spectrometry (ESI)). Measurement conditions for LC / MS include, but are not limited to, the conditions shown below. Unless otherwise specified, "MS (m / z)" is [M+H] ＋(Measurement Condition 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. In the specification, the term MS (m / z) refers to the value observed by mass spectrometry. Unless otherwise specified, [M+H] ＋ In the specification, "Compound No." represents the compound number, and "Structure" represents the chemical structure.

[0112] Reference Example 1 Synthesis of Compound 3 Step 1: Synthesis of Compound 2 3-Nitropyrazole (1 g, 8.84 mmol), 2-chloro-6-difluoromethylpyridine (1.59 g, 9.73 mmol), and potassium carbonate (1.47 g, 10.6 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at 120°C for 6 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was suspended in a hexane-ethyl acetate mixed solvent and filtered to obtain Compound 2 (1.53 g, yield 72%). 1H-NMR (CDCl) δ: 6.65 (t, J = 55.2 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 8.08 (dd, J = 8.0, 8.0 Hz, 1H), 8.24 (dd, J = 8.4, 0.8 Hz, 1H), 8.69 (d, J = 2.8 Hz, 1H). Step 2: Synthesis of Compound 3 Iron powder (1.78 g, 31.9 mmol) and ammonium chloride (1.70 g, 31.9 mmol) were added to compound 2 (1.53 g, 6.37 mmol), and then ethanol (30.6 mL) and water (15.3 mL) were added. The mixture was stirred at 80 °C for 30 minutes. After cooling, the reaction mixture was diluted with ethyl acetate and insoluble matter was filtered off. Water was added to the resulting solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was suspended in a hexane-ethyl acetate mixed solvent and filtered to obtain compound 3 (1.15 g, yield 86%). 1 H-NMR (CDCl3) δ: 3.90 (brs, 2H), 5.89 (d, J = 2.4 Hz, 1H), 6.56 (t, J = 55.6 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.80-7.89 (m, 2H), 8.34 (d, J = 2.8 Hz, 1H).

[0113] Reference Example 2 Synthesis of Compound 6 Step 1: Synthesis of Compound 5 Compound 4 (50 g, 267 mmol) was dissolved in dichloromethane (500 mL) and water (500 mL). Methoxyacetic acid (48.2 g, 535 mmol), silver nitrate (4.54 g, 26.7 mmol), and ammonium peroxodisulfate (122 g, 535 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Potassium carbonate (92 g, 668 mmol), water (100 mL), and saturated saline (100 mL) were added, and the mixture was filtered through Celite® to remove insoluble materials. Extraction was performed with chloroform (200 mL), and the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 5 (60.1 g, yield 97%). 1 H-NMR (CDCl) δ: 2.66 (s, 6H), 3.53 (s, 3H), 4.58 (s, 2H). Step 2: Synthesis of Compound 6. Compound 5 (30 g, 130 mmol), bis(pinacolato)diboron (65.9 g, 260 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (9.5 g, 13 mmol), and potassium acetate (31.9 g, 325 mmol) were added to 1,4-dioxane (300 mL) and stirred at 100°C for 8 hours. After cooling, the reaction mixture was filtered through Celite®. Insoluble matter was removed, and the mother liquor solvent was evaporated under reduced pressure. Hexane was added to the resulting residue, and the precipitated insoluble matter was again removed by filtration. The mother liquor solvent was evaporated under reduced pressure. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate). The resulting crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 6 (26.1 g, yield 72%). 1 H-NMR(CDCl3) δ: 1.40 (s, 12H), 2.61 (s, 6H), 3.52 (s, 3H), 4.61 (s, 2H).

[0114] Example 1 Synthesis of Compound I-011 Step 1: Synthesis of Compound 8 Compound 7 (10 g, 36.6 mmol), potassium carbonate (7.58 g, 54.9 mmol), sodium iodide (5.48 g, 36.6 mmol), and (2-bromoethoxy)-tert-butyldimethylsilane (10.5 g, 43.9 mmol) were suspended in N,N-dimethylformamide (100 mL) and stirred at 60°C for 2 hours and at 70°C for 3 hours. After cooling, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 8 (15.35 g, yield 97%). 1 H-NMR (CDCl) δ: 0.11 (s, 6H), 0.90 (s, 9H), 4.02 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 7.04 (d, J = 9.2 Hz, 1H). Step 2: Synthesis of Compound 9. Compound 8 (12.7 g, 29.4 mmol), compound 6 (12.27 g, 44.1 mmol), PdCl(dtbpf) (1.92 g, 2.94 mmol), and potassium carbonate (8.13 g, 58.8 mmol) were suspended in 1,4-dioxane (127 mL) and water (25.4 mL) and stirred at 100°C under a nitrogen atmosphere for 6 hours. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 9 (8.92 g, yield 67%). 1H-NMR (CDCl3) δ: -0.07 (s, 6H), 0.81 (s, 9H), 2.28 (s, 6H), 3.55 (s, 3H), 3.83 (t, J = 4.6Hz, 2H), 4.07 (t, J = 4.6Hz, 2H), 4.67 (s, 2H), 7.34 (d, J = 9.2Hz, 1H). Step 3 Synthesis of compound 10 Toluene (400 μL) was added to compound 3 (22.1 mg, 0.105 mmol), compound 9 (40 mg, 0.088 mmol), cesium carbonate (57.2 mg, 0.175 mmol), BINAP (10.9 mg, 0.018 mmol), and tris(dibenzylideneacetone)dipalladium (8.0 mg, 0.0088 mmol), and the mixture was stirred at 100° C. for 9 hours. After cooling, the reaction mixture was filtered through Celite®, and the solvent in the mother liquor was evaporated under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (hexane-ethyl acetate) to obtain compound 10 (36.7 mg, yield 66%). 1H-NMR (CDCl3) δ: -0.06 (s, 6H), 0.83 (s, 9H), 2.34 (s, 6H), 3.60 (s, 3H), 3.80 (t, J = 4.8 Hz, 2H), 3.97 (t, J = 4.8 Hz, 2H), 4.70 (s, 2H), 6.59 (t, J = 55.7 Hz, 1H), 6.93 (d, J = 2.8 Hz, 1H), 7.18-7.21 (m, 1H), 7.30 (d, J = 11.8 Hz, 1H), 7.44 (dd, J = 6.5, 1.7 Hz, 1H), 7.87-7.93 (m, 2H), 8.38 (d, J = 2.8 Hz, 1H). Step 4 Synthesis of Compound I-011 Compound 10 (36 mg, 0.057 mmol) was dissolved in tetrahydrofuran (360 μL), and a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (86 μL, 0.086 mmol) was added, followed by stirring at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added, and the organic layer was extracted with chloroform. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol). Diisopropyl ether-hexane was added to precipitate a solid, which was then collected by filtration to obtain Compound I-011 (23.5 mg, 80% yield). 1 H-NMR (CDCl3) δ: 1.65 (br s, 1H), 2.36 (s, 6H), 3.62 (s, 3H), 3.80-3.81 (m, 2H), 4.00 (t, J = 4.5 Hz, 2H), 4.71 (s, 2H), 6.59 (t, J = 55.4 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 7.24-7.26 (m, 2H), 7.44 (dd, J = 7.0, 1.2 Hz, 1H), 7.87-7.93 (m, 2H), 8.38 (d, J = 2.8 Hz, 1H).

[0115] Example 2 Synthesis of Compound I-046 Step 1: Synthesis of Compound 12 Compound 11 (100 mg, 0.76 mmol) was dissolved in dichloromethane (3 mL), and 3-fluorophenylboronic acid (214 mg, 1.53 mmol), pyridine (123 μL, 1.53 mmol), and copper(II) acetate (152 mg, 0.84 mmol) were added, followed by stirring at room temperature for 3 days. 3-Fluorophenylboronic acid (214 mg, 1.53 mmol), pyridine (123 μL, 1.53 mmol), and copper(II) acetate (152 mg, 0.84 mmol) were then added, followed by stirring at room temperature for 6 days. The reaction mixture was then diluted with chloroform, and insoluble matter was filtered off. After concentration, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 12 (106 mg, 62% yield). 1 H-NMR (CDCl) δ: 6.65 (1H, d, J = 5.6 Hz), 7.15-7.24 (1H, m), 7.45-7.56 (3H, m). Step 2: Synthesis of Compound 13. Iron powder (117 mg, 2.1 mmol) and ammonium chloride (112 mg, 2.1 mmol) were added to compound 12 (105 mg, 0.47 mmol), and then ethanol (1.6 mL) and water (0.8 mL) were added. The mixture was stirred at 80 °C for 2.3 hours. After cooling, the mixture was diluted with ethyl acetate and insoluble matter was filtered off. Water was added to the resulting solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 13 (88 mg, 97% yield). 1H-NMR (CDCl) δ: 3.80 (2H, s), 5.40 (1H, d, J = 5.1 Hz), 6.88-6.97 (1H, m), 7.31-7.60 (3H, m). Step 3: Synthesis of Compound 14. Compound 9 (30 mg, 0.066 mmol) was dissolved in toluene (0.6 mL), and compound 13 (15 mg, 0.079 mmol), BINAP (8.2 mg, 0.013 mmol), cesium carbonate (43 mg, 0.13 mmol), and tris(dibenzylideneacetone)dipalladium (6.0 mg, 6.6 μmol) were added, followed by stirring at 100°C for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 14 (36 mg) as a crude product. Step 4 Synthesis of Compound I-046 The crude product of Compound 14 obtained above (36 mg) was dissolved in THF (0.36 mL), and a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (88 μL, 0.088 mmol) was added, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was then added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (acetonitrile-water) to obtain Compound I-046 (18 mg, 56% yield over two steps). 1 H-NMR (CDCl3) δ: 2.34 (s, 6H), 3.61 (s, 3H), 3.77-3.83 (m, 2H), 3.99 (t, J = 4.5 Hz, 2H), 4.71 (s, 2H), 6.45 (d, J = 5.0 Hz, 1H), 6.93-7.01 (m, 2H), 7.10 (brs, 2H), 7.24 (s, 1H), 7.34-7.44 (m, 3H).

[0116] Reference Example 3 Synthesis of Compound 16 Step 1: Synthesis of Compound 15 Compound 1 (1.54 g, 13.6 mmol) was dissolved in dimethyl sulfoxide (15.4 mL), potassium carbonate (4.23 g, 15.0 mmol) and 2,2,3,3,3-pentafluoropropyl triflate (2.74 g, 9.73 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain compound 15 (3.54 g) as a crude product. 1 H-NMR (CDCl) δ: 4.85 (t, J = 14.0 Hz, 2H), 7.03 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H). Step 2: Synthesis of Compound 16. Compound 15 (3 g, 12.2 mmol) was dissolved in ethanol (60 mL) and water (20 mL), and ammonium chloride (3.27 g, 61.2 mmol) and iron powder (3.42 g, 61.2 mmol) were added. The mixture was stirred at 80 °C for 1 hour. After cooling, the mixture was diluted with ethanol and insoluble matter was filtered off through Celite. Water was added to the resulting solution, which was then extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound 16 (2.42 g, 92% yield). 1 H-NMR (CDCl3) δ: 3.79 (brs, 2H), 4.52 (t, J = 14.0 Hz, 2H), 5.72 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H).

[0117] Example 3 Synthesis of Compound I-066 Step 1 Synthesis of Compound 17 Compound 8 (5 g, 11.6 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.65 g, 12.7 mmol), PdCl ２(dtbpf) (0.76 g, 1.16 mmol) and potassium carbonate (3.20 g, 23.2 mmol) were suspended in 1,4-dioxane (50 mL) and water (10 mL) and stirred at 100°C for 4 hours under a nitrogen atmosphere. After cooling, ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 17 (3.97 g, yield 89%). 1 H-NMR (CDCl) δ: 0.06 (s, 6H), 0.88 (s, 9H), 3.97-4.00 (m, 2H), 4.10 (s, 3H), 4.12-4.15 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H). Step 2: Synthesis of Compound 18. Compound 17 (2.71 g, 7.02 mmol) was dissolved in DMF (27 mL), and N-bromosuccinimide (1.38 g, 7.72 mmol) was added. The mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. The reaction solution was quenched with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 18 (2.45 g, yield 75%). 1H-NMR (CDCl) δ: −0.01 (s, 6H), 0.83 (s, 9H), 3.81 (s, 3H), 3.93–3.96 (m, 2H), 4.11–4.14 (m, 2H), 7.37 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H). Step 3: Synthesis of Compound 19 Toluene (1 mL) was added compound 18 (100 mg, 0.22 mmol), compound 16 (55.5 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (19.7 mg, 0.022 mmol), BINAP (26.8 mg, 0.043 mmol), and cesium carbonate (140 mg, 0.43 mmol), and the mixture was stirred at 100° C. for 4 hours. After cooling, the reaction solution was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 19 (82 mg, yield 59%). 1 H-NMR (CDCl3) δ: 0.00 (s, 6H), 0.85 (s, 9H), 3.81 (s, 3H), 3.87-3.90 (m, 2H), 4.00-4.03 (m, 2H), 4.60 (t, J = 14.0 Hz, 2H), 6.98 (d, Step 4 Synthesis of compound I-066 Compound 19 (70 mg, 0.109 mmol) was dissolved in tetrahydrofuran (0.7 mL), and water (0.7 mL) and acetic acid (0.5 mL) were added, followed by stirring at 60°C for 4 hours. After cooling, the mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-066 (55 mg, yield 95%). 1H-NMR (CDCl3) δ: 2.01 (t, J = 6.0 Hz, 1H), 3.83 (s, 3H), 3.86-3.90 (m, 2H), 4.00-4.06 (m, 2H), 4.61 (t, J = 14.0 Hz, 2H), 6.93 (d, J = 2.4 Hz, 1H), 7.15-7.17 (m, 1H), 7.24 (d, J = 11.2 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.54 (s, 1H).

[0118] Reference Example 4 Synthesis of Compound 21 Step 1: Synthesis of Compound 21 Potassium tert-butoxide (1.95 g, 17.4 mmol) was dissolved in tert-butanol (20 mL) and heated and stirred at 80°C for 10 minutes. Compound 20 (1 g, 6.94 mmol) and 3-ethoxyacrylonitrile (674 mg, 6.94 mmol) were added to the reaction solution, and the mixture was further stirred for 5 minutes. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The residue was solidified from (hexane-ethyl acetate) and collected by filtration to obtain compound 21 (374 mg, yield 28%). 1 H-NMR (CDCl3) δ: 3.81 (brs, 2H), 5.85 (d, J = 2.4 Hz, 1H), 6.91-6.97 (m, 2H), 7.71-7.80 (m, 2H).

[0119] Example 4 Synthesis of Compound I-081 Step 1: Synthesis of Compound 22 Compound 9 (1 g, 2.19 mmol) was dissolved in tetrahydrofuran (10 mL), and a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (3.29 mL, 3.29 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was further extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 22 (670 mg, yield 89%). 1 H-NMR (CDCl3) δ: 1.81 (t, J = 6.0 Hz, 1H), 2.29 (s, 6H), 3.57 (s, 3H), 3.83-3.88 (m, 2H), 4.07-4.11 (m, 2H), 4.67 (s, 2H), 7.28 (d, J = 9.2 Hz, 1H). Step 2 Synthesis of compound I-081 Compound 22 (20 mg, 0.059 mmol) was dissolved in toluene (0.5 mL), and compound 21 (15 mg, 0.076 mmol), BINAP (7.3 mg, 0.012 mmol), cesium carbonate (38 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium (5.4 mg, 5.9 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to obtain compound I-081 (26 mg, 88% yield). 1 H-NMR (CDCl3) δ: 1.70 (brs, 1H), 2.36 (s, 6H), 3.61 (s, 3H), 3.60-3.62 (m,2H), 3.99 (t, J = 4.8 Hz, 2H), 4.70 (s, 2H), 6.90 (d, J = 2.8 Hz, 1H), 6.95-7.00 (m, 2H), 7.22-7.26 (m, 2H), 7.74-7.80 (m, 2H).

[0120] Example 5 Synthesis of Compound I-114 Step 1: Synthesis of Compound I-114 Compound 22 (20 mg, 0.059 mmol) was dissolved in toluene (0.5 mL), and 1-(3,5-difluorophenyl)-1H-pyrazol-3-amine (15 mg, 0.076 mmol), BINAP (7.3 mg, 0.012 mmol), cesium carbonate (38 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium (5.4 mg, 5.9 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give Compound I-114 (26 mg, 88% yield). 1 H-NMR (CDCl3) δ: 1.71 (t, J = 6.1 Hz, 1H), 2.35 (s, 6H), 3.61 (s, 3H), 3.78-3.83 (m, 2H), 4.00 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 6.65 (tt, J = 8.8, 2.3 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 7.15-7.19 (m, 2H), 7.22-7.27 (m, 2H), 7.71 (d, J = 2.8 Hz, 1H).

[0121] Example 6 Synthesis of Compound I-144 Step 1 Synthesis of Compound 23 Compound 8 (5.0 g, 11.58 mmol), 2,4,6-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (4.31 g, 17.37 mmol), PdCl ２(dtbpf) (0.76 g, 1.16 mmol) and potassium carbonate (3.20 g, 23.2 mmol) were suspended in 1,4-dioxane (50 mL) and water (10 mL) and stirred at 100°C for 2 hours under a nitrogen atmosphere. Ethyl acetate and water were added, and the layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 23 (4.04 g, yield 82%). 1 H-NMR (CDCl3) δ: -0.08 (s, 6H), 0.81 (s, 9H), 2.22 (s, 6H), 2.70 (s, 3H), 3.83 (t, J = 4.5 Hz, 2H), 4.06 (t, J = 4.5 Hz, 2H), 7.31 (d, J = 9.3 Hz, 1H). Step 2: Synthesis of Compound 24. Compound 23 (0.61 g, 1.43 mmol) was dissolved in tetrahydrofuran (6.1 mL), and 1 mol / L tetrabutylammonium fluoride in tetrahydrofuran (2.15 mL, 2.15 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound 24 (380 mg, yield 85%). 1H-NMR (CDCl) δ: 1.97 (t, J = 6.0 Hz, 1H), 2.23 (s, 6H), 2.69 (s, 3H), 3.85-3.90 (m, 2H), 4.10 (t, J = 4.5 Hz, 2H), 7.27 (d, J = 9.1 Hz, 1H). Step 3: Synthesis of Compound I-144 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and compound 13 (16 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added thereto, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent and passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse phase liquid chromatography (acetonitrile-water) to obtain compound I-144 (28.9 mg, yield 96%). 1 H-NMR (CDCl3) δ: 1.79 (t, J = 6.0 Hz, 1H), 2.29 (s, 6H), 2.74 (s, 3H), 3.78-3.85 (m, 2H), 4.00 (t, J = 4.4 Hz, 2H), 6.47 (d, J = 4.8 Hz, 1H), 6.92-7.03 (m, 1H), 7.08-7.12 (m, 1H), 7.21-7.27 (m, 1H), 7.34-7.46 (m, 3H).

[0122] Example 7 Synthesis of Compound I-145 Step 1: Synthesis of Compound I-145 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and 1-(3,5-difluorophenyl)-1H-pyrazol-3-amine (16 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give Compound I-145 (28.9 mg, yield 96%). 1 H-NMR (CDCl3) δ: 1.86 (t, J = 5.8 Hz, 1H), 2.30 (s, 6H), 2.73 (s, 3H), 3.79-3.84 (m, 2H), 4.00 (t, J = 4.4 Hz, 2H), 6.62-6.69 (m, 1H), 6.94 (d, J = 2.5 Hz, 1H), 7.15-7.25 (m, 3H), 7.71 (d, J = 2.6 Hz, 1H).

[0123] Example 8 Synthesis of Compound I-262 Step 1: Synthesis of Compound 25 Compound 1 (2.5 g, 22.11 mmol), 2,6-difluoropyridine (12.7 g, 111 mmol), and potassium carbonate (3.67 g, 26.5 mmol) were suspended in dimethyl sulfoxide (25 mL) and stirred at 40°C for 1.5 hours, and then at 45°C for an additional 1.5 hours. After cooling, water was added, and the resulting solid was collected by filtration and washed with water and hexane. The solid was dissolved again in chloroform and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 25 (2.24 g, yield 49%). 1H-NMR (CDCl3) δ: 6.97-7.01 (m, 1H), 7.09 (d, J = 2.8 Hz, 1H), 7.97-8.06 (m, 2H), 8.57 (d, J = 2.8 Hz, 1H). Step 2: Synthesis of Compound 26. Potassium t-butoxide (140 mg, 1.25 mmol) was dissolved in tetrahydrofuran (2 mL) and cooled to 0 °C. 3,3-Difluoropropan-1-ol (138 mg, 1.44 mmol) and Compound 25 (200 mg, 0.96 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The mixture was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was suspended in hexane and filtered to obtain Compound 26 (251 mg, yield 92%). 1 H-NMR (CDCl3) δ: 2.31-2.46 (m, 2H), 4.55 (t, J = 6.2 Hz, 2H), 6.08 (tt, J = 56.4, 4.6 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 2.8 Step 3 Synthesis of compound 27 Ethanol (2.4 mL) and water (1.2 mL) were added to a mixture of compound 26 (240 mg, 0.844 mmol), iron powder (236 mg, 4.22 mmol), and ammonium chloride (226 mg, 4.22 mmol), and the mixture was stirred at 80°C for 1 hour. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting solid was suspended in a hexane / diisopropyl ether mixed solvent system and filtered to obtain compound 27 (177 mg, 82% yield). 1H-NMR (CDCl3) δ: 2.27-2.42 (m, 2H), 3.87 (br s, 2H), 4.50 (t, J = 6.2 Hz, 2H), 5.85 (d, J = 2.5 Hz, 1H), 6.07 (tt, J = 56.6, 4.7 Hz, Step 4 Synthesis of compound I-262 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and compound 27 (21 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give compound I-262 (33.4 mg, 99% yield). 1 H-NMR (CDCl3) δ: 1.79 (t, J = 5.6 Hz, 1H), 2.28-2.44 (m, 2H), 2.31 (s, 6H), 2.73 (s, 3H), 3.79-3.84 (m, 2H), 3.99 (t, J = 4.4 Hz, 2H), 4.51 (t, J = 6.0 Hz, 2H), 6.06 (tt, J = 56.4, 4.8 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 7.19-7.30 (m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.0, 8.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H).

[0124] Example 9 Synthesis of Compound I-266 Step 1: Synthesis of Compound 28 Ethanol (1.4 mL) and sodium ethoxide (20% ethanol solution, 0.54 mL, 1.25 mmol) were added to compound 25 (200 mg, 0.96 mmol), and the mixture was stirred at 75° C. for 5 hours. The mixture was cooled to 0° C. and quenched with a saturated aqueous ammonium chloride solution. Water was added, and the precipitated solid was collected by filtration and washed with water and hexane to obtain compound 28 (211 mg, yield 94%). 1 H-NMR (CDCl) δ: 1.45 (t, J = 7.1 Hz, 3H), 4.42 (q, J = 7.1 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H). Step 2: Synthesis of Compound 29 Ethanol (2.1 mL) and water (1.0 mL) were added to a mixture of compound 28 (208.7 mg, 0.891 mmol), iron powder (249 mg, 4.46 mmol), and ammonium chloride (238 mg, 4.46 mmol), and the mixture was stirred at 80°C for 1 hour. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting solid was suspended in a hexane / diisopropyl ether mixed solvent system and filtered to obtain compound 29 (90 mg, yield 50%). 1H-NMR (CDCl3) δ: 1.42 (t, J = 7.1 Hz, 3H), 3.86 (br s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 5.83 (d, J = 2.6 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H). Step 3 Synthesis of compound I-266 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and compound 29 (17 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give compound I-266 (30.1 mg, 98% yield). 1 H-NMR (CDCl3) δ: 1.42 (t, J = 7.2 Hz, 3H), 1.80-1.90 (m, 1H), 2.30 (s, 6H), 2.73 (s, 3H), 3.78-3.84 (m, 2H), 3.99 (t, J = 4.8 Hz, 2H), 4.38 (td, J = 7.2, 7.2 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 7.20-7.32 (m, 3H), 7.64 (t, J = 8.0 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H).

[0125] Example 10 Synthesis of Compound I-267 Step 1: Synthesis of Compound 30 3-Nitropyrazole (210 mg, 1.86 mmol), 2-bromo-6-(1,1-difluoroethyl)pyridine (454 mg, 2.04 mmol), cesium carbonate (605 mg, 1.86 mmol), and copper iodide (35.4 mg, 0.186 mmol) were suspended in NMP (2.1 mL) and stirred at 120°C for 7 hours. Copper iodide (35.4 mg, 0.186 mmol) was then added, and the mixture was stirred at 120°C for 2 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 30 (363 mg, 77% yield). 1 H-NMR (CDCl) δ: 2.06 (t, J = 18.6 Hz, 3H), 7.11 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 8.04 (t, J = 7.9 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.68 (d, J = 2.6 Hz, 1H). Step 2: Synthesis of Compound 31. Iron powder (388 mg, 6.94 mmol) and ammonium chloride (371 mg, 6.94 mmol) were added to compound 30 (353 mg, 1.39 mmol), and ethanol (3.5 mL) and water (1.8 mL) were added. The mixture was stirred at 80 °C for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration through Celite. Water was added to the resulting solution, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The resulting residue was suspended in a hexane-diisopropyl ether mixed solvent and filtered to obtain compound 31 (272 mg, yield 87%). 1H-NMR (CDCl3) δ: 2.03 (t, J = 18.6 Hz, 3H), 3.90 (br s, 2H), 5.88 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 7.4, 1.0 Hz, 1H), 7.76-7.87 (m, 2H), 8.34 (d, J = 2.8 Hz, 1H). Step 3 Synthesis of compound I-267 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and compound 31 (19 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give compound I-267 (30.9 mg, 97% yield). 1 H-NMR (CDCl3) δ: 1.83-1.92 (m, 1H), 2.03 (t, J = 17.6 Hz, 3H), 2.30 (s, 6H), 2.73 (s, 3H), 3.77-3.86 (m, 2H), 3.96-4.04 (m, 2H), 6.92 (d, J = 2.8 Hz, 1H), 7.19-7.29 (m, 2H), 7.43-7.50 (m, 1H), 7.81-7.92 (m, 2H), 8.39 (d, J = 2.8 Hz, 1H).

[0126] Reference Example 5 Synthesis of Compound 33 Step 1: Synthesis of Compound 32 3-Nitropyrazole (200 mg, 1.77 mmol), 6-bromo-3-fluoro-2-methylpyridine (437 mg, 2.30 mmol), cesium carbonate (576 mg, 1.77 mmol), and copper iodide (34 mg, 0.177 mmol) were suspended in NMP (2 mL) and stirred at 120°C under microwave irradiation for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 32 (240 mg, yield 61%). 1 H-NMR (CDCl) δ: 2.56 (d, J = 2.9 Hz, 3H), 7.07 (d, J = 2.8 Hz, 1H), 7.53 (dd, J = 8.5, 8.5 Hz, 1H), 7.92 (dd, J = 8.8, 3.0 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H). Step 2: Synthesis of Compound 33. Iron powder (483 mg, 8.64 mmol) and ammonium chloride (231 mg, 4.32 mmol) were added to compound 32 (240 mg, 1.08 mmol), and ethanol (5.3 mL) and water (2.7 mL) were added. The mixture was stirred at 90 °C for 1 hour. After cooling, saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, and the insoluble matter was filtered off. The resulting solution was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 33 (144 mg, yield 82%). 1 H-NMR (CDCl3) δ: 2.48 (d, J = 3.0 Hz, 3H), 3.83 (br s, 2H), 5.84 (d, J = 2.6 Hz, 1H), 7.36 (dd, J = 8.6, 8.6 Hz, 1H), 7.52 (dd, J = 8.8, 3.2 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H).

[0127] Example 11 Synthesis of Compound I-166 Step 1: Synthesis of Compound I-166 Compound 24 (20 mg, 0.064 mmol) was dissolved in toluene (0.5 mL), and compound 33 (16 mg, 0.083 mmol), BINAP (8.0 mg, 0.013 mmol), cesium carbonate (41.8 mg, 0.128 mmol), and tris(dibenzylideneacetone)dipalladium (5.9 mg, 6.4 μmol) were added, followed by stirring at 110°C for 4 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in an ethyl acetate-methanol mixed solvent, passed through a silica gel pad, and the solvent was evaporated under reduced pressure again. The resulting residue was purified by reverse-phase liquid chromatography (acetonitrile-water) to give compound I-166 (24.6 mg, 82% yield). 1 H-NMR (CDCl3) δ: 1.87 (br s, 1H), 2.31 (s, 6H), 2.50 (d, J = 3.0 Hz, 3H), 2.73 (s, 3H), 3.80-3.83 (m, 2H), 3.99 (t, J = 4.5 Hz, 2H), 6.88 (d, J = 2.6 Hz, 1H), 7.20-7.26 (m, 2H), 7.40 (t, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.7, 3.2 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H).

[0128] The following compounds were synthesized according to the above general synthesis methods and the methods described in the Examples. The structures and physical properties (LC / MS data) are shown in the following table.

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] Biological test examples for the compounds of the present invention are described below. The compounds of the present invention can be tested essentially as in the test examples below. The compounds represented by formula (I) according to the present invention may be any compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity. Specifically, in the evaluation methods described below, the Ki value is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[0190] Test Example 1: 5-HT2A receptor binding inhibition test (Experimental conditions) Cell membrane: Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor) Assay buffer: NaCl 120 mmol / L, MgCl ２ ・6H ２ O 1 mmol / L, KCl 5 mmol / L, 0.1% BSA and CaCl ２ 2 mmol / L Tris-HCl 50 mmol / L (pH 7.4) Radioactive ligand: The final concentration is near the Kd value calculated by the following method [ ３[H]-Ketanserin Nonspecific Ligand: Ketanserin at a final concentration of 5 μmol / L. The Kd value is calculated when changing the cell membrane lot. 0.5 μL of 1 mmol / L nonspecific binding calculation compound or DMSO dissolved in DMSO is dispensed into a microplate, and the cell membrane is diluted with assay buffer. The radioactive ligand solution is serially diluted and counted using a liquid scintillator. 50 μL / well of the assay buffer containing the diluted cell membrane is dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution is dispensed into the microplate, and the plate is sealed. The plate is left to stand at room temperature (25°C) for 1.5 hours. During this time, 50 μL / well of Tris-HCl (pH 7.4) is dispensed into the UniFilter plate, and the plate is left to stand at 4°C for at least 1 hour. Then, filtration is performed using a Cell Harvester (PerkinElmer). 10 μL / well of the radioactive ligand solution is dispensed into empty wells of the UniFilter plate. After the UniFilter plate is dried at room temperature, 50 μL / well of MicroScinti20 is dispensed into the UniFilter plate and the plate is sealed. The UniFilter plate is left standing at room temperature overnight. ３The radioactivity of [H]-Ketanserin is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve is plotted from the measured values, and the Kd value is calculated from the slope of the Scatchard plot. (Binding test of the compound of the present invention) 0.5 μL of compound solution dissolved in DMSO is dispensed into a microplate in advance, and the cell membrane and hot ligand are each diluted with assay buffer. Then, 50 μL / well of the assay buffer containing the diluted cell membrane is dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution is dispensed into the microplate, and the plate is sealed. Then, the plate is left to stand at room temperature (25°C) for 1.5 hours. During this time, 50 μL / well of Tris-HCl (pH 7.4) is dispensed into the UniFilter plate and left to stand at 4°C for at least 1 hour. Then, filtration is performed using a Cell Harvester (PerkinElmer). After drying the UniFilter plate at room temperature, 50 μL / well of MicroScinti20 is dispensed into the UniFilter plate and the plate is sealed. The UniFilter plate is left to stand overnight at room temperature. ３ The radioactivity of [H]-Ketanserin is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Non-specific binding is measured in the presence of 5 μmol / L unlabeled ligand Ketanserin, and total binding is measured in the absence of the compound of the present invention (vehicle). ３ The binding activity of the compounds of the present invention is calculated from the radioactivity of [H]-Ketanserin. Finally, the Ki value is calculated from the dose-response curve. (The binding activity of the compounds of the present invention is calculated from the binding inhibition rate (%) below.) Inhibition rate (%) = [1 - (ca) / (ba)] x 100 a; mean cpm of non-specific binding b; mean cpm of total binding c; cpm in the presence of test compound The compounds of the present invention were tested essentially as described above. The test results for the human serotonin 5-HT2A receptor binding activity (h 5-HT2A Ki) of the compounds of the present invention are shown below. (Results)

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] Test Example 2: 5-HT2C receptor binding inhibition test (Experimental conditions) Cell membrane: Jump-In HEK cell membrane (expressing human recombinant 5-HT2C receptor) Assay buffer: NaCl 120 mmol / L, MgCl ２ ・6H ２ O 1 mmol / L, KCl 5 mmol / L, 0.1% BSA and CaCl ２ 2 mmol / L Tris-HCl 50 mmol / L (pH 7.4) Radioactive ligand: The final concentration is near the Kd value calculated by the following method [ ３[H]-Mesulergine Nonspecific Ligand: Ketanserin (final concentration 5 μmol / L). The Kd value is calculated when the cell membrane lot is changed. 0.5 μL of 1 mmol / L nonspecific binding calculation compound or DMSO dissolved in DMSO is dispensed into a microplate, and the cell membrane is diluted with assay buffer. The radioactive ligand solution is serially diluted and counts are confirmed using a liquid scintillator. 50 μL / well of the assay buffer containing the diluted cell membrane is dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution is dispensed into the microplate, and the plate is sealed. The plate is left to stand at 37°C for 2 hours. During this time, 50 μL / well of Tris-HCl (pH 7.4) is dispensed into the UniFilter plate, and the plate is left to stand at 4°C for at least 1 hour. Then, filtration is performed using a Cell Harvester (PerkinElmer). 10 μL / well of the radioactive ligand solution is dispensed into empty wells of the UniFilter plate. After the UniFilter plate is dried at room temperature, 50 μL / well of MicroScinti20 is dispensed into the UniFilter plate and the plate is sealed. The UniFilter plate is left standing at room temperature overnight. ３The radioactivity of [H]-mesulergine is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve is plotted from the measured values, and the Kd value is calculated from the slope of the Scatchard Plot. (Binding Test of the Compound of the Present Invention) 0.5 μL of compound solution dissolved in DMSO is dispensed into a microplate in advance, and the cell membrane and hot ligand are each diluted with assay buffer. Then, 50 μL / well of the assay buffer containing the diluted cell membrane is dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution is dispensed into the microplate, and the plate is sealed. Then, the plate is left to stand at 37°C for 2 hours. During this time, Tris-HCl (pH 7.4) is dispensed into the UniFilter plate at 50 μL / well and left to stand at 4°C for at least 1 hour. Then, filtration is performed using a Cell Harvester (PerkinElmer). After drying the UniFilter plate at room temperature, MicroScinti20 is dispensed into the UniFilter plate at 50 μL / well and sealed. The UniFilter plate is left to stand overnight at room temperature. ３ The radioactivity of [H]-Mesulergine is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Non-specific binding is measured in the presence of 5 μmol / L unlabeled ligand Ketanserin, and total binding is measured in the absence of the compound of the present invention (vehicle). ３ The binding activity of the compounds of the present invention is calculated from the radioactivity of [H]-mesulergine. Finally, the Ki value is calculated from the dose-response curve. (The binding activity of the compounds of the present invention is calculated from the binding inhibition rate (%) below.) Inhibition rate (%) = [1 - (ca) / (ba)] x 100 a; mean cpm of non-specific binding b; mean cpm of total binding c; cpm in the presence of test compound The compounds of the present invention were tested essentially as described above. The test results for the human serotonin 5-HT2C receptor binding activity (h 5-HT2C Ki) of the compounds of the present invention are shown below. (Results)

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] Test Example 2-2: 5-HT2A Receptor Inverse Agonist Test To evaluate the 5-HT2A receptor inverse agonist activity of the compounds of the present invention, an inositol monophosphate (IP1) homogeneous time-resolved fluorescence (HTRF) assay was used. HEK293 cells were transiently transfected with recombinant human 5-HT2A receptors using the MaxCyte STX system (MaxCyte). One day after transfection, IP1 accumulation was measured using the HTRF IP-One Gq Detection Kit (Revvity). Compounds were diluted in DMSO and pre-aliquoted into 384-well assay plates. Transfected cells were harvested, resuspended in stimulation buffer, and then aliquoted into 384-well assay plates at 20,000 cells / well / 9 μL. The plates were then incubated at 37°C for 2 hours. After incubation, lysis buffer containing d2-labeled IP1 and Tb cryptate IP1 antibody was added to each well. After incubation at room temperature for 1 hour, IP1 was quantified by measuring wavelengths of 665 / 620 nm using a PHERAstar FSX (BMG Labtech). The amount of IP1 accumulated in the absence of the compound of the present invention (Vehicle) was defined as 0% inverse agonist activity, and the amount of IP1 accumulated upon addition of 10 μmol / L Ritanserin was defined as 100% maximum inhibition of inverse agonist activity. The maximum inhibition rate (Imax) of the compound of the present invention was calculated from the IP1 concentration in each well using TIBCO Spotfire (Cloud Software Group). The compounds of the present invention can be tested essentially as described above.

[0203] Test Example 2-3: 5-HT2C Receptor Inverse Agonist Test To evaluate the 5-HT2C receptor inverse agonist activity of the compounds of the present invention, an inositol monophosphate (IP1) homogeneous time-resolved fluorescence (HTRF) assay was used. HEK293 cells were transiently transfected with recombinant human 5-HT2C receptors using the MaxCyte STX system (MaxCyte). One day after transfection, IP1 accumulation was measured using the HTRF IP-One Gq Detection Kit (Revvity). Compounds were diluted in DMSO and pre-aliquoted into a 384-well assay plate. Transfected cells were harvested, resuspended in stimulation buffer, and then aliquoted into a 384-well assay plate at 5,000 cells / well / 9 μL. The plates were then incubated at 37°C for 2 hours. After incubation, lysis buffer containing d2-labeled IP1 and Tb cryptate IP1 antibody was added to each well. After incubation at room temperature for 1 hour, IP1 was quantified by measuring wavelengths of 665 / 620 nm using a PHERAstar FSX (BMG Labtech). The amount of IP1 accumulated in the absence of the compound of the present invention (Vehicle) was defined as 0% inverse agonist activity, and the amount of IP1 accumulated upon addition of 10 μmol / L Ritanserin was defined as 100% maximum inhibition of inverse agonist activity. The maximum inhibition rate (Imax) of the compound of the present invention was calculated from the IP1 concentration in each well using TIBCO Spotfire (Cloud Software Group). The compounds of the present invention can be tested essentially as described above.

[0204] Test Example 3: hERG Test To assess the risk of electrocardiogram QT interval prolongation of the compounds of the present invention, the action of the compound is examined by evaluating potassium channel activity using CHO cells expressing the human ether-a-go-go related gene (hERG) channel. The evaluation is carried out using a FluxORII Green Potassium Ion Channel Assay kit (Thermo Fisher Scientific). Cells are seeded in a 384-well assay plate (4000 cells / well / 40 μL) and incubated overnight (37°C, 5% CO ２ After replacing the medium with wash buffer (1x HBSS, 20 mM HEPES) using a microplate washer, the fluorescent indicator dye was added to the loading buffer provided with the kit, and the plate was incubated for 1 hour (37°C, 5% CO) to allow the fluorescent indicator dye to be incorporated into the cells. ２ ) is placed on a cell-based kinetic assay system FLIPR (Molecular Devices), and a compound is added to the cells to the desired concentration and allowed to react for 10 minutes. When a mixture of potassium and thallium, which are stimulants, is added to the cells, the potassium channel opens, and the thallium that flows into the cells binds to the fluorescent indicator dye, increasing the intracellular fluorescent signal, and the potassium channel current is detected as a fluorescent signal. The inhibition rate at each concentration is calculated from the signal intensity at each concentration, with the signal intensity when E-4031 is added to the cells at a final concentration of 10.3 μmol / L defined as 100% inhibition, and the signal intensity when DMSO is added to the cells at a final concentration of 0.5% defined as 0% inhibition. The inhibition rate is calculated from the signal intensity at each concentration. The IC ５０ Compounds of the invention can be tested essentially as described above.

[0205] Test Example 4: BA Test - Examination of Oral Absorbability Experimental Materials and Methods (1) Animals: Mice or rats are used. (2) Breeding Conditions: Mice or rats are allowed free access to solid feed and tap water. (3) Dosage and Grouping: Oral and intravenous administration is performed at the specified dosage. Groups are set up as follows. The dosage is changed for each compound as needed. Oral Administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous Administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of Dosage Solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization. (5) Administration Method: Oral administration is administered by forced administration into the stomach using an oral probe. Intravenous administration is administered via the tail vein using a syringe with an injection needle attached. (6) Evaluation item: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention is calculated using moment analysis of the plasma concentration profile of the compound of the present invention. The bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups. The dilution concentration and dilution solvent are changed as necessary. The compound of the present invention can be tested essentially as described above.

[0206] Test Example 5: Clearance Evaluation Test Experimental Materials and Methods (1) Animals: SD rats were used. (2) Breeding Conditions: SD rats were allowed free access to solid feed and tap water. (3) Dose and Grouping: Intravenous administration was performed at a predetermined dose. Groups were set up as follows: Intravenous administration: 1 μmol / kg (n=2) (4) Preparation of Dosage Solution: Solubilized and administered using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent. (5) Administration Method: Administered via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical Analysis: The total body clearance (CLtot) was calculated using moment analysis of the plasma concentration of the compound of the present invention. The dilution concentration and dilution solvent were changed as necessary. The compound of the present invention can be tested essentially as described above.

[0207] Test Example 6: Metabolic Stability Test Commercially available pooled human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reacted and unreacted samples to evaluate the extent of hepatic metabolism of the compound of the present invention. Human liver microsomes were reacted in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidation reaction). After the reaction, 70 μL of the reaction mixture was added to 140 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifuged supernatant was quantified by LC / MS / MS, and the residual rate was expressed as the ratio of the amount of compound after the reaction to the amount of compound at 0 minutes, which is defined as 100%. The hydrolysis reaction is carried out in the absence of NADPH, and the glucuronidation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the subsequent procedures are the same. The dilution concentration and dilution solvent may be changed as necessary. The compounds of the present invention can be tested essentially as described above.

[0208] Test Example 7: P-gp Substrate Test A compound of the present invention was added to one side of a Transwell (registered trademark, CORNING) containing a monolayer culture of human MDR1-expressing cells or parental cells, and allowed to react for a certain period of time. The membrane permeability coefficients for the MDR1-expressing cells and parental cells in the apical-to-basolateral direction (A→B) and the basolateral-to-apical direction (B→A) were calculated, and the efflux ratio (ER; ratio of the membrane permeability coefficients B→A and A→B) values ​​for the MDR1-expressing cells and parental cells were calculated. The efflux ratios (ER values) for the MDR1-expressing cells and parental cells were compared to determine whether the compound of the present invention is a P-gp substrate. The compounds of the present invention can be tested essentially as described above.

[0209] Test Example 8: CYP3A4 (MDZ) MBI Test This test evaluates the mechanism-based inhibition (MBI) ability of the compound of the present invention in terms of metabolic potentiation of CYP3A4 inhibition. Using pooled human liver microsomes, CYP3A4 inhibition was evaluated using the 1-hydroxylation reaction of midazolam (MDZ) as an indicator. The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL pre-reaction, 0.05 mg / mL (10-fold dilution) pre-reaction; and compound of the present invention concentrations in the pre-reaction, 0.83, 5, 10, and 20 μmol / L (4 points). Pooled human liver microsomes and a solution of the compound of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) at the pre-reaction composition described above. A portion of this mixture was transferred to another 96-well plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the coenzyme NADPH was added to initiate the reaction used as an indicator (no pre-reaction). After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. NADPH was also added to the remaining pre-reaction solution to initiate the pre-reaction (pre-reaction). After the specified reaction time, a portion of this mixture was transferred to another plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the reaction used as an indicator was started. After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. Each plate in which the indicator reaction was performed was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the compound of the present invention was dissolved, to the reaction system. The residual activity (%) was calculated when each concentration of the compound of the present invention was added, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The Shifted IC value was calculated as the IC at 0 min preincubation / IC at 30 min preincubation, with a Shifted IC of 1.5 or greater being considered positive and a Shifted IC of 1.0 or less being considered negative. The compounds of the present invention can be tested essentially as described above.

[0210] Test Example 9: Solubility Test The solubility of the compounds of the present invention was determined under conditions containing 1% DMSO. A 10 mmol / L compound solution was prepared in DMSO, and 2 μL of the compound solution was added to 198 μL of the 18th Edition Japanese Pharmacopoeia Dissolution Test Fluid 1 (2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and water to make 1000 mL) or 198 μL of the 2nd Dissolution Test Fluid (1.7 g of potassium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL). After shaking for 3 hours at room temperature, the mixture was filtered under suction. The filtrate was diluted 100-fold with methanol / acetonitrile / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate was measured using LC / MS / MS with the absolute calibration curve method. The compounds of the present invention can be tested essentially as described above. Description from the 18th Edition of the Japanese Pharmacopoeia: Dissolution test 1st fluid: Dissolve 2.0 g of sodium chloride in 7.0 mL of 35% hydrochloric acid and water to make 1000 mL. This solution is colorless and clear, and its pH is approximately 1.2. Dissolution test 2nd fluid: Add 1 volume of water to 1 volume of pH 6.8 phosphate buffer. pH 6.8 phosphate buffer: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.

[0211] Test Example 9-2: Powder Solubility Test An appropriate amount of the compound of the present invention was placed in an appropriate container, and 200 μL of the following solution was added to each container: Dissolution Test Fluid 1 (2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and water to 1000 mL), Dissolution Test Fluid 2 (1.7 g of potassium dihydrogen phosphate, 1.775 g of anhydrous disodium hydrogen phosphate, and water to 1000 mL), and 20 mmol / L sodium taurocholate (TCA) / Dissolution Test Fluid 2 (1.08 g of TCA and Dissolution Test Fluid 2 to 100 mL). If the entire amount was dissolved after adding the test solution, additional compound of the present invention was added as appropriate. The container was sealed and shaken at 37°C for 1 hour, then filtered. Each filtrate was diluted with methanol. The dilution ratio was adjusted as necessary. After checking for the presence of bubbles and precipitates, the container was sealed and shaken. The compound of the present invention was quantified using HPLC using the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0212] Test Example 10: MK801-Induced Hyperlocomotion Inhibition Test 6-10 week-old Wistar male rats were used. 30 mmol / L HCl or 0.5% methylcellulose was used as the solvent to prepare the test compound administration solution, and physiological saline was used as the solvent to prepare the MK801 administration solution. The MK801-induced hyperlocomotion inhibition test was performed using SCANET (Melquest), the data acquisition program SCL-40, and transparent plastic cages as follows: In the breeding room, the compound administration solution (solvent or test compound solution) was administered subcutaneously or orally, and the animals were returned to their cages. Thirty minutes later, the animals were brought into the laboratory and allowed to acclimate to the laboratory. 15 minutes later, the rats were gently removed, and MK801 administration solution (solvent or MK801 solution) was administered intraperitoneally or subcutaneously, and the rats were returned to their cages. 15 minutes after MK801 administration, the rats were removed and gently placed in the SCANET, and locomotion measurement was initiated. The measurements are completed 30 minutes after the start of the measurements, and the amount of locomotion for each individual over the 30 minutes is totaled. The test results are analyzed as follows: A Student-T Test (significance level: two-sided 5%) is performed on the test compound administration group and the vehicle administration group. If the test compound administration group shows a significant suppression of locomotion compared to the vehicle administration group, it is determined to have antipsychotic effects. The compounds of the present invention can be tested essentially as described above.

[0213] Test Example 11: Fluctuation Ames Test The mutagenicity of the compound of the present invention was evaluated. 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking at 37°C for 9 hours. For the TA98 strain, 6.00 to 16.00 mL of the bacterial solution was centrifuged (1100 to 2000 × g, 10 minutes) to remove the culture medium. The same volume of Micro F buffer (K ２ HPO ４ :3.5g / L, KH ２ P.O. ４ : 1 g / L, (NH ４ ) ２ SO ４: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ４ ・7H ２ The bacteria are suspended in 0.0:0.1 g / L) and added to 120 mL of Exposure medium (MicroF buffer containing biotin: 8 μg / mL, L-histidine hydrochloride monohydrate: 0.2 μg / mL, glucose: 8 mg / mL). For the TA100 strain, 2.00 mL of the bacterial solution is added to 120 mL of Exposure medium to prepare a test bacterial solution. DMSO solution of the compound of the present invention (diluted in several steps at 2- to 3-fold common ratios from the maximum dose of 50 mg / mL), DMSO as a negative control, 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain as a positive control under non-metabolic activation conditions, 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain as a positive control, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain under metabolic activation conditions, 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain as a positive control, 12 μL each of which was mixed with 588 μL of test bacterial solution (a mixture of 498 μL of test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was mixed with 2300 μL of Indicator medium (MicroF buffer containing 8 μg / mL biotin, 0.2 μg / mL L-histidine hydrochloride monohydrate, 8 mg / mL glucose, and 37.5 μg / mL bromocresol purple), and 50 μL of the mixture was dispensed into 48 wells of a microplate per dose and incubated statically at 37°C for 3 days. Wells containing bacteria that have acquired the ability to grow due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to a pH change. The number of wells showing yellow bacterial growth per dose was counted and evaluated by comparing them with the negative control group. Negative mutagenicity was indicated by (-) and positive by (+). The dilution concentration and dilution solvent were adjusted as necessary. The compounds of the present invention can be tested essentially as described above.

[0214] Test Example 12: Ames Test Using Salmonella typhimurium TA98, TA100, TA1535, and TA1537 and Escherichia coli WP2uvrA as test strains, the Ames test was performed under metabolically non-activated and metabolically activated conditions by the pre-incubation method to examine the gene mutagenicity of the compound of the present invention. 0.1 mL of a DMSO solution of the compound of the present invention was mixed with 0.5 mL of S9mix under metabolically activated conditions, or 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under metabolically activated conditions, and the mixture was shaken and cultured at 37°C for 20 minutes. 2 mL of soft agar containing histidine and biotin or tryptophan was added and layered on a minimal glucose agar plate. At the same time, a negative control substance (DMSO) and a positive control substance (4-nitroquinoline 1-oxide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) are tested in the same manner. After 48 hours of incubation at 37°C, the number of revertant colonies that appear is counted and evaluated by comparison with the negative control group. A positive result is determined when the number of revertant colonies increases in a concentration-dependent manner and is at least twice the number of colonies in the negative control group. The compounds of the present invention can be tested essentially as described above.

[0215] Test Example 13: In vitro micronucleus test In this test, the micronucleus induction activity of the compounds of the present invention is evaluated using TK6 cells (derived from human lymphoblasts). ５To 2.5 mL of the culture medium (2.45 mL for the 3-hour treatment group under metabolically activated conditions and the 24-hour continuous treatment group), or 2.12 mL for the 3-hour treatment group under metabolically activated conditions, 0.05 mL of a DMSO solution of the compound of the present invention and 0.33 mL of S9mix for the 3-hour treatment group under metabolically activated conditions were added, and the mixture was incubated at 37°C. At the same time, the same procedure was performed for the negative control substance (DMSO) and the positive control substance (mitomycin C, cyclophosphamide, or colchicine). After the 3-hour treatment group, the cells were washed and replaced with 5 mL of fresh medium and incubated for an additional 21 hours. After incubation, the number of viable cells was counted to confirm cytotoxicity. If the compound of the present invention exhibits cytotoxicity at the end of treatment, the dose exhibiting a relative cell population doubling rate of approximately 50% was selected; if no cytotoxicity was observed, 500 μg / mL was selected; and if precipitation was observed, the lowest dose at which precipitation was observed during incubation was selected as the maximum dose for the test. At least three doses were selected. The selected cell suspension is treated with fixative and dropped onto a slide to prepare a specimen. The slide is stained with acridine orange and observed under a fluorescent microscope to count the number of mononuclear cells with micronuclei. A statistically significant increase in the number of micronucleated cells compared to the negative control group and a concentration-dependent increase are considered positive. The compounds of the present invention can be tested essentially as described above.

[0216] Test Example 14: Neutral Red Uptake Phototoxicity Test Using 3T3 Mouse Fibroblasts The phototoxicity of the compound of the present invention was examined using mammalian cultured cells (BALB / 3T3 cells). One 96-well plate was used for each of non-irradiated (-Irr) and irradiated (+Irr) conditions. The dose of the compound of the present invention was determined in accordance with the "Guidelines for Photosafety Evaluation of Pharmaceuticals," with a final concentration of 100 μg / mL as the maximum dose, and a total of eight doses set with a common ratio of 2. A vehicle (DMSO) treatment group for the compound of the present invention was used as a negative control. A chlorpromazine (CPZ) treatment group was used as a positive control, and an ethanol treatment group, the vehicle for the positive control, was used as a solvent control group. 1 x 10 ５ 100 μL (1 × 10 ４After culturing for about 24 hours, the culture medium is removed from each well, the cells are washed, and then a treatment solution prepared by diluting the compound of the present invention and each control substance with the culture medium to a predetermined concentration is added to each well. ２ After 1 hour of treatment in the incubator, the UV-A irradiation intensity of the light irradiation device was approximately 1.7 mW / cm ２ The irradiated plate is placed at the position and irradiated for 50 minutes. ２ Place in an incubator for 50 minutes. Remove the treatment solution from each well, wash the cells twice, add 150 μL of fresh culture medium, and culture for 20-22 hours. After incubation, remove the culture medium from each well, wash, and then add 100 μL of Neutral Red solution (50 μg / mL) dissolved in serum-free culture medium to each well and culture for 3 hours. After incubation, remove the Neutral Red solution from each well and wash the cells. Add 150 μL of Neutral Red extract to each well and shake for 10 minutes on a microplate mixer. Measure the absorbance of Neutral Red extracted from the cells at a wavelength of 540 nm using a Multiscan Ascent to calculate cell viability. According to OECD Software for Test Guideline 432, the IC is the concentration at which cell viability is reduced by 50%. ５０ is calculated for each of the non-irradiated and irradiated plates. When precipitation of the compound of the present invention is observed, the dose is determined to be IC ５０ The Photo Irritation Factor (PIF) and Mean Photo Effect (MPE) are also calculated in the same manner. The PIF is the ratio of the IC ５０ The IC is calculated from the ratio of either the non-irradiated or the irradiated plate. ５０ If the PIF is not calculated, the MPE is calculated by comparing the reactivity in the non-irradiated and irradiated plates. The results are judged by the IC ５０ When the calculated value is 0, the result is judged from the PIF. ５０If PIF is not calculated, the result is judged from MPE. Note that if PIF<5 or MPE<0.15, it is judged as non-phototoxic, and if 5≦PIF or 0.15≦MPE, it is judged as phototoxic. Compounds of the present invention can be tested essentially as described above.

[0217] Test Example 15: Cardiovascular system test in conscious dogs The compound of the present invention is administered to conscious dogs, and the effects on the cardiovascular system are evaluated using blood pressure (systolic blood pressure, diastolic blood pressure, and mean blood pressure (mmHg)), heart rate (beats / min), electrocardiogram parameters (PR interval, QRS interval, QT interval, and QTc (ms)) and toxicokinetic results. The compound of the present invention is added to 0.5% phosphate buffered saline (vehicle) to prepare a 2 mg / mL solution, and this is orally administered (5 mL / kg) to beagle dogs (male) by force according to the schedule in the following table. Blood pressure and electrocardiogram waveforms are recorded via a telemetry system into a data acquisition and analysis computer system (Ponemah Physiology Platform 5.3 or 5.4, Data Sciences International) from the day before administration until 24 hours and 5 minutes after administration. Evaluation time points are before administration and 1, 2, 4, 8, and 24 hours after administration. Ponemah Physiology Platform 5.4 (Data Sciences International) is used for analysis. The average value (integer) for each 5 minutes before and after each evaluation time point (10 minutes in total) is used. Heart rate is calculated from the blood pressure pulse wave. QTc is calculated using the individual correction formula (QTci = QT / (RR / 750) β) is calculated. The individual correction coefficient (β value) of this correction formula is calculated using the RR interval and QT interval during the 12-hour light phase of the previously measured data (during acclimation administration). The β value is determined by analyzing the relationship between the RR and QT intervals using linear regression [log(QT) = α + β log(RR)]. Furthermore, the electrocardiogram waveforms at each analysis time point are visually inspected for the presence or absence of arrhythmia-like waveforms. The percentage change in QTc from the pre-administration value is calculated (pre-administration value is considered 100%). At the same evaluation time point, the corresponding QTc value is compared with the vehicle value. For toxicokinetics, approximately 0.5 mL of blood is collected from the cephalic vein using a syringe containing heparin sodium and immediately cooled on ice. Plasma samples are obtained by centrifugation (4°C, 10,000 × g, 3 minutes). The plasma isolation procedure is carried out on ice or at 4° C., and the resulting plasma (TK sample) is stored in an ultra-low temperature cabinet (set temperature: −80° C.) Compounds of the invention can be tested essentially as described above.

[0218] Test Example 16: Cardiovascular System Test in Conscious Monkeys Three doses of the compound of the present invention are administered to conscious monkeys, and the effects on the cardiovascular system are evaluated using blood pressure (systolic blood pressure, diastolic blood pressure, and mean blood pressure (mmHg)), heart rate (beats / min), electrocardiogram parameters (PR interval, QRS interval, QT interval, and QTc (ms)) and toxicokinetic results. The compound of the present invention is added to 0.5% phosphate buffered saline (vehicle) to prepare a 2 mg / mL solution, which is then orally administered (5 mL / kg) to male cynomolgus monkeys according to the schedule in the table below. Blood pressure and electrocardiogram waveforms are recorded via a telemetry system into a data acquisition and analysis computer system (Ponemah Physiology Platform 5.5, Data Sciences International) from the day before administration until 24 hours and 5 minutes after administration. Evaluation time points are before administration and 1, 2, 4, 8, and 24 hours after administration. The average value (integer) for 5 minutes before and after each evaluation time point (10 minutes in total) is used. Heart rate is calculated from the blood pressure pulse wave. QTc is calculated using an individual correction formula (QTci = QT / (RR / 500) β) is calculated. The individual correction coefficient (β value) of this correction formula is calculated using the RR interval and QT interval during the 12-hour light phase of the previously measured data (during acclimation administration). The β value is determined by analyzing the relationship between the RR and QT intervals using linear regression [log(QT) = α + β log(RR)]. Furthermore, the electrocardiogram waveforms at each analysis time point are visually inspected for the presence or absence of arrhythmia-like waveforms. The percentage change in QTc from the pre-administration value is calculated (pre-administration value is considered 100%). At the same evaluation time point, the corresponding QTc value is compared with the vehicle value. For toxicokinetics, approximately 0.5 mL of blood is collected from the cephalic vein using a syringe containing heparin sodium and immediately cooled on ice. Plasma samples are obtained by centrifugation (4°C, 10,000 × g, 3 minutes). The plasma isolation procedure is carried out on ice or at 4° C., and the resulting plasma (TK sample) is stored in an ultra-low temperature cabinet (set temperature: −80° C.) Compounds of the invention can be tested essentially as described above.

[0219] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0220] The compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic activity, and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions involving the serotonin 5-HT2A receptor and / or the serotonin 5-HT2C receptor.

Claims

1. Formula (I): (In the formula, R １ is a substituted or unsubstituted 6-membered aromatic heterocyclic group, a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a substituted or unsubstituted 6-membered aromatic carbocyclic group; １ is CR ２ or N; ２ is CR ３ or N; ３ is CR ４ or N; R ２ , R ３ and R ４ are each independently a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; Ring B is a substituted or unsubstituted pyrazole or a substituted or unsubstituted pyrazolopyridine; R １５ and R １６ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R １７ and R １８ each independently represents a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof.

2. R １５ and R １６ is a hydrogen atom, and R １７ and R １８ The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein each of is independently a hydrogen atom, a halogen, or an unsubstituted alkyl.

3. R １５ , R １６ , R １７ and R １８ The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

4. R １ But the formula: (In the formula, R ６ and R ７ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a cyano (provided that R ６ When is a hydrogen atom, R ７ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or cyano; R ８ and R ９ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a cyano, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ The compound according to any one of claims 1 to 3, wherein R is a group represented by the formula: R is substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof.

5. R １ But the formula: (In the formula, R ６ , R ７ are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano; R ８ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３１ The compound according to any one of claims 1 to 4, wherein R is a group represented by the formula: R is substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof.

6. A １ But, CR ２ or N; R ２ is a hydrogen atom; ２ But, CR ３ or N; R ３ is defined as in claim 1; ３ But, CR ４ or N; R ４ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

7. A １ But, CR ２ or N; R ２ is defined as in claim 1; ２ But, CR ３ or N; R ３ is a hydrogen atom or a halogen; ３ But, CR ４ or N; R ４ The compound according to any one of claims 1 to 5, wherein: is defined as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

8. (i) A １ is CH, and A ２ is N and A ３ is CH; or (ii) A １ is CH, and A ２ is CR ３ and R ３ is a hydrogen atom or a halogen atom, and A ３ The compound according to any one of claims 1 to 7, wherein is N, or a pharma- ceutically acceptable salt thereof.

9. Ring B is of the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R １２ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R １３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １４ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R ２５ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; and n is an integer of 0 to 4), or a pharma- ceutically acceptable salt thereof.

10. R １２ , R １４ and R ２７ The compound according to claim 9 or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

11. Ring B is of the formula: (In the formula, R １０ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R １１ is a hydrogen atom or a halogen; R １２ is a hydrogen atom; R ２６ are each independently halogen or substituted or unsubstituted alkyl; R ２７ is a hydrogen atom; and n is an integer of 0 to 2), or a pharma- ceutically acceptable salt thereof.

12. Ring B is of the formula: (In the formula, R １０ , R １１ and R １２ The compound according to claim 11, or a pharma- ceutically acceptable salt thereof, wherein R is a ring represented by the formula:

13. R １０ The compound according to any one of claims 1 to 12, wherein is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof.

14. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of compounds I-027, I-028, I-071, I-114, I-144, I-145, I-155, I-158, I-166, I-257, I-262, I-266 and I-267.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 15, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist.

17. The pharmaceutical composition according to claim 15, which is an antagonist and / or inverse agonist of the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor.

18. A method for treating and / or preventing a disease associated with the serotonin 5-HT2A receptor, comprising administering a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof.

19. A method for treating and / or preventing a disease associated with serotonin 5-HT2A receptors and serotonin 5-HT2C receptors, comprising administering a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof.

20. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A receptor.

21. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving serotonin 5-HT2A receptors and serotonin 5-HT2C receptors.

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