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WO2025121409A1 - Dérivé carbocyclique aromatique et hétérocyclique aromatique contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine - Google Patents

Dérivé carbocyclique aromatique et hétérocyclique aromatique contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine Download PDF

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Publication number
WO2025121409A1
WO2025121409A1 PCT/JP2024/043197 JP2024043197W WO2025121409A1 WO 2025121409 A1 WO2025121409 A1 WO 2025121409A1 JP 2024043197 W JP2024043197 W JP 2024043197W WO 2025121409 A1 WO2025121409 A1 WO 2025121409A1
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substituted
unsubstituted
compound
group
halogen
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Japanese (ja)
Inventor
卓也 小熊
秀爾 米澤
龍治 岡本
佳世子 畑
佑斗 宇納
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Shionogi Apnimed Sleep Science LLC
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Shionogi Apnimed Sleep Science LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having serotonin 5-HT2A receptor antagonistic and/or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic activity, or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition containing the same.
  • the present invention further relates to a compound or a pharma- ceutically acceptable salt thereof useful in the treatment and/or prevention of a disease caused by the serotonin 5-HT2A receptor and/or the serotonin 5-HT2C receptor, and a pharmaceutical composition containing the compound or the salt.
  • Neurodegenerative disorders are a group of related human diseases that share a common pathophysiological feature: 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 its own 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 a genetic mechanism that is unique to each disorder (Non-Patent Document 1).
  • Non-Patent Documents 4, 5 Although most existing treatments, including antipsychotics and antidepressants, are often effective in these patients, they are very poorly tolerated (Non-Patent Document 6).
  • available Parkinson's disease treatments, including L-dopa and dopamine agonists are generally effective, but cause the appearance of severe treatment-limiting side effects that cannot be addressed by pharmacological therapy at present.
  • Non-Patent Document 7 the 5-HT2A receptor inverse agonist pimavanserin was approved in the United States for the first time for the indication of hallucinations and delusions associated with Parkinson's disease.
  • this drug has not been reported to have side effects such as worsening of motor symptoms or decreased cognitive function.
  • the main pharmacological action of pimavanserin is serotonin 5-HT2A receptor inverse agonism/antagonism, but it also has serotonin 5-HT2C receptor inverse agonism/antagonism (Non-Patent Document 8).
  • Patent Documents 1 to 16 and 21 and Non-Patent Documents 10 to 14 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 describes or suggests any compound related to the present invention.
  • Patent Document 17 a benzamide derivative having interleukin-6 inhibitory activity is disclosed in Patent Document 17, there is no description of serotonin 5-HT2A receptor antagonistic and/or inverse agonistic activity and therapeutic effect against hallucinations and delusions, and no description or suggestion of compounds related to the present invention.
  • the object of the present invention is to provide a novel compound having serotonin 5-HT2A receptor antagonistic and/or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic activity. More preferably, the present invention provides a novel compound or a pharma- ceutical acceptable salt thereof, which has serotonin 5-HT2A receptor antagonistic and/or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic activity and is therefore effective against diseases involving serotonin, including hallucinations and delusions associated with Parkinson's disease and/or dementia, as well as medicines containing the same.
  • R 1 is a group represented by 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 when R 6 is a hydrogen atom, R 7 is 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); R 8 and R 9 are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alky
  • R 1 is a group represented by the formula: (In the formula, R 6 and 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 is a substituted or unsubstituted alkyl), or a pharma- ceutically acceptable salt thereof.
  • R 1 is a group represented by the formula: (wherein each symbol has the same meaning as in (5) above) or a pharma- ceutically acceptable salt thereof.
  • a 1 is CR 2 or N; R2 is a hydrogen atom; A2 is CR3 or N; R3 has the same meaning as defined above in (1); A3 is CR4 or N; The compound or a pharma- ceutically acceptable salt thereof according to any one of the above (1) to (5) and (5'), wherein R4 is a hydrogen atom.
  • a 1 is CR 2 or N; R2 has the same meaning as defined above in (1); A2 is CR3 or N; R 3 is a hydrogen atom or a halogen; A3 is CR4 or N; The compound according to any one of the above (1) to (5) and (5'), wherein R 4 has the same meaning as in the above (1), or a pharma- ceutically acceptable salt thereof.
  • (i) A 1 is CH, A 2 is N, and A 3 is CH; or (ii) A 1 is CH, A 2 is CR 3 , R 3 is a hydrogen atom or a halogen, and A 3 is N; The compound according to any one of the above (1) to (7) and (5') or a pharma- ceutically acceptable salt thereof.
  • 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 unsubstit
  • 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 26 is halogen or substituted or unsubstituted alkyl; R 27 is a hydrogen atom; n is an integer from 0 to 2.
  • Ring B is a group represented by the formula: (12) wherein R 10 , R 11 and R 12 are as defined above in (11), or a pharma- ceutically acceptable salt thereof.
  • (14') The following compound: The compound according to the above (1) or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (15) A pharmaceutical composition comprising the compound according to any one of (1) to (14), (5') and (14') above or a pharma- ceutically acceptable salt thereof. (16) The pharmaceutical composition according to (15) above, which is a serotonin 5-HT2A receptor antagonist and/or inverse agonist. (17) The pharmaceutical composition according to (15) above, which is an antagonist and/or inverse agonist of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.
  • a method for treating and/or preventing a disease involving the serotonin 5-HT2A receptor comprising administering a compound according to any one of (1) to (14), (5') and (14') above, or a pharma- ceutically acceptable salt thereof.
  • a method for treating and/or preventing a disease involving serotonin 5-HT2A receptor and serotonin 5-HT2C receptor comprising administering a compound according to any one of (1) to (14), (5') and (14') above, or a pharma- ceutical acceptable salt thereof.
  • the compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and/or inverse agonistic effects and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic effects, and are useful as therapeutic and/or preventive agents for hallucinations and delusions associated with Parkinson's disease and/or dementia.
  • halogen includes fluorine, chlorine, bromine and iodine atoms. In particular, fluorine and chlorine atoms are preferred. As the "halogen" in R7 , a chlorine atom and a bromine atom are preferable.
  • alkyl includes 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.
  • alkyl examples 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.
  • C1-C3 alkyl includes methyl, ethyl, n-propyl, and isopropyl.
  • 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.
  • 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.
  • Alkyloxy refers to a group in which the above “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, and the like.
  • 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.
  • Haloalkyloxy refers to a group in which the above “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, 2,2,3,3,4,4,4-heptafluorobutyloxy, and the like.
  • 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.
  • alkenyl includes straight-chain or branched hydrocarbon groups having one or more double bonds at any position and 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.
  • Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like.
  • Preferred embodiments of "alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.
  • alkynyl includes linear or branched hydrocarbon groups 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, which have 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, and decynyl.
  • alkynyl examples include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.
  • aromatic carbocyclic group refers to a monocyclic or bicyclic or more aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, and phenanthryl.
  • aromatic carbocyclic group is phenyl.
  • aromatic carbocyclic ring refers to a ring derived from the above-mentioned "aromatic carbocyclic group”.
  • aromatic carbocyclic group includes phenyl.
  • non-aromatic carbocyclic group refers to a monocyclic or bicyclic or more ring cyclic saturated or unsaturated non-aromatic hydrocarbon group.
  • non-aromatic carbocyclic group having two or more rings also includes a monocyclic or bicyclic or more ring non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group” is condensed.
  • non-aromatic carbocyclic group also includes groups that form bridged or spiro rings, such as those described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and further preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • the non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms, and examples thereof include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
  • Non-aromatic carbocyclic ring means a ring derived from the above “non-aromatic carbocyclic group.”
  • aromatic heterocyclic group means a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring.
  • the aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more ring aromatic heterocyclic group condensed with a ring in the above-mentioned "aromatic carbocyclic group", and the bond may be on any of the rings.
  • the monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered.
  • Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc.
  • Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • the bicyclic aromatic heterocyclic group is preferably an 8- to 10-membered ring, more preferably an 9- or 10-membered ring, and 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
  • 9-membered aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, oxazolopyridyl, thiazolopyridyl, and the like.
  • Examples of the 10-membered aromatic heterocyclic group include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, and the like.
  • the aromatic heterocyclic group having three or more rings is preferably a group having 13 to 15 members, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
  • Aromatic heterocycle means a ring derived from the above-mentioned “aromatic heterocyclic group.”
  • non-aromatic heterocyclic group refers to a monocyclic or bicyclic or more non-aromatic cyclic group having in the ring one or more identical or different heteroatoms selected from O, S, and N.
  • a bicyclic or more non-aromatic heterocyclic group includes a monocyclic or bicyclic or more non-aromatic heterocyclic group fused with each of the rings in the above-mentioned "aromatic carbocyclic group", “non-aromatic carbocyclic group”, and/or "aromatic heterocyclic group”, and further includes a monocyclic or bicyclic or more non-aromatic carbocyclic group fused with a ring in the above-mentioned "aromatic heterocyclic group", and the bond may be on any of the rings.
  • non-aromatic heterocyclic group also includes groups that form bridged or spiro rings, such as:
  • the monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered group, more preferably a 5- or 6-membered group.
  • Examples of the 3-membered non-aromatic heterocyclic group include thiiranyl, oxiranyl, and aziridinyl.
  • Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl.
  • Examples of the 5-membered non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl.
  • 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl, etc.
  • Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl, etc.
  • Examples of 8-membered non-aromatic heterocyclic groups include azocane, thiocane, oxocane, etc.
  • the non-aromatic heterocyclic group having two or more rings is preferably 8 to 20-membered, more preferably 8 to 10-membered, and examples thereof include indolinyl, isoindolinyl, chromanyl, isochromanyl, and the like.
  • Non-aromatic heterocycle means a ring derived from the above “non-aromatic heterocyclic group”.
  • Trialkylsilyl refers to a group in which three of the above “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.
  • Carbon atoms 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 which may be substituted with substituent group ⁇ , alkenyloxy which may be substituted with substituent group ⁇ , alkynyloxy which may be substituted with substituent group ⁇ , alkylcarbonyloxy which may be substituted with substituent group ⁇ , alkenylcarbonyloxy which may be substituted with substituent group ⁇ , alkynylcarbon
  • Substituent group ⁇ 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.
  • Substituent group ⁇ halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alkylsulfinyl optional
  • Substituent group ⁇ Substituent group ⁇ , alkyl, alkyl substituted with alkyloxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.
  • Substituent group ⁇ ' Substituent group ⁇ and oxo.
  • 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 ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , alkyloxy optionally substituted with substituent group ⁇ , alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ ,
  • substituent group C can be mentioned as the substituent on the ring.
  • 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.
  • nonaromatic carbocycle and “nonaromatic heterocycle” are substituted with “oxo”, it means a ring in which 2 hydrogen atoms on a carbon atom are replaced as follows:
  • substituents of "substituted amino”, “substituted imino”, “substituted carbamoyl” and “substituted sulfamoyl” include the following Substituent Group D.
  • Each of the "substituted amino”, “substituted imino”, “substituted carbamoyl” and “substituted sulfamoyl” 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 ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally
  • 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 R 1 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 substituted non
  • substituents of the "substituted alkyl", “substituted alkyloxy”, “substituted alkenyl” and “substituted alkynyl” in R6 and R7 include, for example, halogen.
  • Substituents of "substituted alkyl” and “substituted alkyloxy” in R8 and R9 include, for example, 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.
  • 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” in R8 and R9 include halogen.
  • substituents of the "substituted alkyl" and “substituted alkyloxy" in R2 , R3 and R4 include, for example, halogen.
  • Substituents on the ring of the "substituted pyrazole” and “substituted pyrazolopyridine” in ring B include, for example, 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, alkenyl substituted with an aromatic carbocyclic group substituted with a halogen, unsubstituted alkyloxy, haloalkyloxy, unsubsti
  • Substituents of the "substituted alkyl" in R 10 and R 13 include, for example, halogen, haloalkyloxy, an aromatic carbocyclic group substituted with a halogen, an aromatic carbocyclic group substituted with a haloalkyl, a non-aromatic carbocyclic group substituted with a halogen, an unsubstituted non-aromatic carbocyclic group, and a non-aromatic carbocyclic group substituted with a halogen.
  • Carbon atoms at any position may be substituted with one or more groups selected from these.
  • Substituents of the "substituted aromatic carbocyclic group", “substituted phenyl” and “substituted aromatic heterocyclic group” in R 10 and R 13 include, for example, 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.
  • substituents of the "substituted non-aromatic carbocyclic group" for R 10 and R 13 include, for example, halogen.
  • the substituent of the "substituted alkyl" for R 11 includes, for example, halogen.
  • Substituents of the "substituted aromatic carbocyclic group" and “substituted aromatic heterocyclic group” in R 11 include, for example, alkyl, halogen, alkyloxy, haloalkyl, and haloalkyloxy. Carbon atoms at any position may be substituted with one or more groups selected from these.
  • the substituent of the "substituted non-aromatic carbocyclic group" for R 11 includes, for example, halogen.
  • the substituents of the "substituted alkyl" for R 12 , R 14 and R 27 include, for example, halogen.
  • the substituent of the "substituted alkyl" for R25 includes, for example, halogen.
  • the substituent of the "substituted alkyl" in R26 includes, for example, halogen.
  • the substituent of the "substituted alkyl" in R27 includes, for example, halogen.
  • the substituents of the "substituted alkyl" in R 15 and R 16 include, for example, halogen.
  • the substituents of the "substituted alkyl" in R 17 and R 18 include, for example, halogen.
  • R 1 , R 6 , R 7 , R 8 , R 9 , R 31 , A 1 , A 2 , 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 are shown below.
  • 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 are shown below.
  • embodiments of all combinations of the specific examples shown below are exemplified.
  • R 1 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).
  • R1 is a group represented by the formula: (wherein each symbol has the same meaning as in (4) above) (hereinafter referred to as A-2).
  • A-3 wherein each symbol has the same meaning as in (5) above
  • R1 is a group represented by the formula: (wherein each symbol has the same meaning as in (5') above) (hereinafter referred to as A-4).
  • R1 is a group represented by the formula: (wherein each symbol has the same meaning as in (5') above) (hereinafter referred to as A-5). R1 is a group represented by the formula: (wherein each symbol is as defined in the above (5)) (hereinafter referred to as A-6).
  • R1 is a group represented by the formula: (wherein R 7 is halogen or unsubstituted alkyl, R 31 is unsubstituted alkyl, R 6 is unsubstituted alkyl, and R 8 is unsubstituted alkyl, alkyl substituted with unsubstituted alkyloxy, or alkyl substituted with unsubstituted non-aromatic heterocyclic oxy) (hereinafter referred to as A-6').
  • R1 is a group represented by the formula: (wherein each symbol is as defined in (5) above) (hereinafter referred to as A-7).
  • R1 is a group represented by the formula: (wherein R 7 is halogen, unsubstituted alkyl or cyano, and R 31 is unsubstituted alkyl) (hereinafter, referred to as A-8).
  • R1 is a group represented by the formula: (wherein each symbol is as defined in the above (5)) (hereinafter, referred to as A-9).
  • R1 is a group represented by the formula: (wherein R 6 is an unsubstituted alkyl, R 7 is an 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).
  • R 6 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).
  • R 6 is, for example, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano (hereinafter referred to as B-2).
  • R 6 is substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (hereinafter referred to as B-3).
  • R 6 can be an unsubstituted alkyl or an unsubstituted alkyloxy (hereinafter referred to as B-4).
  • R 6 is methyl or methyloxy (hereinafter, referred to as B-5).
  • R6 includes methyl (hereinafter, referred to as B-6).
  • R 7 is a hydrogen atom, a halogen, 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 when R 6 is a hydrogen atom, R 7 is a halogen, 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 C-1).
  • R 7 is, for example, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or cyano (hereinafter referred to as C-2).
  • R 7 can be halogen, substituted or unsubstituted alkyl, or cyano (hereinafter referred to as C-3).
  • R 7 can be halogen, unsubstituted alkyl, haloalkyl or cyano (hereinafter referred to as C-4).
  • R 7 can be halogen, unsubstituted alkyl or cyano (hereinafter referred to as C-5).
  • R 7 is halogen, methyl, ethyl, isopropyl or cyano (hereinafter referred to as C-6).
  • R 7 includes halogen, methyl and cyano (hereinafter referred to as C-7).
  • R 7 can be halogen or unsubstituted alkyl (hereinafter referred to as C-8).
  • R 7 is, for example, halogen or methyl (hereinafter, referred to as C-9).
  • R 7 can be an unsubstituted alkyl (hereinafter, referred to as C-10).
  • R7 is methyl (hereinafter, referred to as C-11).
  • R 7 may be a halogen (hereinafter, referred to as C-12).
  • R8 may be 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).
  • R8 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).
  • R 8 is a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as D-3).
  • R 8 may be substituted or unsubstituted alkyl (hereinafter referred to as D-4).
  • D-4 is, for example, 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).
  • D-5 is methyl, methyl substituted with unsubstituted alkyloxy, or methyl substituted with unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as D-6).
  • R 8 is methyl substituted with methyloxy, methyl substituted with oxetanyloxy, or methyl (hereinafter referred to as D-7). R 8 is methyl substituted with methyloxy or methyl (hereinafter referred to as D-8).
  • R 9 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).
  • R 9 is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as E-2).
  • R 9 is a hydrogen atom, a halogen atom or an unsubstituted alkyl (hereinafter referred to as E-3).
  • R 9 is, for example, a hydrogen atom or a halogen (hereinafter, referred to as E-4).
  • R 31 may be a substituted or unsubstituted alkyl (hereinafter referred to as E′-1).
  • R 31 can be an unsubstituted alkyl (hereinafter referred to as E′-2).
  • R 31 includes methyl, ethyl, propyl, and isopropyl (hereinafter, referred to as E'-3).
  • R 31 is methyl (hereinafter, referred to as E'-4).
  • a 1 includes CR 2 or N (hereinafter referred to as F-1).
  • A1 includes CR2 (hereinafter, referred to as F-2).
  • A1 may be N (hereinafter referred to as F-3).
  • R 2 is, for example, a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter, referred to as G-1).
  • R 2 is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as G-2).
  • R 2 is a hydrogen atom, a halogen atom or an unsubstituted alkyl (hereinafter, referred to as G-3).
  • R2 is, for example, a hydrogen atom or a halogen (hereinafter, referred to as G-4).
  • R2 may be a hydrogen atom (hereinafter, referred to as G-5).
  • A2 includes CR3 or N (hereinafter referred to as H-1).
  • A2 includes CR3 (hereinafter referred to as H-2).
  • A2 may be N (hereinafter referred to as H-3).
  • R3 is, for example, a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter, referred to as J-1).
  • R3 is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as J-2).
  • R3 is, for example, halogen or substituted or unsubstituted alkyl (hereinafter, referred to as J-3).
  • R3 can be halogen or unsubstituted alkyl (hereinafter, referred to as J-4).
  • R3 may be a hydrogen atom or a halogen (hereinafter, referred to as J-5).
  • R3 can be a hydrogen atom (hereinafter, referred to as J-6).
  • R3 may be halogen (hereinafter, referred to as J-7).
  • A3 includes CR4 or N (hereinafter referred to as K-1).
  • A3 includes CR4 (hereinafter referred to as K-2).
  • A3 may be N (hereinafter referred to as K-3).
  • R 4 is, for example, a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as L-1).
  • R 4 is, for example, a hydrogen atom, a halogen atom, a cyano, an unsubstituted alkyl, or an unsubstituted alkyloxy (hereinafter, referred to as L-2).
  • R 4 is, for example, a hydrogen atom or a halogen (hereinafter, referred to as L-3).
  • R4 may be a hydrogen atom (hereinafter referred to as L-4).
  • Ring B may be a substituted or unsubstituted pyrazole or a substituted or unsubstituted pyrazolopyridine (hereinafter referred to as M-1). Ring B is of the formula: (wherein each symbol has the same meaning as in (9) above) (hereinafter referred to as M-2). Ring B is of the formula: (wherein each symbol has the same meaning as in (11) above) (hereinafter referred to as M-3).
  • Ring B is of the formula: (In the formula, R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ', or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ' (substituent group ⁇ ': 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 may be a substituted or unsubstituted pyrazole (hereinafter referred to as M-5). Ring B is of the formula: (wherein each symbol has the same meaning as in (9) above) (hereinafter referred to as M-6). Ring B is of the formula: (wherein each symbol is as defined above in (11)) (hereinafter referred to as M-7).
  • Ring B is of the formula: (In the formula, R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ', or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ' (substituent group ⁇ ': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R 11 is a hydrogen atom or a halogen; and R 12 is a hydrogen atom) (hereinafter, referred to as M-8).
  • Ring B is of the formula: (In the formula, R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ', or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ' (substituent group ⁇ ': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group); R 11 is a hydrogen atom; and R 12 is a hydrogen atom) (hereinafter, referred to as M-9).
  • Ring B is of the formula: (In the formula, R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ′′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′′: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy); R 11 is a hydrogen atom or a halogen; and R 12 is a hydrogen atom) (hereinafter, referred to as M-9').
  • Ring B is of the formula: (In the formula, R 10 is phenyl substituted with one or more groups selected from the substituent group ⁇ ′′ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′′: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy); R 11 is a hydrogen atom; and R 12 is a hydrogen atom) (hereinafter, referred to as M-10).
  • R 10 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 N-1).
  • R 10 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 N-2).
  • R 10 may be 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).
  • R 10 includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ , unsubstituted phenyl, a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ , or an unsubstituted 6-membered aromatic heterocyclic group (substituent group ⁇ : halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-4).
  • R 10 includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ , and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ (substituent group ⁇ : halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-5).
  • R 10 includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ ', and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ' (substituent group ⁇ ': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-6).
  • R 10 may be a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ′′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as N-6′).
  • R 10 can be phenyl substituted with one or more groups selected from the substituent group ⁇ ′′ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′′: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy) (hereinafter, referred to as N-7).
  • R 13 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).
  • R 13 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).
  • R 13 may be 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).
  • R 13 includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ , unsubstituted phenyl, a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ , or an unsubstituted 6-membered aromatic heterocyclic group (substituent group ⁇ : halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter, referred to as O-4).
  • R 13 includes haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ , and a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ (substituent group ⁇ : halogen, cyano, unsubstituted alkyloxy, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter, referred to as O-5).
  • R 13 can be a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ', or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ' (substituent group ⁇ ': halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, haloalkyloxy, and unsubstituted non-aromatic carbocyclic group) (hereinafter, referred to as O-6).
  • R 13 can be a phenyl substituted with one or more groups selected from the substituent group ⁇ ′′ or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′′: halogen, unsubstituted alkyl, unsubstituted alkyloxy, haloalkyl, and haloalkyloxy) (hereinafter, referred to as O-7).
  • R 11 may be 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).
  • R 11 may be a hydrogen atom or a halogen (hereinafter referred to as P-2).
  • R 11 can be a hydrogen atom (hereinafter, referred to as P-3).
  • R 11 may be a halogen (hereinafter, referred to as P-4).
  • R 12 is, for example, a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as Q-1).
  • R 12 may be a hydrogen atom or a halogen (hereinafter, referred to as Q-2).
  • R 12 can be a hydrogen atom (hereinafter, referred to as Q-3).
  • R 12 may be a halogen (hereinafter, referred to as Q-4).
  • R 14 may be a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as R-1).
  • R 14 may be a hydrogen atom or a halogen (hereinafter referred to as R-2).
  • R 14 may be a hydrogen atom (hereinafter referred to as R-3).
  • R 14 may be a halogen (hereinafter referred to as R-4).
  • R 27 is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as S-1).
  • R 27 is, for example, a hydrogen atom or a halogen (hereinafter, referred to as S-2).
  • R 27 can be a hydrogen atom (hereinafter, referred to as S-3).
  • R 27 may be a halogen (hereinafter, referred to as S-4). (if applicable).
  • R 25 is, for example, a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as T-1).
  • R 25 is, for example, a hydrogen atom, a halogen atom or an alkyl group (hereinafter, referred to as T-2).
  • R 25 is, for example, a hydrogen atom, a halogen atom or a C1-C3 alkyl group (hereinafter, referred to as T-3).
  • R 25 is, for example, a hydrogen atom or a halogen (hereinafter, referred to as T-4).
  • R 25 can be a hydrogen atom (hereinafter, referred to as T-5).
  • R 25 may be a halogen (hereinafter, referred to as T-6). (if applicable).
  • Each R 26 independently represents a halogen or a substituted or unsubstituted alkyl (hereinafter referred to as U-1). Each R 26 independently represents halogen, unsubstituted alkyl, or haloalkyl (hereinafter referred to as U-2). Each R 26 independently represents halogen or haloalkyl (hereinafter referred to as U-3). R 26 can be a halogen (hereinafter, referred to as U-4). R 26 may be haloalkyl (hereinafter, referred to as U-5).
  • n is an integer of 0 to 4 (hereinafter referred to as V-1). n is an integer of 0 to 2 (hereinafter, referred to as V-2). n is 1 or 2 (hereinafter, referred to as V-3). n is 1 (hereinafter, referred to as V-4). n is 0 or 1 (hereinafter referred to as V-5).
  • R 15 is, for example, a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter, referred to as W-1).
  • R 15 is, for example, a hydrogen atom or an unsubstituted alkyl (hereinafter, referred to as W-2).
  • R 15 can be a hydrogen atom (hereinafter, referred to as W-3).
  • R 16 is, for example, a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter, referred to as X-1).
  • R 16 can be a hydrogen atom or an unsubstituted alkyl (hereinafter, referred to as X-2).
  • R 16 can be a hydrogen atom (hereinafter, referred to as X-3).
  • R 17 is, for example, a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as Y-1).
  • R 17 is, for example, a hydrogen atom, a halogen atom or an unsubstituted alkyl (hereinafter, referred to as Y-2).
  • R 17 can be a hydrogen atom (hereinafter, referred to as Y-3).
  • R 18 is, for example, a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter, referred to as Z-1).
  • R 18 is, for example, a hydrogen atom, a halogen atom or an unsubstituted alkyl (hereinafter, referred to as Z-2).
  • R 18 can be a hydrogen atom (hereinafter, referred to as Z-3).
  • R1 is a group represented by the formula:
  • R 6 and 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
  • R1 is a group represented by the formula:
  • R 6 and 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 is a substituted or unsubstituted alkyl group;
  • R1 is a group represented by the formula:
  • R 6 and 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 group;
  • the combination of (A 1 , A 2 , A 3 ) is (CH, N, CH) or (CH, CR 3 , N);
  • R3 is a hydrogen atom or a halogen;
  • Ring B is of 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
  • R1 is a group represented by the formula:
  • R6 is unsubstituted alkyl or unsubstituted alkyloxy
  • R7 is halogen, unsubstituted alkyl, or unsubstituted alkyloxy
  • R 8 is unsubstituted alkyl, alkyl substituted with unsubstituted alkyloxy, or alkyl substituted with unsubstituted non-aromatic heterocycleoxy
  • R 31 is an unsubstituted alkyl group
  • the combination of (A 1 , A 2 , A 3 ) is (CH, N, CH) or (CH, CR 3 , N);
  • R3 is a hydrogen atom or a halogen
  • Ring B is of the formula:
  • R 10 is haloalkyl, phenyl substituted with one or more groups selected from the substituent group ⁇ , or a 6-membered aromatic heterocyclic group substitute
  • R1 is a group represented by the formula:
  • R6 is unsubstituted alkyl or unsubstituted alkyloxy;
  • R7 is halogen, unsubstituted alkyl, or unsubstituted alkyloxy;
  • R 8 is unsubstituted alkyl, alkyl substituted with unsubstituted alkyloxy, or alkyl substituted with unsubstituted non-aromatic heterocycleoxy;
  • R 31 is an unsubstituted alkyl group;
  • the combination of (A 1 , A 2 , A 3 ) is (CH, N, CH) or (CH, CR 3 , N);
  • R3 is a hydrogen atom or a halogen;
  • Ring B is of the formula:
  • R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ', or a 6-membered aromatic hetero
  • R1 is a group represented by the formula:
  • R6 is unsubstituted alkyl
  • R7 is halogen or unsubstituted alkyl
  • R 8 is unsubstituted alkyl, alkyl substituted with unsubstituted alkyloxy, or alkyl substituted with unsubstituted non-aromatic heterocycleoxy
  • R 31 is an unsubstituted alkyl group
  • the combination of (A 1 , A 2 , A 3 ) is (CH, CR 3 , N); R3 is halogen;
  • Ring B is of the formula:
  • R 10 is a haloalkyl, a phenyl substituted with one or more groups selected from the substituent group ⁇ ′′, or a 6-membered aromatic heterocyclic group substituted with one or more groups selected from the substituent group ⁇ ′′ (substituent group ⁇ ′′: halogen, unsubstitute
  • the compounds represented by formula (I) are not limited to any particular isomer, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.
  • One or more hydrogen, carbon and/or other atoms of the compound represented by formula (I) may be replaced with isotopes of hydrogen, carbon and/or other atoms.
  • isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H , 3H , 11C , 13C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F , 123I and 36Cl .
  • the compound represented by formula (I) also includes compounds replaced with such isotopes. The compounds replaced with said isotopes are also useful as pharmaceuticals.
  • the compound represented by formula (I) includes all radioactively labeled compounds of the compound represented by formula (I) replaced with radioactive isotopes contained in said isotopes. Also encompassed by the present invention is a "radiolabeling method" for producing said "radiolabeled substance,” which is useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies, binding assays.
  • Radiolabeled compounds of formula (I) can be prepared by methods well known in the art.
  • tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a particular compound of formula (I) by catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of the compound 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.
  • a suitable catalyst such as Pd/C
  • 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 can be prepared by using a raw material having 14 C carbon.
  • 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,
  • suitable salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and amino acids, and salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid
  • the present invention includes the following aspects.
  • the compound of the present invention represented by formula (I) may form a salt or a cocrystal.
  • the compound of the present invention represented by formula (I) also includes solvates (eg, hydrates, etc.) and/or crystal polymorphs.
  • the pharma- ceutically acceptable salts of the compounds of the present invention represented by formula (I) also include solvates (eg, hydrates, etc.) and/or crystal polymorphs.
  • the co-crystal of the compound represented by formula (I) of the present invention also includes solvates (eg, hydrates, etc.) and/or crystal polymorphs.
  • a "solvate” may be coordinated with a compound of formula (I) with any number of solvent molecules (eg, water molecules, etc.).
  • solvent molecules eg, water molecules, etc.
  • a pharma- ceutically acceptable salt of the compound represented by formula (I) of the present invention, or a co-crystal of the compound represented by formula (I) of the present invention is left in the air, it may absorb moisture, and adsorbed water may adhere to the compound or a hydrate may be formed.
  • the cocrystal of the compound represented by formula (I) of the present invention means that the compound represented by formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
  • Co-crystals are distinguished from salts in that the compound of formula (I) remains essentially uncharged or neutral.
  • Cocrystals are distinguished from solvates (eg, hydrates, etc.) in that the counter molecule is not water or a solvent. In general, salts are considered to be a state in which proton transfer occurs between a compound and a counter molecule, but it is also known that in some cases, proton transfer may not be complete.
  • a pharma- ceutically acceptable salt of a compound of formula (I) includes co-crystals and refers to a pharma- ceutically acceptable salt or co-crystal of a compound of formula (I).
  • a pharma- ceutically acceptable salt of a compound of formula (I) includes co-crystals and refers to a pharma- ceutically acceptable salt or co-crystal of a compound of formula (I).
  • the compound of the present invention represented by formula (I) may be amorphous.
  • the pharma- ceutically acceptable salt of the compound represented by formula (I) of the present invention may be amorphous.
  • the compound of the present invention represented by formula (I) or a pharma- ceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs.
  • a prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes a pharma- ceutically active compound of the present invention in vivo by solvolysis or under physiological conditions.
  • Prodrugs include compounds that are converted to a compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the living body, and compounds that are converted to a compound of formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
  • examples of the prodrug include an acyloxy derivative or a sulfonyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride or a mixed anhydride, or by reacting the compound using a condensing agent.
  • the compound according to the present invention has serotonin 5-HT2A receptor antagonistic and/or inverse agonistic effects and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic effects, and is therefore useful as a therapeutic and/or preventive agent for diseases involving serotonin 5-HT2A receptors and/or serotonin 5-HT2C receptors.
  • Serotonin 5-HT2A receptors and/or serotonin 5-HT2C receptors 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 disorder, obstructive sleep apnea syndrome, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, and sexual dysfunction.
  • 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 disorder
  • 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.
  • the compound of the present invention represented by formula (I) can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by the treatments carried out in ordinary organic chemistry experiments.
  • the compounds of the present invention can be synthesized with reference to techniques known in the art.
  • Process 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 from 0°C to the reflux temperature, preferably from 60°C to 80°C.
  • the reaction time is from 0.5 to 12 hours, preferably from 1 to 6 hours.
  • Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, 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.
  • Process 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.
  • metal catalyst examples 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, XPhos Pd G3, and the like. These 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 hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and the like, and the base can be used in an amount of 1 to 5 molar equivalents relative to compound (a-2).
  • the compound (a-7) can be used in an amount of 1 to 5 molar equivalents relative to the compound (a-2).
  • the reaction temperature is from 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 from 0.1 to 48 hours, preferably from 0.5 to 12 hours.
  • reaction solvents examples include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination.
  • Process 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.
  • the metal catalyst include (dibenzylideneacetone)palladium, palladium acetate, and palladium chloride.
  • the ligand to be combined with these include Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, and 1,1′-bis(diphenylphosphinoferrocene).
  • Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and the like.
  • the base can be used in an amount of 1 to 5 molar equivalents relative to compound (a-3).
  • the compound (a-8) can be used in an amount of 1 to 5 molar equivalents relative to the compound (a-3).
  • the reaction temperature is from 50° 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 from 1 to 48 hours, preferably from 1 to 12 hours.
  • reaction solvents examples include tetrahydrofuran, toluene, dioxane, etc., and these can be used alone or in combination.
  • Process 4 Compound (a-5) can be obtained by reacting compound (a-4) with a deprotecting agent.
  • the deprotecting agent include tetrabutylammonium fluoride, hydrogen fluoride-pyridine, trifluoroacetic acid, and hydrochloric acid, and can be used in an amount of 0.2 to 10 molar equivalents relative to compound (a-4).
  • the reaction temperature is from 0°C to 60°C, preferably from 20°C to 60°C.
  • the reaction time is from 0.5 to 24 hours, preferably from 0.5 to 2 hours.
  • the reaction solvent include tetrahydrofuran, dichloromethane, dichloroethane, methanol, etc., and these can be used alone or in combination.
  • X1 is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom
  • X4 is 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).
  • Process 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 from 0°C to 150°C, preferably from room temperature to 100°C.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 6 hours.
  • Examples of the base include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, pyridine, triethylamine, DBU, and the like, 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, and NMP, and these can be used alone or in combination.
  • Process 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.
  • Process 3 Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of Method A above.
  • X1 is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom
  • X5 is 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 above in (1) and (9).
  • Process 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 from room temperature to 150°C, preferably from 60 to 120°C.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 6 hours.
  • Examples of the base include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, DBU, and the like, and can be used in an amount of 1 to 5 molar equivalents relative to compound (b-1).
  • the metal catalyst copper chloride, copper bromide, copper iodide, etc. can be used, and as a ligand of the catalyst, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylcyclohexanediamine, etc. can be added.
  • reaction solvents include acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, and NMP, and these can be used alone or in combination.
  • Process 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.
  • Process 3 Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of Method A above.
  • the base includes pyridine, triethylamine, DBU, etc., and can be used in an amount of 1 molar equivalent to the solvent amount relative to the compound (b-1).
  • the metal catalyst copper acetate, copper chloride, copper bromide, etc. can be used.
  • reaction solvents include acetonitrile, toluene, methanol, dichloromethane, DMF, DMA, and the like.
  • Bases such as pyridine and triethylamine can also be used as the solvent. These can be used alone or in combination.
  • Process 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.
  • Process 3 Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of Method A above.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 6 hours.
  • the base include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, pyridine, triethylamine, DBU and the like, and can be used in an amount of 1 to 5 molar equivalents relative to compound (e-1).
  • reaction solvents include acetonitrile, tetrahydrofuran, dioxane, DMF, DMA, DMSO, and NMP, and these can be used alone or in combination.
  • Process 2 Compound (b-2) can be obtained by reacting compound (e-2) with a reducing agent.
  • the reaction temperature is from room temperature to 100°C, preferably from room temperature to 60°C.
  • the reaction time is from 0.5 to 24 hours, preferably from 1 to 6 hours.
  • metal salts such as iron powder and tin chloride, and hydrogen gas in the presence of palladium on carbon can be used.
  • reaction solvents include methanol, ethanol, tetrahydrofuran, ethyl acetate, water, etc., and these can be used alone or in combination with a reducing agent in an appropriate combination.
  • Process 3 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.
  • Process 4 Compound (b-4) can be obtained from compound (b-3) by the method described in step 4 of Method A above.
  • 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 therefore useful as a therapeutic and/or preventive agent for hallucinations and delusions associated with Parkinson's disease and/or dementia.
  • the compound according to the present invention has pharmaceutical utility and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits favorable pharmacokinetics, such as high bioavailability and moderate clearance.
  • composition of the present invention can be administered either orally or parenterally.
  • Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.
  • the drug 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, aromatic preparations, extracts, decoctions, tinctures, etc.), in accordance with the usual methods.
  • solid preparations for internal use e.g., tablets, powders, granules, capsules, pills, films, etc.
  • liquid preparations for internal use e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic preparations, extracts, decoctions, tinctures, etc.
  • 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.
  • any of the commonly used dosage forms such as injections, drops, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered.
  • Injections may be emulsions such as O/W, W/O, O/W/O, and W/O/W types.
  • a pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as necessary.
  • the pharmaceutical composition can be prepared as a pharmaceutical composition for children, elderly people, seriously ill patients, or surgical patients by appropriately changing the effective amount of the compound of the present invention, the dosage form, and/or various pharmaceutical additives.
  • a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years.
  • a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.
  • the dosage of the pharmaceutical composition of the present invention is desirably set 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 within the range of 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 within the range of 0.01 to 1 mg/kg/day. This can be administered once or in divided doses several times a day.
  • the compound of the present invention can be used in combination with anti-Parkinson's drugs, anti-Alzheimer's drugs, antipsychotic drugs, and antidepressants (hereinafter referred to as concomitant drugs) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound.
  • concomitant drugs antidepressants
  • 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 at the same time or at different times.
  • 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 those active ingredients.
  • the dosage of the concomitant drug can be appropriately selected based on the dose used clinically.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • 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
  • CDCl 3 deuterated chloroform
  • DBU 1,8-diazabicyclo[5.4.0]-7-undecene
  • DMSO-d 6 Deuterated dimethylsulfoxide
  • DMF N,N-d
  • 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), ethanol (30.6 mL) and water (15.3 mL) were added, and 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 extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated.
  • Step 2 Synthesis of compound 9
  • Compound 8 (12.7 g, 29.4 mmol), compound 6 (12.27 g, 44.1 mmol), PdCl2(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 the mixture was stirred at 100°C for 6 hours under a nitrogen atmosphere. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated saline and then dried over anhydrous magnesium sulfate.
  • Step 3 Synthesis of Compound 10
  • 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) were added with toluene (400 ⁇ L) and stirred at 100° C. for 9 hours. After cooling, the reaction mixture was filtered through Celite (registered trademark), and the solvent of the mother liquor was distilled off under reduced pressure.
  • Celite registered trademark
  • Step 4 Synthesis of Compound I-011
  • Compound 10 (36 mg, 0.057 mmol) was dissolved in tetrahydrofuran (360 ⁇ L), and 1 mol/L tetrabutylammonium fluoride tetrahydrofuran solution (86 ⁇ L, 0.086 mmol) was added, followed by stirring at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added, and the organic layer was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol).
  • 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), ethanol (1.6 mL) and water (0.8 mL) were added, and 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, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated to obtain compound 13 (88 mg, yield 97%).
  • reaction solution was quenched by adding a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium thiosulfate, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 18 (2.45 g, yield 75%).
  • Step 3 Synthesis of Compound 19 Toluene (1 mL) was added to 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, 59% yield).
  • 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 aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-066 (55 mg, yield 95%).
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • 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 further stirred at 45° C. for 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 in chloroform again and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 25 (2.24 g, yield 49%).
  • 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 saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting solid was suspended and filtered in a mixed solvent system of hexane/diisopropyl ether to obtain compound 27 (177 mg, yield 82%).
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • 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 the reaction was quenched with a saturated aqueous ammonium chloride solution. Water was further added to the mixture, and the precipitated solid was collected by filtration and washed with water and hexane to obtain Compound 28 (211 mg, yield 94%).
  • 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 saline and then dried over anhydrous sodium sulfate.
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • 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), ethanol (3.5 mL) and water (1.8 mL) were added, and the mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate, and insoluble matter was filtered off by celite filtration. Water was added to the resulting solution, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated.
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • 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), ethanol (5.3 mL) and water (2.7 mL) were added, and the mixture was stirred at 90° C. for 1 hour. After cooling, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture, and 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 removed under reduced pressure to obtain compound 33 (144 mg, yield 82%).
  • 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 ⁇ mol) were added and stirred 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 distilled off under reduced pressure.
  • the compounds of the present invention can be tested essentially as described in the following test examples.
  • the compound represented by formula (I) according to the present invention may be any compound having serotonin 5-HT2A receptor antagonistic activity and/or inverse agonistic activity and serotonin 5-HT2C receptor antagonistic activity and/or inverse agonistic activity.
  • the Ki value is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.
  • Test Example 1 5-HT2A receptor binding inhibition test (each experimental condition)
  • Cell membrane Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor)
  • Assay buffer Tris-HCl 50 mmol/L (pH 7.4) containing 120 mmol/L NaCl, 1 mmol/L MgCl2.6H2O , 5 mmol/L KCl, 0.1% BSA and 2 mmol/L CaCl2.
  • Radioactive ligand The final concentration was [ 3 H]-Ketanserin near the Kd value calculated by the following method.
  • Non-specific ligand Ketanserin at a final concentration of 5 ⁇ mol/L The Kd value is calculated when the cell membrane lot is changed.
  • the radioactive ligand solution is serially diluted, and the count is confirmed with a liquid scintillator.
  • Nonspecific binding is calculated from the radioactivity of [ 3 H]-Ketanserin in the presence of 5 ⁇ mol/L unlabeled ligand Ketanserin, and total binding is calculated from the radioactivity of [ 3 H]-Ketanserin in the absence of the compound of the present invention (Vehicle). Finally, the Ki value is calculated from the dose-response curve.
  • the binding activity of the compound of the present invention is calculated from the following binding inhibition rate (%).
  • Inhibition rate (%) [1-(c-a)/(b-a)] x 100 a: Mean cpm of non-specific binding b Average cpm of total binding c: cpm in the presence of test compound
  • 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 Tris-HCl 50 mmol/L (pH 7.4) containing 120 mmol/L NaCl, 1 mmol/L MgCl2.6H2O , 5 mmol/L KCl, 0.1% BSA and 2 mmol/L CaCl2.
  • Radioactive ligand The final concentration was [ 3 H]-Mesulergine near the Kd value calculated by the following method.
  • Non-specific ligand Ketanserin at a final concentration of 5 ⁇ mol/L The Kd value is calculated when the cell membrane lot is changed.
  • the radioactive ligand solution is serially diluted, and the count is confirmed with a liquid scintillator.
  • the binding activity of the compound of the present invention is calculated from the following binding inhibition rate (%).
  • Inhibition rate (%) [1-(c-a)/(b-a)] x 100 a: Mean cpm of non-specific binding b Average cpm of total binding c: cpm in the presence of test compound
  • h 5-HT2C Ki human serotonin 5-HT2C receptor binding activity
  • Test Example 2-2 5-HT2A Receptor Inverse Agonist Test Inositol monophosphate (IP1) homogeneous time-resolved fluorescence (HTRF) assay is used to evaluate the 5-HT2A receptor inverse agonist activity of the compound of the present invention.
  • IP1 homogeneous time-resolved fluorescence
  • HEK293 cells are transiently transfected with recombinant human 5-HT2A receptor using the MaxCyte STX system (MaxCyte).
  • IP1 accumulation is measured using the HTRF IP-One Gq Detection Kit (Revvity).
  • Compounds diluted in DMSO are prepared and dispensed into 384-well assay plates in advance.
  • Transfected cells are harvested and resuspended in Stimulation Buffer, and then dispensed into 384-well assay plates at 20,000 cells/well/9 ⁇ L. Then, incubate at 37°C for 2 hours. After incubation, add a dissolution buffer containing d2-labeled IP1 and Tb cryptate IP1 antibody to each well. After incubation at room temperature for 1 hour, measure the wavelength of 665/620 nm using PHERAstar FSX (BMG Labtech) to quantify IP1.
  • the amount of IP1 accumulated in the absence of the compound of the present invention (Vehicle) is defined as the standard of 0% inverse agonist activity, and the amount of IP1 accumulated when 10 ⁇ mol/L Ritanserin is added is defined as the maximum inhibition rate of inverse agonist activity of 100%, and the maximum inhibition rate (Imax) of the compound of the present invention is calculated from the IP1 concentration in each well using TIBCO Spotfire (Cloud Software Group).
  • the compounds of the invention can be tested essentially as described above.
  • IP1 5-HT2C Receptor Inverse Agonist Test
  • Inositol monophosphate (IP1) homogeneous time-resolved fluorescence (HTRF) assay is used to evaluate the 5-HT2C receptor inverse agonist activity of the compound of the present invention.
  • HEK293 cells are transiently transfected with recombinant human 5-HT2C receptor using the MaxCyte STX system (MaxCyte).
  • IP1 accumulation is measured using the HTRF IP-One Gq Detection Kit (Revvity).
  • Compounds diluted in DMSO are prepared and dispensed into 384-well assay plates in advance.
  • Transfected cells are harvested and resuspended in Stimulation Buffer, and then dispensed into 384-well assay plates at 5000 cells/well/9 ⁇ L. Then, incubate at 37°C for 2 hours. After incubation, add a dissolution buffer containing d2-labeled IP1 and Tb cryptate IP1 antibody to each well. After incubation at room temperature for 1 hour, measure the wavelength of 665/620 nm using PHERAstar FSX (BMG Labtech) to quantify IP1.
  • the amount of IP1 accumulated in the absence of the compound of the present invention (Vehicle) is defined as the standard of 0% inverse agonist activity, and the amount of IP1 accumulated when 10 ⁇ mol/L Ritanserin is added is defined as the maximum inhibition rate of inverse agonist activity of 100%, and the maximum inhibition rate (Imax) of the compound of the present invention is calculated from the IP1 concentration in each well using TIBCO Spotfire (Cloud Software Group).
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 3 For the purpose of evaluating the risk of electrocardiogram QT interval prolongation of the compound 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 activity is evaluated using a FluxORII Green Potassium IonChannel Assay kit (Thermo Fisher Scientific). The cells are seeded in a 384 assay plate (4000 cells/well/40 ⁇ L) and incubated overnight (37° C., 5% CO 2 ).
  • the fluorescent indicator dye is added to the loading buffer included in the kit, and the plate is incubated for 1 hour (37° C., 5% CO 2 ) to allow the fluorescent indicator dye to be incorporated into the cells.
  • the cell plate is placed in a cell-based kinetic assay system FLIPR (Molecular Devices), and the compound is added to the cells to the desired concentration and allowed to react for 10 minutes.
  • FLIPR Cell-based kinetic assay system
  • the inhibition rate of each concentration is defined as 100% inhibition, which is the signal intensity when E-4031 is added to the cells at a final concentration of 10.3 ⁇ mol/L, and as 0% inhibition, which is the signal intensity when DMSO is added to the cells at a final concentration of 0.5%, and the inhibition rate is calculated from the signal intensity of each concentration.
  • IC 50 is calculated from the inhibition rate at each concentration.
  • Oral administration is by forcibly administering the compound into the stomach using an oral tube, whereas intravenous administration is by administering the compound into the tail vein using a syringe with a needle attached.
  • 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.
  • Statistical analysis Regarding the change in plasma concentration of the compound of the present invention, the area under the plasma concentration-time curve (AUC) is calculated by moment analysis, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral administration group and the intravenous administration group. The dilution concentration and dilution solvent may be changed as necessary.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 6 Metabolic stability test Commercially available pooled human liver microsomes are reacted with the compound of the present invention for a certain period of time, and the remaining rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver.
  • buffer solution 50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride
  • the reaction is carried out in the presence of 1 mmol/L NADPH at 37°C for 0 or 30 minutes (oxidation reaction).
  • the compound of the present invention in the centrifugal supernatant is quantified by LC/MS/MS, and the ratio of the amount of the compound of the present invention at 0 minutes of reaction to the amount of the compound after the reaction is shown as the residual rate, with the amount of the compound of the present invention at 0 minutes being taken 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 same operation is carried out thereafter.
  • the dilution concentration and dilution solvent are changed as necessary.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 7 P-gp substrate test
  • the compound of the present invention is added to one side of a transwell (registered trademark, CORNING) in which human MDR1 expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time.
  • the membrane permeability coefficients of the MDR1 expressing cells and parent cells are calculated from the apical side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A), and the Efflux Ratio (ER; ratio of membrane permeability coefficients of B ⁇ A and A ⁇ B) values of the MDR1 expressing cells and parent cells are calculated.
  • the Efflux Ratio (ER value) of the MDR1 expressing cells and parent cells is compared to determine whether the compound of the present invention is a P-gp substrate.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 8 CYP3A4 (MDZ) MBI Test This is a test to evaluate the mechanism based inhibition (MBI) ability of the compound of the present invention from the enhancement by metabolic reaction regarding CYP3A4 inhibition. CYP3A4 inhibition is evaluated using pooled human liver microsomes with the 1-hydroxylation reaction of midazolam (MDZ) as an index.
  • reaction conditions were as follows: substrate, 10 ⁇ mol/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 at pre-reaction and 0.05 mg/mL (at 10-fold dilution) at reaction; concentration of the compound of the present invention at pre-reaction, 0.83, 5, 10, and 20 ⁇ mol/L (4 points).
  • the reaction system was treated as a control (100%) with only DMSO, the solvent in which the compound of the present invention was dissolved, and the residual activity (%) was calculated when the compound of the present invention was added at each concentration.
  • the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The IC at 0 min preincubation/IC at 30 min preincubation was determined as the Shifted IC value, and if the Shifted IC was 1.5 or more, it was determined as Positive, and if the Shifted IC was 1.0 or less, it was determined as Negative.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 9 Solubility Test The solubility of the compound of the present invention is determined under the condition of adding 1% DMSO. A 10 mmol/L compound solution is prepared in DMSO, and 2 ⁇ L of the compound solution of the present invention is added to 198 ⁇ L of the 18th Revised Japanese Pharmacopoeia dissolution test first fluid (2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and water to make 1000 mL) or the dissolution test second fluid (1.7 g of potassium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate are dissolved in water to make 1000 mL). After shaking for 3 hours at room temperature, the mixture is filtered by suction.
  • first fluid 2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and water to make 1000 mL
  • dissolution test second fluid 1.7 g of potassium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate
  • the compounds of the invention can be tested essentially as described above.
  • Dissolution test according to the 18th Edition of the Japanese Pharmacopoeia Solution 1: 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 about 1.2.
  • Dissolution test 2nd solution Add 1 volume of water to 1 volume of phosphate buffer solution having a pH of 6.8.
  • Phosphate buffer solution, pH 6.8 Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.
  • Test Example 9-2 Powder solubility test Put an appropriate amount of the compound of the present invention into a suitable container, and add 200 ⁇ L of the 18th Revised Japanese Pharmacopoeia Dissolution Test 1st Fluid (2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and add water to make 1000 mL), Dissolution Test 2nd Fluid (1.7 g of potassium dihydrogen phosphate, 1.775 g of anhydrous disodium hydrogen phosphate, and add water to make 1000 mL), and 20 mmol/L sodium taurocholate (TCA)/Dissolution Test 2nd Fluid (1.08 g of TCA and add Dissolution Test 2nd Fluid to make 100 mL) to each container.
  • 1st Fluid 2.0 g of sodium chloride, 7.0 mL of 35% hydrochloric acid, and add water to make 1000 mL
  • Dissolution Test 2nd Fluid 1.7 g of potassium dihydrogen phosphate, 1.775 g of anhydrous disodium hydrogen
  • the compound of the present invention If the entire amount is dissolved after adding the test fluid, add the compound of the present invention as appropriate. After sealing and shaking at 37°C for 1 hour, filter, and dilute each filtrate with methanol. The dilution ratio is changed as necessary. Check for air bubbles and precipitates, seal and shake. Quantify the compound of the present invention using HPLC by the absolute calibration curve method. The compounds of the invention can be tested essentially as described above.
  • Test Example 10 MK801-induced hyperactivity inhibition test 6-10 week old Wistar male rats are used. 30 mmol/L HCl or 0.5% methylcellulose is used as a solvent to prepare the administration solution of the test compound, and physiological saline is used as a solvent to prepare the administration solution of MK801. MK801-induced hyperactivity inhibition test is carried out as follows using SCANET manufactured by Melquest, data acquisition program SCL-40, and a transparent plastic cage. In the breeding room, the compound administration solution (solvent or test compound solution) is administered subcutaneously or orally, and the rat is returned to the breeding cage. After 30 minutes, the rat is brought into the laboratory and habituated to the laboratory.
  • the rat is gently removed, and the MK801 administration solution (solvent or MK801 solution) is administered intraperitoneally or subcutaneously, and the rat is returned to the breeding cage.
  • MK801 administration solution solvent or MK801 solution
  • the rat is removed and gently placed in the SCANET, and the measurement of the locomotion amount is started. The measurement is completed 30 minutes after the start of the measurement, and the locomotion amount of each individual rat is totaled for 30 minutes.
  • the analysis of the test results will be carried out as follows. A Student-TTest (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 inhibition of the amount of locomotion compared to the vehicle administration group, it is judged to have an antipsychotic effect.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 11 Fluctuation Ames Test The mutagenicity of the compounds of the present invention is evaluated. 20 ⁇ L of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) is inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking for 9 hours at 37° C. For the TA98 strain, 6.00 to 16.00 mL of the bacterial solution is centrifuged (1100 to 2000 ⁇ g, 10 minutes) to remove the culture medium.
  • the bacteria are suspended in the same volume of Micro F buffer as the bacterial solution used for centrifugation (K 2 HPO 4 : 3.5 g/L, KH 2 PO 4 : 1 g/L, (NH 4 ) 2 SO 4 : 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgSO 4 .7H 2 0: 0.1 g/L) and added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 ⁇ g/mL, L-histidine hydrochloride monohydrate: 0.2 ⁇ g/mL, glucose: 8 mg/mL).
  • Exposure medium Micro F buffer containing biotin: 8 ⁇ g/mL, L-histidine hydrochloride monohydrate: 0.2 ⁇ g/mL, glucose: 8 mg/mL.
  • TA100 strain 2.00 mL of bacterial solution is added to 120 mL of Exposure medium to prepare a test bacterial solution.
  • the compound of the present invention DMSO solution (diluted in several stages at a common ratio of 2 to 3 times from the maximum dose of 50 mg / mL), DMSO as a negative control, 50 ⁇ g / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain as a positive control under non-metabolic activation conditions, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for the TA100 strain, 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA98 strain under metabolic activation conditions, 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, 12 ⁇ L each and 588 ⁇ L of test bacteria solution (a mixture of 498 ⁇ L of
  • 460 ⁇ L of the bacterial solution exposed to the compound of the present invention is mixed with 2300 ⁇ L of Indicator medium (MicroF buffer containing biotin: 8 ⁇ g/mL, L-histidine hydrochloride monohydrate: 0.2 ⁇ g/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 ⁇ g/mL), and 50 ⁇ L is dispensed into 48 wells of a microplate per dose, and the wells are statically cultured at 37° C. for 3 days.
  • Indicator medium MicroF buffer containing biotin: 8 ⁇ g/mL, L-histidine hydrochloride monohydrate: 0.2 ⁇ g/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 ⁇ g/mL
  • Test Example 12 Ames Test Using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA as test strains, Ames tests are performed under non-metabolic activation conditions and metabolic activation conditions by the pre-incubation method to examine the presence or absence of gene mutagenicity of the compound according to the present invention.
  • 0.1 mL of DMSO solution of the compound of the present invention is mixed with 0.5 mL of S9mix under metabolic activation conditions, and 0.5 mL of phosphate buffer and 0.1 mL of test bacteria solution under non-metabolic activation conditions, and shake cultured at 37°C for 20 minutes.
  • Test Example 13 In vitro micronucleus test In this test, the micronucleus induction of the compound of the present invention is evaluated using TK6 cells (derived from human lymphoblasts). 2.5 mL of TK6 cell suspension (approximately 4 x 105 cells/mL) is added with 2.45 mL of culture medium for the non-metabolic activation condition of the 3-hour treatment group and the 24-hour continuous treatment group, and 2.12 mL for the metabolic activation condition of the 3-hour treatment group, and 0.05 mL of DMSO solution of the compound of the present invention and 0.33 mL of S9mix for the metabolic activation condition of the 3-hour treatment group are added, and incubated at 37°C.
  • TK6 cells derived from human lymphoblasts
  • the negative control substance (DMSO) and positive control substance (mitomycin C, cyclophosphamide, or colchicine) are also similarly performed.
  • the cells are washed after the treatment, replaced with 5 mL of new medium, and incubated for another 21 hours. After the culture is completed, the number of live cells is counted to confirm cytotoxicity.
  • the dose showing a relative cell population doubling rate of about 50% is selected as the maximum dose for the test, if there is no cytotoxicity, 500 ⁇ g/mL is selected as the maximum dose for the test, and if precipitation is observed, the minimum dose at which precipitation is observed during culture is selected as the maximum dose for the test.
  • the selected cell suspension is treated with a fixative and dropped onto a slide to prepare a specimen.
  • the slide specimen is stained with acridine orange and observed under a fluorescent microscope to count mononuclear cells with micronuclei. If the number of cells with micronuclei increases statistically significantly compared to the negative control group and a concentration-dependency is observed, the result is judged to be positive.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 14 Neutral Red Uptake Phototoxicity Test Using 3T3 Mouse Fibroblasts
  • the presence or absence of phototoxicity of the compound of the present invention is examined using mammalian cultured cells (BALB/3T3 cells).
  • One 96-well plate is used for each of non-irradiated (-Irr) and irradiated (+Irr) conditions.
  • the dose of the compound of the present invention is set in accordance with the "Guidelines for Photosafety Evaluation of Pharmaceuticals" with a final concentration of 100 ⁇ g/mL as the maximum dose, and a total of eight doses are set with a common ratio of 2.
  • a group treated with the vehicle (DMSO) of the compound of the present invention is set as a negative control.
  • a chlorpromazine (CPZ) treatment group is set as a positive control
  • an ethanol treatment group which is the vehicle for the positive control
  • 100 ⁇ L (1 ⁇ 10 4 cells/well) of a cell suspension at 1 ⁇ 10 5 cells/mL is added to each well of a 96-well plate and cultured for about 24 hours. After about 24 hours of culture, the culture medium is removed from each well, the cells are washed, and a treatment solution in which the compound of the present invention and each control substance are diluted to a predetermined concentration with culture medium is added to each well.
  • the irradiated plate After treatment in a CO 2 incubator for 1 hour, the irradiated plate is placed at a position where the UV-A irradiation intensity of the light irradiation device is about 1.7 mW/cm 2 and irradiated for 50 minutes.
  • the non-irradiated plate is placed in a CO 2 incubator for 50 minutes.
  • the treatment solution is removed from each well, the cells are washed twice, 150 ⁇ L of fresh culture medium is added, and cultured for 20 to 22 hours. After the culture is completed, the culture medium is removed and washed from each well, and 100 ⁇ L of Neutral Red solution (50 ⁇ g/mL) dissolved in serum-free culture medium is added to each well and cultured for 3 hours.
  • IC50 which is the concentration at which cell viability is reduced by 50%, is calculated for each of the non-irradiated and irradiated plates. If precipitation of the compound of the present invention is observed, the dose is not used for calculating IC50 .
  • Photo Irritation Factor PIF
  • MPE Mean Photo Effect
  • PIF is calculated from the ratio of IC50 in the non-irradiated and irradiated plates. If IC50 is not calculated for either the non-irradiated or irradiated plate, PIF is not calculated either.
  • MPE is calculated from the comparison of reactivity in the non-irradiated and irradiated plates. When IC50 is calculated for both the non-irradiated and irradiated plates, the results are judged from PIF. When IC50 is not calculated for either the non-irradiated or irradiated plate, the results are judged from MPE. When PIF ⁇ 5 or MPE ⁇ 0.15, it is determined that there is no phototoxicity, and when 5 ⁇ PIF or 0.15 ⁇ MPE, it is determined that there is phototoxicity.
  • the compounds of the invention can be tested essentially as described above.
  • Test Example 15 Cardiovascular test in conscious dogs A 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 duration, 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 beagle dogs (male) according to the schedule in the table below.
  • the individual correction coefficient ( ⁇ value) of this correction formula is calculated using the RR interval and QT interval of the 12-hour light phase of the data measured in advance (at the time of acclimation administration).
  • the electrocardiogram waveforms at each analysis time point are visually checked for the presence or absence of arrhythmia-like waveforms.
  • the percentage change in QTc from the pre-administration value is calculated (the pre-administration value is considered to be 100%).
  • the relative QTc is compared with the vehicle value.
  • Plasma samples are obtained by centrifugation (4°C, 10,000 x g, 3 minutes). Plasma separation is performed under ice cooling or at 4°C, and the obtained plasma (TK sample) is stored in an ultra-low temperature storage (set temperature: -80°C).
  • TK sample is stored in an ultra-low temperature storage (set temperature: -80°C).
  • Test Example 16 Cardiovascular 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 duration, 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.
  • the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
  • the compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, in particular 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 in the form of intranasal or suppositories.
  • compositions containing the compounds of the present invention in free form or in the form of a pharma-ceutically acceptable salt together with at least one pharma-ceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation or coating methods.
  • oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc.
  • injectable compositions can be solutions or suspensions, which may be sterilized, and may contain preservatives, stabilizers, buffers, etc.
  • the compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and/or inverse agonistic effects and serotonin 5-HT2C receptor antagonistic and/or inverse agonistic effects, 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.

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Abstract

La présente invention concerne un composé ayant une action antagoniste et/ou agoniste inverse du récepteur 5-HT2A de la sérotonine ainsi qu'une action agoniste antagoniste et/ou inverse du récepteur 5-HT2C de la sérotonine, ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également une composition pharmaceutique le contenant.　L'invention concerne un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci. Dans la formule : R1 est un groupe hétérocyclique aromatique à 6 chaînons substitué ou non substitué ou similaire ; A1 est CR2 ou similaire ; A2 est CR3 ou similaire ; A3 est N ou similaire; R2 et R3 sont chacun indépendamment un atome d'hydrogène ou similaire ; le cycle B est un pyrazole substitué ou non substitué ou similaire ; R15 et R16 sont chacun indépendamment un atome d'hydrogène ou similaire ; et R17 et R18 sont chacun indépendamment un atome d'hydrogène ou similaire.
PCT/JP2024/043197 2023-12-07 2024-12-06 Dérivé carbocyclique aromatique et hétérocyclique aromatique contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine Pending WO2025121409A1 (fr)

Applications Claiming Priority (4)

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JP2023-207092 2023-12-07
JP2023207092 2023-12-07
JP2024090961 2024-06-04
JP2024-090961 2024-06-04

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WO2025121409A1 true WO2025121409A1 (fr) 2025-06-12

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060762A2 (fr) * 2004-12-03 2006-06-08 Arena Pharmaceuticals, Inc. Derives de pyrazole en tant que modulateurs du recepteur de serotinine 5-ht2a utiles dans le traitement de troubles associes a ce recepteur
JP2009533442A (ja) * 2006-04-10 2009-09-17 アリーナ ファーマシューティカルズ， インコーポレイテッド ５−ｈｔ２ａセロトニン受容体関連障害の治療のために有用な５−ｈｔ２ａセロトニン受容体のモジュレータとしての３−ピリジニル−ピラゾール誘導体
JP2009537543A (ja) * 2006-05-18 2009-10-29 アリーナ ファーマシューティカルズ， インコーポレイテッド ５−ｈｔ２ａセロトニンレセプターに関連する障害の処置に有用な５−ｈｔ２ａセロトニンレセプターのモジュレーターとしての３−ピラゾリル−ベンズアミド−４−エーテル、二級アミンおよびその誘導体
WO2024122617A1 (fr) * 2022-12-08 2024-06-13 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine et dérivé carbocyclique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060762A2 (fr) * 2004-12-03 2006-06-08 Arena Pharmaceuticals, Inc. Derives de pyrazole en tant que modulateurs du recepteur de serotinine 5-ht2a utiles dans le traitement de troubles associes a ce recepteur
JP2009533442A (ja) * 2006-04-10 2009-09-17 アリーナ ファーマシューティカルズ， インコーポレイテッド ５−ｈｔ２ａセロトニン受容体関連障害の治療のために有用な５−ｈｔ２ａセロトニン受容体のモジュレータとしての３−ピリジニル−ピラゾール誘導体
JP2009537543A (ja) * 2006-05-18 2009-10-29 アリーナ ファーマシューティカルズ， インコーポレイテッド ５−ｈｔ２ａセロトニンレセプターに関連する障害の処置に有用な５−ｈｔ２ａセロトニンレセプターのモジュレーターとしての３−ピラゾリル−ベンズアミド−４−エーテル、二級アミンおよびその誘導体
WO2024122617A1 (fr) * 2022-12-08 2024-06-13 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité de liaison au récepteur de la sérotonine et dérivé carbocyclique

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