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WO2013161929A1 - Pyridinyl morpholinone derivative and drug composition containing same - Google Patents

Pyridinyl morpholinone derivative and drug composition containing same Download PDF

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Publication number
WO2013161929A1
WO2013161929A1 PCT/JP2013/062182 JP2013062182W WO2013161929A1 WO 2013161929 A1 WO2013161929 A1 WO 2013161929A1 JP 2013062182 W JP2013062182 W JP 2013062182W WO 2013161929 A1 WO2013161929 A1 WO 2013161929A1
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Prior art keywords
substituted
unsubstituted
group
compound
aromatic
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PCT/JP2013/062182
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French (fr)
Japanese (ja)
Inventor
一成 服部
健二 高谷
一穂 川瀬
夏枝 青木
義人 石田
Original Assignee
塩野義製薬株式会社
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Publication of WO2013161929A1 publication Critical patent/WO2013161929A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving a voltage-gated sodium channel Nav1.7 (hereinafter referred to as Nav1.7), and a pharmaceutical composition containing the compound.
  • Nav1.7 voltage-gated sodium channel
  • Voltage-gated sodium channels are present in excitable cells such as the central, peripheral, cardiac, skeletal and neuroendocrine cells. Responds to depolarization of cell membrane potential and is involved in action potential generation and conduction. Voltage-gated sodium channels play an important role in signal generation and signal conduction in nerves and myocardium and are essential for maintaining the function of the nervous system, heart and muscle. Abnormalities of voltage-gated sodium channels are involved in diseases such as epilepsy (Non-patent document 1), chronic pain (Non-patent document 2), myotonia (Non-patent document 3), and arrhythmia (Non-patent document 4). Is known (Non-Patent Document 5).
  • the voltage-gated sodium channel is composed of an ⁇ subunit that forms an ion channel pore and a ⁇ subunit that is an auxiliary subunit.
  • the ⁇ subunit is a protein having a molecular weight of about 260 kDa consisting of four homologous domains each having six transmembrane regions (S1 to S6 segments) and a pore loop region existing between the S5 and S6 segments.
  • a channel that permeates sodium ions is formed at the center of the four homology domains.
  • the ⁇ subunit has 9 subtypes, Nav1.1 to Nav1.9, and the sensitivity and expression site of ion channel activity inhibition by the pufferfish tetrodotoxin (TTX) vary depending on each subtype. It has been known.
  • Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7 have ion channel activity inhibited by TTX.
  • Nav1.5, Nav1.8 and Nav1.9 are less sensitive to TTX.
  • Nav1.1, Nav1.2 and Nav1.3 are nervous systems
  • Nav1.4 is skeletal muscle
  • Nav1.5 is myocardium
  • Nav1.6 is nervous system
  • Nav1.7, Nav1.8 and Nav1.9 are mainly It is expressed in the peripheral nervous system. It is known to be related to biological functions related to each expression site (Non-patent Document 5).
  • Nav1.7 is distributed in peripheral nervous systems such as the sympathetic nervous system and sensory nervous system, and forms a TTX sensitive sodium channel. Recently, it has become clear that it is specifically involved in pain signals. In KO mice deficient in the Nav1.7 gene in sensory nerves, it has been reported that mechanical and thermal pain thresholds are increased, and increase in pain sensation is suppressed in an inflammatory pain model (Non-Patent Literature). 6). In addition, the relationship between the mutation of the gene and pain sensation has been found in humans. From the family analysis of extremity erythema showing increased flushing and pain sensation in the periphery of the limb, SCN9A encoding Nav1.7 It has been reported that a gain of function type mutation has occurred (Non-patent Document 7).
  • lidocaine and mexiletine which are subtype non-specific sodium channel inhibitors, are known to exhibit analgesic action in clinical practice and are used as pain therapeutic agents (Non-patent Document 9).
  • Nav1.7 selective inhibitor having a weak inhibitory activity against Nav1.5 exhibits a powerful analgesic action and is very useful as a therapeutic agent for various pain pathologies overcoming safety concerns. It is done.
  • Patent Documents 1 and 2 describe compounds having a Nav1.7 inhibitory action, but differ in structure from the compounds of the present invention.
  • Patent Documents 3 to 5 describe compounds having a structure similar to that of the compound of the present invention, but there is no description or suggestion regarding Nav1.7 inhibitory action.
  • An object of the present invention is to provide a novel compound having a Nav1.7 inhibitory action and a pharmaceutical composition having a Nav1.7 inhibitory action.
  • the present invention relates to the following (1) to (12) and (1 ′) to (8 ′).
  • -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
  • Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted al
  • (4) -X- is a single bond, -O- (CH 2 ) p-, or -N (H)-(CH 2 ) r-; p and r are each independently 0 or 1, The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof.
  • R 3 is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group.
  • R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group A heterocyclic group;
  • -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
  • Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
  • Each R 5b independently represents a hydrogen atom, substituted or unsubstituted
  • R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group
  • —X— represents a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—
  • p and r are each independently 0 or 1 -Y- is a single bond or substituted or unsubstituted alkylene
  • R 3 represents a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Group, or substituted or unsubstituted non-aromatic heterocyclic group
  • a pharmaceutical composition comprising the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof.
  • (12) A disease associated with Nav1.7, comprising administering the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof. Treatment and / or prevention methods.
  • the compound according to the present invention has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for a disease or condition involving Nav1.7.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, 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, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Yet another embodiment includes methyl, ethyl, n-propyl, isopropyl, tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position. Examples of “alkynyl” include ethynyl, propynyl, butynyl, pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included. These may further have a double bond at an arbitrary position. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Examples of the “aromatic carbocyclic group” include phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more 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.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a 5- to 7-membered non-aromatic heterocyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring, A non-aromatic heterocyclic group in which two or more of them are independently fused, A 5- to 7-membered non-aromatic heterocycle having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring is one or more rings in the above “aromatic carbocyclic group”, A non-aromatic heterocyclic group fused with a ring in the “non-aromatic carbocyclic group”, or a ring in the “aromatic heterocyclic group”, or A non-aromatic heterocyclic group in which the ring in the “aromatic heterocyclic group” is fused with one or more rings in the “non-aromatic carbocyclic group”; Is included.
  • non-aromatic heterocyclic group includes a group which forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuran, dihydrobenzodioxin and the like.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Examples of the “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom.
  • vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like can be mentioned.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the above “halogens” are bonded to the above “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Examples of the “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Examples of the “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Examples of the “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned. Examples of the “monoalkylamino” include methylamino and ethylamino.
  • Dialkylamino means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like. Examples of the “dialkylamino” include dimethylamino and diethylamino.
  • dialkylaminoalkyl means a group in which the “alkyl” is substituted with the nitrogen atom of the “dialkylamino”. Examples thereof include dimethylaminoalkyl, diethylaminoalkyl, N, N-diisopropylaminoalkyl, N-methyl-N-ethylaminoalkyl, N-isopropyl-N-ethylaminoalkyl and the like. Examples of the “dialkylaminoalkyl” include dimethylaminoalkyl and diethylaminoalkyl.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • alkylsulfonyl include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Examples of the “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Examples of the “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like. Examples of the “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Examples of the “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • alkylcarbonyloxy include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • alkyloxycarbonyl include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc. Examples of the “aromatic carbocyclic alkyl” include benzyl, phenethyl, and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl part is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • non-aromatic heterocyclic alkyloxy means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”.
  • non-aromatic heterocyclic alkyloxyalkyl substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • aromatic carbocyclic oxy means a group in which an “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocyclic carbonyl means a group in which an “aromatic carbocycle” is bonded to a carbonyl group.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl”
  • the “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • the “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like can be mentioned.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like.
  • aromatic heterocycle moiety of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl”
  • Aromatic heterocycle oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • Aromatic heterocycle carbonyl means a group in which “aromatic heterocycle” is bonded to a carbonyl group.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle for example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic oxycarbonyl” means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkeny
  • An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkylcarbonyl, alkyl,
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
  • R 1 is a substituted or unsubstituted monocyclic aromatic carbocyclic group, a substituted or unsubstituted monocyclic nonaromatic carbocyclic group, a substituted or unsubstituted monocyclic aromatic heterocyclic group, or a substituted group Or an unsubstituted monocyclic non-aromatic heterocyclic group is mentioned.
  • R 1 includes substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, or substituted or unsubstituted cyclohexyl. .
  • R 1 include substituted or unsubstituted phenyl.
  • —X— includes a single bond, —O— (C (R 5a ) (R 5b )) p—, or —N (R 7 ) — (C (R 8a ) (R 8b )) r—.
  • Examples of —X— include a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—.
  • Examples of —X— include a single bond and —O— (CH 2 ) p—.
  • p, q, and r are each independently 0 or 1. Examples of p, q and r include 0.
  • R 5a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 5b include independently a hydrogen atom or substituted or unsubstituted alkyl.
  • R 6a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
  • Examples of R 6b include independently a hydrogen atom or substituted or unsubstituted alkyl.
  • R 7 includes a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 8a includes a hydrogen atom or substituted or unsubstituted alkyl.
  • R 8b includes a hydrogen atom, or substituted or unsubstituted alkyl.
  • R 3 is a hydrogen atom, halogen, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Examples include substituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy.
  • R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic group Heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic ring Oxy is mentioned.
  • R 3 includes substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted tetrahydropyranyl, substituted Or an unsubstituted phenoxy is mentioned.
  • R 3 includes substituted or unsubstituted phenyl.
  • n may be 0. As m, 0 or 1 is mentioned. m may be 0.
  • the compound represented by the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) or a pharmaceutically acceptable salt thereof is defined as each substituent shown above. Or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.
  • the compound in which the “—Y—R 6 ” group is hydrogen includes the following tautomers.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted 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
  • 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fum
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent.
  • the compound represented by the above general formula (I) has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions involving Nav1.7.
  • Nav1.7 is considered to be involved in pain (Non-Patent Documents 6 to 8 etc.), and as diseases and / or conditions in which Nav1.7 is involved, for example, acute pain, chronic pain, neuropathic pain, inflammation Pain, visceral pain, nociceptive pain, including postoperative pain, visceral, gastrointestinal tract, skull, musculoskeletal system, spine, genitourinary system, cardiovascular and central nervous system cancer pain, and back There are multiple types of pain including pain and orofacial pain.
  • a more preferred compound of the present invention is a pharmaceutical composition having a selective Nav1.7 inhibitory action.
  • lidocaine and mexiletine which are subtype non-specific sodium channel inhibitors, also show an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11).
  • Non-patent Documents 10 and 11 Have safety concerns that can affect cardiac function, which is particularly important in For this reason, it is expected to ensure Nav1.7 inhibition selectivity especially for Nav1.5 inhibition.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
  • Hal is a halogen;
  • Lg 1 is a leaving group;
  • R A and R B are each independently hydrogen or substituted or unsubstituted alkyl, or substituted together Or forms an unsubstituted non-aromatic heterocycle;
  • each R 4a independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl Substituted or unsubstituted monoalkylamino, and Is substituted or un
  • Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound A1.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • reaction solvent examples include dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.
  • Process 2 Compound A4 can be obtained by adding a base to compound A3.
  • the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
  • the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Process 3 Compound A6 can be obtained by allowing compound A4 to react with compound A5 having a leaving group and a base.
  • the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl and the like.
  • Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Compound A8 can be obtained by reacting compound A6 with boronic acid or boronic ester A7 in the presence of a metal catalyst and a base.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound A6.
  • Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like.
  • 0.001 to 0.5 molar equivalent can be used.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on Compound A6.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate and the like, and 1 to 10 molar equivalents can be used with respect to compound A6.
  • Boronic acid or boronic acid ester A7 can be used at 1 to 10 molar equivalents relative to compound A6.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water, ethanol, 2-propanol, tert-butanol and the like, and these can be used alone or in combination.
  • R A and R B are each independently hydrogen or substituted or unsubstituted alkyl or taken together are substituted or unsubstituted non-aromatic
  • Each R 4b independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted Monoalkylamino or substituted or unsubstituted di M2 is
  • Examples of the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl, and the like.
  • Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazane, lithium diisopropylamide and the like, and 1 to 5 molar equivalents can be used with respect to compound A6.
  • the reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • Process 2 Compound B3 can be obtained by the method described in the fourth step of Method A using Compound B2 instead of Compound A6.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound C1.
  • Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like.
  • 0.001 to 0.5 molar equivalent can be used.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on the compound C1.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound C1.
  • the primary or secondary amine C2 can be used in an amount of 1 to 10 molar equivalents relative to the compound C1.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound D1.
  • the phosphine ligand includes (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2 ′, 4 ′, 6 ′.
  • [(2-biphenyl) dicyclohexylphosphine] palladium which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound D1.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus
  • Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound D1.
  • Phenol D2 can be used at 1 to 10 molar equivalents relative to compound D1.
  • the reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
  • More preferred compounds of the present invention have not only a Nav1.7 inhibitory action but also usefulness as a medicament, and have any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • b) Good pharmacokinetics such as high bioavailability and moderate clearance.
  • d) Does not exhibit irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • Specific examples of the compound of the present invention include compounds having the following Rp and Rq in the following general formula (III ′).
  • Example 1 (1) Synthesis of compound 2 Compound 1 (50.00 g, 0.204 mol) and chloroacetic acid (23.09 g, 0.244 mol) were suspended in dry dichloromethane (1 L), and diisopropylethylamine (71 mL, 0.407 mol) was added under a nitrogen atmosphere. . The solid in the reaction solution was dissolved over about 10 minutes at room temperature, and the reaction solution became orange. 2-hydroxypyridine-N-oxide (27.15 g, 0.244 mol) and EDC hydrochloride (46.80 g, 0.244 mol) were sequentially added, and the mixture was stirred for 2.5 hours at room temperature under a nitrogen atmosphere. The disappearance of the raw material was confirmed by LC / MS.
  • the reaction solution was cooled in an ice-water bath, and a saturated aqueous ammonium chloride solution (250 mL) was added dropwise while maintaining the reaction solution temperature at about 10 degrees to stop the reaction.
  • the organic layer was separated and the aqueous layer was washed 3 times with ethyl acetate (250 mL).
  • the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure.
  • Isohexane about 200 mL was added to the obtained residue to solidify it.
  • the solid was collected by filtration and washed twice with isohexane (100 mL). It was dried at 40 ° C. under reduced pressure for 4 hours to obtain Compound 3 (24.02 g, yield 93%).
  • the resulting reddish brown solution is stirred at room temperature for 20 minutes.
  • the reaction is cooled with an ice-water bath and alkyl halide (75 mmol, 1.5 eq) is added over 10 minutes while maintaining the reaction temperature at 10-15 degrees. Remove the ice-water bath and stir at room temperature.
  • the reaction solution is cooled in an ice-water bath and quenched with water (50 mL).
  • the reaction solution was concentrated under reduced pressure to remove DMF. To the obtained residue are added ethyl acetate (400 mL), saturated brine (100 mL), and water (100 mL), and the mixture is separated.
  • aqueous layer is washed four times with ethyl acetate (400 mL), and the combined organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the resulting residue is solidified in diethyl ether and purified by filtration or by silica gel column chromatography (100% dichloromethane to 5% methanol-95% dichloromethane, or 80% ethyl acetate-isohexane to 100% ethyl acetate). Purification can give compound 4.
  • Example 2 Synthesis of Compound I-262 Process 1 To a solution of 2-amino-2- (5-bromopyridin-3-yl) ethanol hydrochloride (10 g, 39.4 mmol) and chloroacetic acid (4.5 g, 47.3 mmol) in dichloromethane (200 mL) was added DIEA (6. 9 mL, 39.4 mmol) was added. After stirring at room temperature for 10 minutes, 2-hydroxypyridine-1-oxide (5.3 g, 47.3 mmol) and EDC (9.1 g, 47.3 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
  • Example 5 Synthesis of Compound I-275 To a solution of compound 9 (40 mg, 0.12 mmol) obtained in the same manner as in Example 2 in DMF (0.3 mL) was added potassium tert-butoxide (20 mg, 0.17 mmol), bromomethylcyclohexane (17 mg, 0 mL). .17 mmol) was added. After stirring at room temperature overnight, ethyl acetate was added, washed with saturated brine, and the organic layer was concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound I-275 (42 mg, yield: 82%).
  • Test Example 1 Evaluation of Nav1.7 inhibitory activity The degree to which the compound of the present invention inhibits Nav1.7 function was evaluated by the following method.
  • HEK293 cells stably expressing human Nav1.7 were seeded at 8000 cells / well in a 384-well microtiter plate, cultured for 24 hours in a 37 ° C., 5% CO 2 incubator and used as an assay plate. Each well of the assay plate was washed with assay buffer (10 mmol / L HEPES, 10 mmol / L Glucose, 137 mmol / L NaCl, 4 mmol / L KCl, 1 mmol / L MgCl2, 1.8 mmol / L CaCl2, pH 7.4). .
  • the assay plate was set in a kinetic fluorescence measurement apparatus FLIPR TETRA (Molecular devices), and the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm. .
  • FLIPR TETRA Molecular devices
  • the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm.
  • Using a pipetter with built-in FLIPR TETRA in each well add 10 ⁇ L of the compound solution of the present invention diluted with assay buffer immediately after the start of measurement, and further open 10 ⁇ L of sodium channel diluted with assay buffer approximately 5 minutes after the start of measurement.
  • the agent Veratridine solution was added and mixed (final concentration of Veratridine: 40 ⁇ mol / L).
  • IC50 value The calculation method of Nav1.7 inhibitory activity (IC50 value) of the compound of the present invention is shown below. For each well, the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity value from immediately before the addition of Veratridine solution to 3 minutes later was calculated.
  • the inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO as a solvent of the compound of the present invention as a negative control and a well added with mexiletine (final concentration of mexiletine: 500 ⁇ mol / L) as a positive control.
  • Inhibition rate (1- (change amount by the compound of the present invention ⁇ change amount by positive control) / (change amount by negative control ⁇ change amount by positive object)) ⁇ 100
  • the inhibition rate was determined for the compound concentrations of the present invention of 0.156, 0.312, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 ⁇ mol / L (8 points), and the IC50 value ( ⁇ mol / L) was calculated by the logistic approximation method.
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • Intravenous administration is performed from the tail vein using a syringe with a needle.
  • Evaluation item Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
  • the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 7.
  • Micro F buffer 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:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL) To the MicroF buffer).
  • TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • HEK293 cells expressing human ether-a-go-related gene (hERG) channels are used for ventricular repolarization process.
  • I Kr delayed rectifier K + current
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, depolarization stimulation of +40 mV was applied.
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
  • Test Example 7-2 hERG Test Ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.
  • the compound according to the present invention has an inhibitory action against Nav1.7, and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving Nav1.7.

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Abstract

Disclosed is the compound represented in formula (I) or a pharmaceutically acceptable salt of same (in the formula: R1 is an aromatic carbon ring group or the like; -X- is a single bond, -O(C(R5a)(R5b))p- or the like; R5a and R5b are hydrogen atoms or the like; p is 0 or the like; R2 is a halogen or the like; n is 0 or the like; -Y- is a single bond, a substituted or unsubstituted alkylene or the like; R3 is a hydrogen atom or the like; R4 is a halogen or the like; and m is 0 or the like).

Description

ピリジニルモルホリノン誘導体およびそれらを含有する医薬組成物Pyridinyl morpholinone derivatives and pharmaceutical compositions containing them
　本発明は、電位依存性ナトリウムチャネルＮａｖ１．７（以下、Ｎａｖ１．７と示す。）が関与する疾患または状態を治療するのに有用な化合物、および該化合物を含有する医薬組成物に関する。 The present invention relates to a compound useful for treating a disease or condition involving a voltage-gated sodium channel Nav1.7 (hereinafter referred to as Nav1.7), and a pharmaceutical composition containing the compound.
　電位依存性ナトリウムチャネルは、中枢神経、末梢神経、心筋、骨格筋ならびに神経内分泌細胞などの興奮性細胞に存在する。細胞膜電位の脱分極に応答し、活動電位の発生やその伝導に関与する。電位依存性ナトリウムチャネルは、神経および心筋におけるシグナル発生およびシグナル伝導において重要な働きをすることから、神経系、心臓および筋肉の機能維持に必須である。電位依存性ナトリウムチャネルの異常は、てんかん (非特許文献１)、慢性疼痛(非特許文献２)、筋緊張症 (非特許文献３) および不整脈 (非特許文献４) などの疾患に関与することが知られている（非特許文献５)。
　電位依存性ナトリウムチャネルは、イオンチャネルポアを形成するαサブユニットおよび補助サブユニットであるβサブユニットから構成される。αサブユニットは、それぞれ６つの膜貫通領域(Ｓ１～Ｓ６セグメント)、ならびにＳ５およびＳ６セグメントの間に存在するポアループ領域を持つ、4つの相同ドメインより成る分子量が約２６０ｋＤａのタンパクである。その４つの相同ドメインの中心に、ナトリウムイオンを透過するチャネルを形成する。αサブユニットには、Ｎａｖ１．１ ~ Ｎａｖ１．９の９つのサブタイプが存在し、フグ毒であるテトロドトキシン（ＴＴＸ）によるイオンチャネル活性阻害の感受性や発現する部位は、それぞれのサブタイプにより異なる事が知られている。例えば、Ｎａｖ１．１、Ｎａｖ１．２、Ｎａｖ１．３、Ｎａｖ１．４、Ｎａｖ１．６およびＮａｖ１．７は、ＴＴＸによりイオンチャネル活性が阻害される。Ｎａｖ１．５、Ｎａｖ１．８およびＮａｖ１．９は、ＴＴＸに対する感受性が低い。Ｎａｖ１．１、Ｎａｖ１．２およびＮａｖ１．３は神経系、Ｎａｖ１．４は骨格筋、Ｎａｖ１．５は心筋、Ｎａｖ１．６は神経系、ならびにＮａｖ１．７、Ｎａｖ１．８およびＮａｖ１．９は主に末梢神経系において発現している。それぞれの発現部位に関連した生体機能に関わっていることが知られている（非特許文献５）。 Voltage-gated sodium channels are present in excitable cells such as the central, peripheral, cardiac, skeletal and neuroendocrine cells. Responds to depolarization of cell membrane potential and is involved in action potential generation and conduction. Voltage-gated sodium channels play an important role in signal generation and signal conduction in nerves and myocardium and are essential for maintaining the function of the nervous system, heart and muscle. Abnormalities of voltage-gated sodium channels are involved in diseases such as epilepsy (Non-patent document 1), chronic pain (Non-patent document 2), myotonia (Non-patent document 3), and arrhythmia (Non-patent document 4). Is known (Non-Patent Document 5).
The voltage-gated sodium channel is composed of an α subunit that forms an ion channel pore and a β subunit that is an auxiliary subunit. The α subunit is a protein having a molecular weight of about 260 kDa consisting of four homologous domains each having six transmembrane regions (S1 to S6 segments) and a pore loop region existing between the S5 and S6 segments. A channel that permeates sodium ions is formed at the center of the four homology domains. The α subunit has 9 subtypes, Nav1.1 to Nav1.9, and the sensitivity and expression site of ion channel activity inhibition by the pufferfish tetrodotoxin (TTX) vary depending on each subtype. It has been known. For example, Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7 have ion channel activity inhibited by TTX. Nav1.5, Nav1.8 and Nav1.9 are less sensitive to TTX. Nav1.1, Nav1.2 and Nav1.3 are nervous systems, Nav1.4 is skeletal muscle, Nav1.5 is myocardium, Nav1.6 is nervous system, and Nav1.7, Nav1.8 and Nav1.9 are mainly It is expressed in the peripheral nervous system. It is known to be related to biological functions related to each expression site (Non-patent Document 5).
　特に、Ｎａｖ１．７は交感神経系および感覚神経系などの末梢神経系に分布し、ＴＴＸ感受性ナトリウムチャネルを形成する。近年、痛覚シグナルに特異的に関与する事が明らかとなった。感覚神経におけるＮａｖ１．７遺伝子を欠損させたＫＯマウスでは、機械的および熱性の痛覚閾値が上昇すること、ならびに炎症性疼痛モデルにおいて、痛覚増大が抑制されることが報告されている(非特許文献６)。また、同遺伝子の変異と痛覚との関連は、ヒトにおいても見出されており、四肢末梢の紅潮、痛覚の増大を示す肢端紅痛症の家系解析から、Ｎａｖ１．７をコードするＳＣＮ９Ａにgain of function型の変異が起こっていることが報告されている (非特許文献７)。さらに、他の感覚が正常にもかかわらず痛覚のみが消失している無痛症の家系解析よりＳＣＮ９Ａにloss of function型（ナトリウムチャネル機能の消失）変異が起こっていることが報告されている (非特許文献８)。以上の通り、同ナトリウムチャネルサブタイプと痛覚との特異的な関連が示唆されていることから、Ｎａｖ１．７阻害剤は様々な疼痛疾患の治療薬として有用であると考えられている。 In particular, Nav1.7 is distributed in peripheral nervous systems such as the sympathetic nervous system and sensory nervous system, and forms a TTX sensitive sodium channel. Recently, it has become clear that it is specifically involved in pain signals. In KO mice deficient in the Nav1.7 gene in sensory nerves, it has been reported that mechanical and thermal pain thresholds are increased, and increase in pain sensation is suppressed in an inflammatory pain model (Non-Patent Literature). 6). In addition, the relationship between the mutation of the gene and pain sensation has been found in humans. From the family analysis of extremity erythema showing increased flushing and pain sensation in the periphery of the limb, SCN9A encoding Nav1.7 It has been reported that a gain of function type mutation has occurred (Non-patent Document 7). Furthermore, it has been reported that a lossＮof function type (disappearance of sodium channel function) mutation has occurred in SCN9A from a family analysis of analgesia in which only pain sensation has disappeared despite other normal sensations. Patent Document 8). As described above, since a specific relationship between the sodium channel subtype and pain sensation has been suggested, it is considered that Nav1.7 inhibitors are useful as therapeutic agents for various pain diseases.
　また、サブタイプ非特異的ナトリウムチャネル阻害剤であるリドカインやメキシレチンは、臨床において鎮痛作用を示すことが知られており、疼痛治療薬として利用されている(非特許文献９)。一方で、心筋に発現するＮａｖ１．５に対しても抑制作用を示すことが知られており(非特許文献１０および１１)、生命維持において特に重要である心臓機能に影響を与え得るという安全性の懸念を有する。
　以上の事から、Ｎａｖ１．５に対する阻害活性が弱いＮａｖ１．７選択的阻害剤は、強力な鎮痛作用を示し、安全性の懸念を克服した各種疼痛病態の治療薬として非常に有用であると考えられる。 Further, lidocaine and mexiletine, which are subtype non-specific sodium channel inhibitors, are known to exhibit analgesic action in clinical practice and are used as pain therapeutic agents (Non-patent Document 9). On the other hand, it is known that it also has an inhibitory effect on Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11), and can safely affect cardiac function that is particularly important in life support. Have concerns.
From the above, it is considered that a Nav1.7 selective inhibitor having a weak inhibitory activity against Nav1.5 exhibits a powerful analgesic action and is very useful as a therapeutic agent for various pain pathologies overcoming safety concerns. It is done.
特許文献１および２には、Ｎａｖ１．７阻害作用を有する化合物が記載されているが、本発明化合物と構造が異なる。
　特許文献３～５には、本発明化合物と構造が類似した化合物が記載されているが、Ｎａｖ１．７阻害作用に関する記載も示唆もない。 Patent Documents 1 and 2 describe compounds having a Nav1.7 inhibitory action, but differ in structure from the compounds of the present invention.
Patent Documents 3 to 5 describe compounds having a structure similar to that of the compound of the present invention, but there is no description or suggestion regarding Nav1.7 inhibitory action.
国際公開第２０１０／０７９４４３号International Publication No. 2010/077943 国際公開第２０１２／００４７４３号International Publication No. 2012/004743 米国公開第２０１２／０１９６８６３号US Publication No. 2012/0196863 国際公開第２０１２／０９５５２１号International Publication No. 2012/095521 国際公開第２０１２／０９５４６９号International Publication No. 2012/095469
　本発明の目的は、Ｎａｖ１．７阻害作用を有する新規化合物およびＮａｖ１．７阻害作用を有する医薬組成物を提供することにある。 An object of the present invention is to provide a novel compound having a Nav1.7 inhibitory action and a pharmaceutical composition having a Nav1.7 inhibitory action.
　本発明は、以下の（１）～（１２）および（１’）～（８’）に関する。
（１）
　式（Ｉ）：
Figure JPOXMLDOC01-appb-I000002

（式中、
　Ｒ１は、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基；
　－Ｘ－は、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、－Ｓ－（Ｃ（Ｒ６a）（Ｒ６ｂ））ｑ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；
　Ｒ５aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ５ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ６aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ６ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ７は、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、または置換若しくは非置換のアルキルカルボニル；
　Ｒ８aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ８ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　ｐ、ｑおよびｒは、それぞれ独立して、０～５の整数；
　Ｒ２は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
　ｎは、０または１；
　－Ｙ－は、単結合、置換若しくは非置換のアルキレン、置換若しくは非置換のアルケニレン、または置換若しくは非置換のアルキニレン；
　Ｒ３は、水素原子、ハロゲン、カルバモイル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、または置換若しくは非置換の非芳香族複素環オキシ；
　Ｒ４は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
　ｍは、０～２の整数）
で示される化合物またはその製薬上許容される塩。 The present invention relates to the following (1) to (12) and (1 ′) to (8 ′).
(1)
Formula (I):
Figure JPOXMLDOC01-appb-I000002

(Where
R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group A heterocyclic group;
-X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 5b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 6a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 6b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 7 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkylcarbonyl;
Each R 8a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 8b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
p, q and r are each independently an integer of 0 to 5;
Each R 2 is independently halogen, hydroxy, carboxy, amino, carbamoyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino Or substituted or unsubstituted dialkylamino;
n is 0 or 1;
-Y- is a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
R 3 is a hydrogen atom, halogen, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted A non-aromatic carbocyclic oxy, a substituted or unsubstituted aromatic heterocyclic oxy, or a substituted or unsubstituted non-aromatic heterocyclic oxy;
Each R 4 independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, or substituted or Unsubstituted dialkylamino;
m is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.
（２）
　Ｒ１が、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基である、上記（１）記載の化合物またはその製薬上許容される塩。
（３）
　－Ｘ－が、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；ｐおよびｒが、それぞれ独立して、０または１；Ｒ５a、Ｒ５ｂ、Ｒ７、Ｒ８a、およびＲ８ｂが、上記（１）と同意義である、上記（１）または（２）に記載の化合物またはその製薬上許容される塩。
（４）
　－Ｘ－が、単結合、－Ｏ－（ＣＨ２）ｐ－、または－Ｎ（Ｈ）－（ＣＨ２）ｒ－であり；ｐおよびｒが、それぞれ独立して、０または１である、上記（１）または（２）に記載の化合物またはその製薬上許容される塩。 (2)
R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group according to (1) above A compound or a pharmaceutically acceptable salt thereof.
(3)
-X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, or -N (R 7 )-(C (R 8a ) (R 8b )) r-; p and r Wherein each independently represents 0 or 1; R 5a , R 5b , R 7 , R 8a , and R 8b are as defined in (1) above, Or a pharmaceutically acceptable salt thereof.
(4)
-X- is a single bond, -O- (CH 2 ) p-, or -N (H)-(CH 2 ) r-; p and r are each independently 0 or 1, The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof.
（５）
　ｎが、０である、上記（１）～（４）のいずれかに記載の化合物またはその製薬上許容される塩。
（６）
　－Ｙ－が、単結合、または置換若しくは非置換のアルキレンである、上記（１）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（７）
　Ｒ３が、水素原子、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、または置換若しくは非置換の芳香族炭素環オキシである、上記（１）～（６）のいずれかに記載の化合物またはその製薬上許容される塩。
（８）
　ｍが、０である、上記（１）～（７）のいずれかに記載の化合物またはその製薬上許容される塩。 (5)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein n is 0.
(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (5), wherein —Y— is a single bond or a substituted or unsubstituted alkylene.
(7)
R 3 is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group The compound according to any one of (1) to (6) above, which is a group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic oxy, or a pharmaceutically acceptable salt thereof Salt.
(8)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), wherein m is 0.
（１’）
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
（式中、　
　Ｒ１は、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基；
　－Ｘ－は、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、－Ｓ－（Ｃ（Ｒ６a）（Ｒ６ｂ））ｑ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；
　Ｒ５aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ５ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ６aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ６ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ７は、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、または置換若しくは非置換のアルキルカルボニル；
　Ｒ８aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　Ｒ８ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
　ｐ、ｑおよびｒは、それぞれ独立して、０～５の整数；
　Ｒ２は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
　ｎは、０または１；
　－Ｙ－は、単結合、置換若しくは非置換のアルキレン、置換若しくは非置換のアルケニレン、または置換若しくは非置換のアルキニレン；
　Ｒ３は、水素原子、ハロゲン、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、または置換若しくは非置換の非芳香族複素環オキシ；
　Ｒ４は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
　ｍは、０～２の整数）
で示される化合物またはその製薬上許容される塩。 (1 ')
Formula (I):
Figure JPOXMLDOC01-appb-C000003
(Where
R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group A heterocyclic group;
-X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 5b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 6a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 6b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 7 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkylcarbonyl;
Each R 8a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
Each R 8b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
p, q and r are each independently an integer of 0 to 5;
Each R 2 is independently halogen, hydroxy, carboxy, amino, carbamoyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino Or substituted or unsubstituted dialkylamino;
n is 0 or 1;
-Y- is a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
R 3 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-substituted Aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
Each R 4 independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, or substituted or Unsubstituted dialkylamino;
m is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.
（２’）
　Ｒ１が、置換若しくは非置換のフェニルである、上記（１’）記載の化合物またはその製薬上許容される塩。
（３’）
　－Ｘ－が、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；ｐおよびｒが、それぞれ独立して、０または１；Ｒ５a、Ｒ５ｂ、Ｒ７、Ｒ８a、およびＲ８ｂが、上記（１’）と同意義である、上記（１’）または（２’）に記載の化合物またはその製薬上許容される塩。
（４’）
　ｎが、０である、上記（１’）～（３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（５’）
　－Ｙ－が、置換若しくは非置換のメチレンである、上記（１’）～（４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（６’）
　Ｒ３が、置換若しくは非置換のフェニルである、上記（１’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（７’）
　ｍが、０である、上記（１’）～（６’）のいずれかに記載の化合物またはその製薬上許容される塩。 (2 ')
The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted or unsubstituted phenyl.
(3 ')
—X— is —O— (C (R 5a ) (R 5b )) p—, or —N (R 7 ) — (C (R 8a ) (R 8b )) r—; Independently 0 or 1; The compound according to (1 ′) or (2 ′) above, wherein R 5a , R 5b , R 7 , R 8a , and R 8b are as defined above (1 ′) Or a pharmaceutically acceptable salt thereof.
(4 ')
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (3 ′), wherein n is 0.
(5 ')
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (4 ′), wherein —Y— is substituted or unsubstituted methylene.
(6 ')
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (5 ′), wherein R 3 is substituted or unsubstituted phenyl.
(7 ')
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1 ′) to (6 ′), wherein m is 0.
（８’）
　式（ＩＩ’）：
Figure JPOXMLDOC01-appb-C000004
　（式中、
　Ｒ１は、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基；
　－Ｘ－は、単結合、－Ｏ－（ＣＨ２）ｐ－、または－Ｎ（Ｈ）－（ＣＨ２）ｒ－；
　ｐおよびｒは、それぞれ独立して、０または１
　－Ｙ－は、単結合、または置換若しくは非置換のアルキレン；
　Ｒ３は、水素原子、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基）
で示される化合物またはその製薬上許容される塩。
（９）
　上記（１）～（８）および（１’）～（８’）のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
（１０）
　Ｎａｖ１．７阻害作用を有する上記（９）記載の医薬組成物。
（１１）
　Ｎａｖ１．７が関与する疾患の治療および／または予防に使用するための、上記（１）～（８）および（１’）～（８’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１２）
　上記（１）～（８）および（１’）～（８’）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、Ｎａｖ１．７が関与する疾患の治療および／または予防方法。
(8 ')
Formula (II ′):
Figure JPOXMLDOC01-appb-C000004
(Where
R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
—X— represents a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—;
p and r are each independently 0 or 1
-Y- is a single bond or substituted or unsubstituted alkylene;
R 3 represents a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Group, or substituted or unsubstituted non-aromatic heterocyclic group)
Or a pharmaceutically acceptable salt thereof.
(9)
A pharmaceutical composition comprising the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof.
(10)
The pharmaceutical composition according to the above (9), which has a Nav1.7 inhibitory action.
(11)
The compound according to any one of the above (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving Nav1.7 Salt.
(12)
A disease associated with Nav1.7, comprising administering the compound according to any one of (1) to (8) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof. Treatment and / or prevention methods.
　本発明に係る化合物は、Ｎａｖ１．７に対する阻害作用を有し、Ｎａｖ１．７が関与する疾患または状態の治療剤および／または予防剤として有用である。 The compound according to the present invention has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for a disease or condition involving Nav1.7.
　以下に、本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、または他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。 The meaning of each term used in this specification is explained below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、およびヨウ素原子を包含する。特にフッ素原子、および塩素原子が好ましい。 “Halogen” includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　「アルキル」の態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに別の態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 “Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, 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, n-decyl and the like.
Examples of the “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Yet another embodiment includes methyl, ethyl, n-propyl, isopropyl, tert-butyl.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Examples of “alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。これらはさらに任意の位置に二重結合を有していてもよい。
　「アルキニル」の態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position.
Examples of “alkynyl” include ethynyl, propynyl, butynyl, pentynyl.
　「アルキレン」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレン、ヘキサメチレン等が挙げられる。 “Alkylene” is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
　「アルケニレン」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、ビニレン、プロペニレン、ブテニレン、ペンテニレン等が挙げられる。 The term “alkenylene” refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group. For example, vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
　「アルキニレン」とは、任意の位置に１以上の三重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。これらはさらに任意の位置に二重結合を有していてもよい。例えば、エチニレン、プロピニレン、ブチニレン、ペンチニレン、ヘキシニレン等が挙げられる。 “Alkynylene” refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position. A linear or branched divalent hydrocarbon group is included. These may further have a double bond at an arbitrary position. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
　「芳香族炭素環式基」とは、単環または２環以上の、環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
　「芳香族炭素環式基」の態様として、フェニルが挙げられる。 “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
Examples of the “aromatic carbocyclic group” include phenyl.
　「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000005
　単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
　２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000005
The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more 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.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。
　２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられる。
　２環の芳香族複素環式基としては、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。　３環以上の芳香族複素環式基としては、例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned. Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する５～７員非芳香族複素環式基、
　それらが独立して２個以上縮合した非芳香族複素環式基、
　Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する５～７員非芳香族複素環が、１以上の上記「芳香族炭素環式基」における環、上記「非芳香族炭素環式基」における環、もしくは上記「芳香族複素環式基」における環、と縮合した非芳香族複素環式基、または、
　上記「芳香族複素環式基」における環が、１以上の上記「非芳香族炭素環式基」における環と縮合した非芳香族複素環式基、
を包含する。
　さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000006
　単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル、等が挙げられる。
　２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル、ジヒドロベンゾフラン、ジヒドロベンゾジオキシン等が挙げられる。 “Non-aromatic heterocyclic group” means a 5- to 7-membered non-aromatic heterocyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring,
A non-aromatic heterocyclic group in which two or more of them are independently fused,
A 5- to 7-membered non-aromatic heterocycle having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring is one or more rings in the above “aromatic carbocyclic group”, A non-aromatic heterocyclic group fused with a ring in the “non-aromatic carbocyclic group”, or a ring in the “aromatic heterocyclic group”, or
A non-aromatic heterocyclic group in which the ring in the “aromatic heterocyclic group” is fused with one or more rings in the “non-aromatic carbocyclic group”;
Is included.
Furthermore, the “non-aromatic heterocyclic group” includes a group which forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000006
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Furyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl Aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thii Le, triazinyl, and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuran, dihydrobenzodioxin and the like.
　「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、へキシルオキシ等が挙げられる。
　「アルキルオキシ」の態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｔｅｒｔ－ブチルオキシが挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Examples of the “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
　「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。
例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom.
For example, vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like can be mentioned.
　「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。
例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
　「ハロアルキル」とは、１以上の上記「ハロゲン」が上記「アルキル」に結合した基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
　「ハロアルキル」の態様として、トリフルオロメチル、トリクロロメチルが挙げられる。 “Haloalkyl” means a group in which one or more of the above “halogens” are bonded to the above “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Examples of the “haloalkyl” include trifluoromethyl and trichloromethyl.
　「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
　「ハロアルキルオキシ」の態様として、トリフルオロメトキシ、トリクロロメトキシが挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Examples of the “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
　「アルキルオキシアルキル」とは、上記「アルキルオキシ」が上記「アルキル」に結合した基を意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル等が挙げられる。 “Alkyloxyalkyl” means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
　「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシ」が上記「アルキルオキシ」に結合した基を意味する。例えば、メトキシメトキシ、メトキシエトキシ、エトキシメトキシ、エトキシエトキシ等が挙げられる。 “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
　「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。
　「アルキルカルボニル」の態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
Examples of the “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
　「モノアルキルアミノ」とは、上記「アルキル」が、アミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルアミノ、エチルアミノ、イソプロピルアミノ等が挙げられる。
　「モノアルキルアミノ」の態様として、メチルアミノ、エチルアミノが挙げられる。 “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
Examples of the “monoalkylamino” include methylamino and ethylamino.
　「ジアルキルアミノ」とは、上記「アルキル」が、アミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルアミノ、ジエチルアミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、Ｎ－イソプロピル－Ｎ－エチルアミノ等が挙げられる。
　「ジアルキルアミノ」の態様として、ジメチルアミノ、ジエチルアミノが挙げられる。 “Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
Examples of the “dialkylamino” include dimethylamino and diethylamino.
　「ジアルキルアミノアルキル」とは、上記「アルキル」が上記「ジアルキルアミノ」の窒素原子で置換された基を意味する。例えば、ジメチルアミノアルキル、ジエチルアミノアルキル、Ｎ，Ｎ－ジイソプロピルアミノアルキル、Ｎ－メチル－Ｎ－エチルアミノアルキル、Ｎ－イソプロピル－Ｎ－エチルアミノアルキル等が挙げられる。
　「ジアルキルアミノアルキル」の態様として、ジメチルアミノアルキル、ジエチルアミノアルキルが挙げられる。 The “dialkylaminoalkyl” means a group in which the “alkyl” is substituted with the nitrogen atom of the “dialkylamino”. Examples thereof include dimethylaminoalkyl, diethylaminoalkyl, N, N-diisopropylaminoalkyl, N-methyl-N-ethylaminoalkyl, N-isopropyl-N-ethylaminoalkyl and the like.
Examples of the “dialkylaminoalkyl” include dimethylaminoalkyl and diethylaminoalkyl.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
　「アルキルスルホニル」の態様として、メチルスルホニル、エチルスルホニルが挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Examples of the “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
　「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「モノアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルボニルアミノ、エチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ等が挙げられる。
　「モノアルキルカルボニルアミノ」の態様としては、メチルカルボニルアミノ、エチルカルボニルアミノが挙げられる。 “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
Examples of the “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
　「ジアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルカルボニル基は、同一でも異なっていてもよい。例えば、ジメチルカルボニルアミノ、ジエチルカルボニルアミノ、Ｎ，Ｎ－ジイソプロピルカルボニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の態様として、ジメチルカルボニルアミノ、ジエチルカルボニルアミノが挙げられる。 “Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
Examples of the “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
　「モノアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ等が挙げられる。
　「モノアルキルスルホニルアミノ」の態様としては、メチルスルホニルアミノ、エチルスルホニルアミノが挙げられる。 “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like.
Examples of the “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
　「ジアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルスルホニル基は、同一でも異なっていてもよい。例えば、ジメチルスルホニルアミノ、ジエチルスルホニルアミノ、Ｎ，Ｎ－ジイソプロピルスルホニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の態様として、ジメチルスルホニルアミノ、ジエチルスルホニルアミノが挙げられる。 “Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
Examples of the “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
　「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
　「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
　「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
　「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
　「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。
　「アルキルカルボニルオキシ」の態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
Examples of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
　「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
　「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
　「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。例えば、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、へキシルオキシカルボニル等が挙げられる。
　「アルキルオキシカルボニル」の態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
Examples of the “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
　「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
　「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
　「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル等が挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
　「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルスルファニル、プロペニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
　「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルスルファニル、プロピニルスルファニル等が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
　「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル基に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
　「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
　「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。例えば、エチニルスルフィニル、プロピニルスルフィニル等が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
　「モノアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルバモイル、エチルカルバモイル等が挙げられる。 “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
　「ジアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「モノアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルファモイル、ジメチルスルファモイル等が挙げられる。 “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
　「ジアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「トリアルキルシリル」とは、上記「アルキル」３個がケイ素原子に結合している基を意味する。３個のアルキルは同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げられる。 “Trialkylsilyl” means a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
　「芳香族炭素環アルキル」、「非芳香族炭素環アルキル」、「芳香族複素環アルキル」、および「非芳香族複素環アルキル」、
「芳香族炭素環アルキルオキシ」、「非芳香族炭素環アルキルオキシ」、「芳香族複素環アルキルオキシ」、および「非芳香族複素環アルキルオキシ」、
「芳香族炭素環アルキルオキシカルボニル」、「非芳香族炭素環アルキルオキシカルボニル」、「芳香族複素環アルキルオキシカルボニル」、および「非芳香族複素環アルキルオキシカルボニル」、
「芳香族炭素環アルキルオキシアルキル」、「非芳香族炭素環アルキルオキシアルキル」、「芳香族複素環アルキルオキシアルキル」、および「非芳香族複素環アルキルオキシアルキル」、ならびに
「芳香族炭素環アルキルアミノ」、「非芳香族炭素環アルキルアミノ」、「芳香族複素環アルキルアミノ」、および「非芳香族複素環アルキルアミノ」のアルキル部分も、上記「アルキル」と同様である。 “Aromatic carbocyclic alkyl”, “non-aromatic carbocyclic alkyl”, “aromatic heterocyclic alkyl”, and “non-aromatic heterocyclic alkyl”,
“Aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, and “non-aromatic heterocyclic alkyloxy”,
“Aromatic carbocyclic alkyloxycarbonyl”, “non-aromatic carbocyclic alkyloxycarbonyl”, “aromatic heterocyclic alkyloxycarbonyl”, and “non-aromatic heterocyclic alkyloxycarbonyl”,
“Aromatic carbocyclic alkyloxyalkyl”, “non-aromatic carbocyclic alkyloxyalkyl”, “aromatic heterocyclic alkyloxyalkyl”, and “non-aromatic heterocyclic alkyloxyalkyl”, and “aromatic carbocyclic alkyl” The alkyl part of “amino”, “non-aromatic carbocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “nonaromatic heterocyclic alkylamino” is the same as the above “alkyl”.
　「芳香族炭素環アルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルを意味する。例えば、ベンジル、フェネチル、フェニルプロピニル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000007
等が挙げられる。
　「芳香族炭素環アルキル」の態様としては、ベンジル、フェネチル、ベンズヒドリルが挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000007
Etc.
Examples of the “aromatic carbocyclic alkyl” include benzyl, phenethyl, and benzhydryl.
　「非芳香族炭素環アルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルを意味する。また、「非芳香族炭素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロへキシルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000008
等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000008
Etc.
　「芳香族複素環アルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルを意味する。また、「芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000009
等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000009
Etc.
　「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルを意味する。また、「非芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000010
等が挙げられる。 The “non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl part is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000010
Etc.
　「芳香族炭素環アルキルオキシ」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピニルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000011
等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000011
Etc.
　「非芳香族炭素環アルキルオキシ」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族炭素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロへキシルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000012
等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000012
Etc.
　「芳香族複素環アルキルオキシ」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、フラニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、オキサゾリルメチルオキシ、イソキサゾリルメチルオキシ、チアゾリルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000013
等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000013
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000014
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000014
Etc.
　「芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、フェニルプロピニルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000015
等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000015
Etc.
　「非芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族炭素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシカルボニル」も包含する。例えば、シクロプロピルメチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロへキシルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000016
等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000016
Etc.
　「芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000017
等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000017
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000018
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000018
Etc.
　「芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピニルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000019
等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000019
Etc.
　「非芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族炭素環アルキルオキシアルキル」は、非芳香族炭素環が結合しているアルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000020
等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000020
Etc.
　「芳香族複素環アルキルオキシアルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「芳香族複素環アルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000021
等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000021
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族複素環アルキルオキシ」は、非芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000022
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxy” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”. Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000022
Etc.
　「芳香族炭素環アルキルアミノ」とは、上記「芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ベンジルアミノ、フェネチルアミノ、フェニルプロピニルアミノ、ベンズヒドリルアミノ、トリチルアミノ、ナフチルメチルアミノ、ジベンジルアミノ等が挙げられる。 “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
　「非芳香族炭素環アルキルアミノ」とは、上記「非芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルメチルアミノ、シクロブチルメチルアミノ、シクロペンチルメチルアミノ、シクロへキシルメチルアミノ等が挙げられる。 “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
　「芳香族複素環アルキルアミノ」とは、上記「芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルメチルアミノ、フラニルメチルアミノ、イミダゾリルメチルアミノ、インドリルメチルアミノ、ベンゾチオフェニルメチルアミノ、オキサゾリルメチルアミノ、イソキサゾリルメチルアミノ、チアゾリルメチルアミノ、イソチアゾリルメチルアミノ、ピラゾリルメチルアミノ、イソピラゾリルメチルアミノ、ピロリジニルメチルアミノ、ベンズオキサゾリルメチルアミノ等が挙げられる。 “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
　「非芳香族複素環アルキルアミノ」とは、上記「非芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、テトラヒドロピラニルメチルアミノ、モルホリニルエチルアミノ、ピペリジニルメチルアミノ、ピペラジニルメチルアミノ等が挙げられる。 “Non-aromatic heterocyclic alkylamino” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
　「芳香族炭素環オキシ」、「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルファニル」、および「芳香族炭素環スルホニル」の「芳香族炭素環」部分も、上記「芳香族炭素環式基」と同様である。
　「芳香族炭素環オキシ」とは、「芳香族炭素環」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。
　「芳香族炭素環カルボニル」とは、「芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、フェニルカルボニル、ナフチルカルボニル等が挙げられる。
　「芳香族炭素環オキシカルボニル」とは、上記「芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。
　「芳香族炭素環スルファニル」とは、「芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。
　「芳香族炭素環スルホニル」とは、「芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 The “aromatic carbocyclic oxy”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic sulfanyl”, and “aromatic carbocyclic sulfonyl” moieties also include The same as the above “aromatic carbocyclic group”.
“Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
“Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
“Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
“Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
“Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
　「非芳香族炭素環オキシ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルファニル」、および「非芳香族炭素環スルホニル」の「非芳香族炭素環」部分も、上記「非芳香族炭素環式基」と同様である。
　「非芳香族炭素環オキシ」とは、「非芳香族炭素環」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロヘキシルオキシ、シクロへキセニルオキシ等が挙げられる。
　「非芳香族炭素環カルボニル」とは、「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロへキセニルカルボニル等が挙げられる。
　「非芳香族炭素環オキシカルボニル」とは、上記「非芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロへキセニルオキシカルボニル等が挙げられる。
　「非芳香族炭素環スルファニル」とは、「非芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロヘキシルスルファニル、シクロヘキセニルスルファニル等が挙げられる。
　「非芳香族炭素環スルホニル」とは、「非芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。 “Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl” The “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
“Non-aromatic carbocyclic oxy” means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
“Non-aromatic carbocycle carbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
“Non-aromatic carbocyclic sulfanyl” means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like can be mentioned.
“Non-aromatic carbocycle sulfonyl” means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like.
　「芳香族複素環オキシ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルファニル」、および「芳香族複素環スルホニル」の「芳香族複素環」部分も、上記「芳香族複素環式基」と同様である。
　「芳香族複素環オキシ」とは、「芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。
　「芳香族複素環カルボニル」とは、「芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピリジルカルボニル、オキサゾリルカルボニル等が挙げられる。
　「芳香族複素環オキシカルボニル」とは、上記「芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。
　「芳香族複素環スルファニル」とは、「芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。
　「芳香族複素環スルホニル」とは、「芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。 The “aromatic heterocycle” moiety of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl” The same as the above “aromatic heterocyclic group”.
“Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
“Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
“Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
“Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
“Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
　「非芳香族複素環オキシ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルファニル」、および「非芳香族複素環スルホニル」の「非芳香族複素環」部分も、上記「非芳香族複素環式基」と同様である。
　「非芳香族複素環オキシ」とは、「非芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピペリジニルオキシ、テトラヒドロフリルオキシ等が挙げられる。
　「非芳香族複素環カルボニル」とは、「非芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピペリジニルカルボニル、テトラヒドロフリルカルボニル等が挙げられる。
　「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。
　「非芳香族複素環スルファニル」とは、「非芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピペリジニルスルファニル、テトラヒドロフリルスルファニル等が挙げられる。
　「非芳香族複素環スルホニル」とは、「非芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 “Non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic sulfanyl”, and “non-aromatic heterocyclic sulfonyl” The “heterocyclic ring” moiety is the same as the above “non-aromatic heterocyclic group”.
“Non-aromatic heterocyclic oxy” means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
“Non-aromatic heterocyclic carbonyl” means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” means a group in which the above “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfanyl” means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfonyl” means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
　「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルキルオキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキニルオキシ」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキニルカルボニル」、「置換若しくは非置換のモノアルキルアミノ」、「置換若しくは非置換のジアルキルアミノ」、「置換若しくは非置換のアルキルスルホニル」、「置換若しくは非置換のアルケニルスルホニル」、「置換若しくは非置換のアルキニルスルホニル」、「置換若しくは非置換のモノアルキルカルボニルアミノ」、「置換若しくは非置換のジアルキルカルボニルアミノ」、「置換若しくは非置換のモノアルキルスルホニルアミノ」、「置換若しくは非置換のジアルキルスルホニルアミノ」、「置換若しくは非置換のアルキルイミノ」、「置換若しくは非置換のアルケニルイミノ」、「置換若しくは非置換のアルキニルイミノ」、「置換若しくは非置換のアルキルカルボニルイミノ」、「置換若しくは非置換のアルケニルカルボニルイミノ」、「置換若しくは非置換のアルキニルカルボニルイミノ」、「置換若しくは非置換のアルキルオキシイミノ」、「置換若しくは非置換のアルケニルオキシイミノ」、「置換若しくは非置換のアルキニルオキシイミノ」、「置換若しくは非置換のアルキルカルボニルオキシ」、「置換若しくは非置換のアルケニルカルボニルオキシ」、「置換若しくは非置換のアルキニルカルボニルオキシ」、「置換若しくは非置換のアルキルオキシカルボニル」、「置換若しくは非置換のアルケニルオキシカルボニル」、「置換若しくは非置換のアルキニルオキシカルボニル」、「置換若しくは非置換のアルキルスルファニル」、「置換若しくは非置換のアルケニルスルファニル」、「置換若しくは非置換のアルキニルスルファニル」、「置換若しくは非置換のアルキルスルフィニル」、「置換若しくは非置換のアルケニルスルフィニル」、「置換若しくは非置換のアルキニルスルフィニル」、「置換若しくは非置換のモノアルキルカルバモイル」、「置換若しくは非置換のジアルキルカルバモイル」、「置換若しくは非置換のモノアルキルスルファモイル」、「置換若しくは非置換のアルキレン」、「置換若しくは非置換のアルケニレン」、「置換若しくは非置換のアルキニレン」、「置換若しくは非置換のメチレン」および「置換若しくは非置換のジアルキルスルファモイル」の置換基としては、次の置換基が挙げられる。任意の位置の炭素原子が次の置換基から選択される１以上の基と結合していてもよい。
　置換基：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or "Unsubstituted alkynyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted monoalkylamino", "substituted Or “unsubstituted dialkylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted monoalkylcarbonylamino”, "Substituted or unsubstituted di- ”Alkylcarbonylamino”, “substituted or unsubstituted monoalkylsulfonylamino”, “substituted or unsubstituted dialkylsulfonylamino”, “substituted or unsubstituted alkylimino”, “substituted or unsubstituted alkenylimino”, “substituted” Or “unsubstituted alkynylimino”, “substituted or unsubstituted alkylcarbonylimino”, “substituted or unsubstituted alkenylcarbonylimino”, “substituted or unsubstituted alkynylcarbonylimino”, “substituted or unsubstituted alkyloxyimino” , “Substituted or unsubstituted alkenyloxyimino”, “substituted or unsubstituted alkynyloxyimino”, “substituted or unsubstituted alkylcarbonyloxy”, “substituted or unsubstituted alkenylcarbonyloxy”, “substituted Is “unsubstituted alkynylcarbonyloxy”, “substituted or unsubstituted alkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”, “substituted or unsubstituted alkynyloxycarbonyl”, “substituted or unsubstituted alkylsulfanyl” ”,“ Substituted or unsubstituted alkenylsulfanyl ”,“ substituted or unsubstituted alkynylsulfanyl ”,“ substituted or unsubstituted alkylsulfinyl ”,“ substituted or unsubstituted alkenylsulfinyl ”,“ substituted or unsubstituted alkynylsulfinyl ” ”,“ Substituted or unsubstituted monoalkylcarbamoyl ”,“ substituted or unsubstituted dialkylcarbamoyl ”,“ substituted or unsubstituted monoalkylsulfamoyl ”,“ substituted or unsubstituted alkylene ”,“ Examples of the substituents of “substituted or unsubstituted alkenylene”, “substituted or unsubstituted alkynylene”, “substituted or unsubstituted methylene” and “substituted or unsubstituted dialkylsulfamoyl” include the following substituents: . The carbon atom at any position may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynyl Sulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonyl Mino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy , Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic Group carbocyclic group, Aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic Carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic hetero Ring oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl , Aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino, non-aromatic Aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic Aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
　「置換若しくは非置換の芳香族炭素環式基」、「置換若しくは非置換の非芳香族炭素環式基」、「置換若しくは非置換の芳香族複素環式基」、および「置換若しくは非置換の非芳香族複素環式基」、「置換若しくは非置換の単環芳香族炭素環式基」、「置換若しくは非置換の単環非芳香族炭素環式基」、「置換若しくは非置換の単環芳香族複素環式基」、および「置換若しくは非置換の単環非芳香族複素環式基」、
「置換若しくは非置換のフェニル」、「置換若しくは非置換のピリジル」、「置換若しくは非置換のチエニル」、「置換若しくは非置換のピロリジニル」、「置換若しくは非置換のピペリジニル」、「置換若しくは非置換のシクロヘキシル」、「置換若しくは非置換のチアゾリル」、「置換若しくは非置換のベンゾチアゾリル」、「置換若しくは非置換のテトラヒドロピラニル」、
「置換若しくは非置換の芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の芳香族複素環オキシ」、および「置換若しくは非置換の非芳香族複素環オキシ」、
「置換若しくは非置換のフェノキシ」、
「置換若しくは非置換の芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の芳香族複素環カルボニル」、および「置換若しくは非置換の非芳香族複素環カルボニル」、
「置換若しくは非置換の芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の芳香族複素環オキシカルボニル」、および「置換若しくは非置換の非芳香族複素環オキシカルボニル」、
「置換若しくは非置換の芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の芳香族複素環スルファニル」、および「置換若しくは非置換の非芳香族複素環スルファニル」、ならびに
「置換若しくは非置換の芳香族炭素環スルホニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、「置換若しくは非置換の芳香族複素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」の「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、および「非芳香族複素環」の環上の置換基としては、次の置換基が挙げられる。環上の任意の位置の原子が次の置換基から選択される１以上の基と結合していてもよい。
　置換基：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、ジアルキルアミノアルキル、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “Substituted or unsubstituted aromatic carbocyclic group”, “Substituted or unsubstituted nonaromatic carbocyclic group”, “Substituted or unsubstituted aromatic heterocyclic group”, and “Substituted or unsubstituted aromatic carbocyclic group” "Non-aromatic heterocyclic group", "substituted or unsubstituted monocyclic aromatic carbocyclic group", "substituted or unsubstituted monocyclic non-aromatic carbocyclic group", "substituted or unsubstituted monocyclic "Aromatic heterocyclic group", and "substituted or unsubstituted monocyclic non-aromatic heterocyclic group",
"Substituted or unsubstituted phenyl", "Substituted or unsubstituted pyridyl", "Substituted or unsubstituted thienyl", "Substituted or unsubstituted pyrrolidinyl", "Substituted or unsubstituted piperidinyl", "Substituted or unsubstituted Cyclohexyl ”,“ substituted or unsubstituted thiazolyl ”,“ substituted or unsubstituted benzothiazolyl ”,“ substituted or unsubstituted tetrahydropyranyl ”,
"Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", and "Substituted or unsubstituted non-aromatic Heterocyclic oxy ",
“Substituted or unsubstituted phenoxy”,
"Substituted or unsubstituted aromatic carbocyclic carbonyl", "Substituted or unsubstituted non-aromatic carbocyclic carbonyl", "Substituted or unsubstituted aromatic heterocyclic carbonyl", and "Substituted or unsubstituted non-aromatic Heterocyclic carbonyl ",
“Substituted or unsubstituted aromatic carbocyclic oxycarbonyl”, “substituted or unsubstituted nonaromatic carbocyclic oxycarbonyl”, “substituted or unsubstituted aromatic heterocyclic oxycarbonyl”, and “substituted or unsubstituted Non-aromatic heterocyclic oxycarbonyl ",
"Substituted or unsubstituted aromatic carbocyclic sulfanyl", "Substituted or unsubstituted non-aromatic carbocyclic sulfanyl", "Substituted or unsubstituted aromatic heterocyclic sulfanyl", and "Substituted or unsubstituted non-aromatic "Heterocyclic sulfanyl", and "substituted or unsubstituted aromatic carbocyclic sulfonyl", "substituted or unsubstituted non-aromatic carbocyclic sulfonyl", "substituted or unsubstituted aromatic heterocyclic sulfonyl", and "substituted or Substituents on the rings of “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of “unsubstituted non-aromatic heterocycle sulfonyl” include The following substituents are mentioned. An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, Alkynylcarbonyl, monoalkylamino, dialkylamino, dialkylaminoalkyl, alkylsulfonyl Alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, Alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl , Monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, Aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic Carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl , Non-aromatic heterocyclic alkyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy Si, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxy Alkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, Non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic hetero Ring sulfonyl and non-aromatic heterocyclic sulfonyl
　また、「置換若しくは非置換の非芳香族炭素環式基」および「置換若しくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の２個の水素原子が置換されている基を意味する。
Figure JPOXMLDOC01-appb-C000023
 Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
Figure JPOXMLDOC01-appb-C000023
　上記、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族複素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」の非芳香族炭素環、および非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい
The above-mentioned “substituted or unsubstituted non-aromatic carbocyclic oxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted "Non-aromatic heterocyclic carbonyl", "substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl", "substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl", "substituted or unsubstituted non-aromatic carbocyclic sulfanyl" , "Substituted or unsubstituted non-aromatic heterocyclic sulfanyl", "substituted or unsubstituted non-aromatic carbocyclic sulfonyl", and "substituted or unsubstituted non-aromatic heterocyclic sulfonyl" non-aromatic carbocycle , And the non-aromatic heterocyclic moiety may be substituted with “oxo” in the same manner as described above.
　本発明の好ましい態様として、以下の化合物またはその製薬上許容される塩が挙げられる。
　式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000024
（式中、Ｒ１、－Ｘ－、Ｒ２、ｎ、－Ｙ－、Ｒ３、Ｒ４、およびｍは上記（１）と同意義）で示される化合物またはその製薬上許容される塩。 Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
Formula (II):
Figure JPOXMLDOC01-appb-C000024
(Wherein R 1 , —X—, R 2 , n, —Y—, R 3 , R 4 , and m are as defined above (1)) or a pharmaceutically acceptable salt thereof.
　式（ＩＩＩ）：
Figure JPOXMLDOC01-appb-C000025
（式中、Ｒ１、－Ｘ－、－Ｙ－、Ｒ３、Ｒ４、およびｍは上記（１）と同意義）で示される化合物またはその製薬上許容される塩。 Formula (III):
Figure JPOXMLDOC01-appb-C000025
(Wherein R 1 , —X—, —Y—, R 3 , R 4 , and m are as defined above (1)) or a pharmaceutically acceptable salt thereof.
　式（ＩＶ）：
Figure JPOXMLDOC01-appb-C000026
（式中、Ｒ１、－Ｘ－、Ｒ２、ｎ、－Ｙ－、Ｒ３、Ｒ４、およびｍは上記（１）と同意義）で示される化合物またはその製薬上許容される塩。 Formula (IV):
Figure JPOXMLDOC01-appb-C000026
(Wherein R 1 , —X—, R 2 , n, —Y—, R 3 , R 4 , and m are as defined above (1)) or a pharmaceutically acceptable salt thereof.
　式（Ｖ）：
Figure JPOXMLDOC01-appb-C000027
（式中、Ｒ１、－Ｘ－、Ｒ２、ｎ、－Ｙ－、Ｒ３、Ｒ４、およびｍは上記（１）と同意義）で示される化合物またはその製薬上許容される塩。 Formula (V):
Figure JPOXMLDOC01-appb-C000027
(Wherein R 1 , —X—, R 2 , n, —Y—, R 3 , R 4 , and m are as defined above (1)) or a pharmaceutically acceptable salt thereof.
　式（Ｉ）、式（ＩＩ）、式（ＩＩＩ）、式（ＩＶ）または式（Ｖ）で示される化合物またはその製薬上許容される塩における、各置換基の具体例を以下に示す。
　Ｒ１としては、置換若しくは非置換の単環芳香族炭素環式基、置換若しくは非置換の単環非芳香族炭素環式基、置換若しくは非置換の単環芳香族複素環式基、または置換若しくは非置換の単環非芳香族複素環式基が挙げられる。
　Ｒ１としては、置換若しくは非置換のフェニル、置換若しくは非置換のピリジル、置換若しくは非置換のチエニル、置換若しくは非置換のピロリジニル、置換若しくは非置換のピペリジル、または置換若しくは非置換のシクロヘキシルが挙げられる。
　Ｒ１としては、置換若しくは非置換のフェニルが挙げられる。 Specific examples of each substituent in the compound represented by the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) or a pharmaceutically acceptable salt thereof are shown below.
R 1 is a substituted or unsubstituted monocyclic aromatic carbocyclic group, a substituted or unsubstituted monocyclic nonaromatic carbocyclic group, a substituted or unsubstituted monocyclic aromatic heterocyclic group, or a substituted group Or an unsubstituted monocyclic non-aromatic heterocyclic group is mentioned.
R 1 includes substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, or substituted or unsubstituted cyclohexyl. .
Examples of R 1 include substituted or unsubstituted phenyl.
　－Ｘ－としては、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－が挙げられる。
　－Ｘ－としては、単結合、－Ｏ－（ＣＨ２）ｐ－、または－Ｎ（Ｈ）－（ＣＨ２）ｒ－が挙げられる。
　－Ｘ－としては、単結合、または－Ｏ－（ＣＨ２）ｐ－が挙げられる。 —X— includes a single bond, —O— (C (R 5a ) (R 5b )) p—, or —N (R 7 ) — (C (R 8a ) (R 8b )) r—. .
Examples of —X— include a single bond, —O— (CH 2 ) p—, or —N (H) — (CH 2 ) r—.
Examples of —X— include a single bond and —O— (CH 2 ) p—.
　ｐ、ｑおよびｒは、それぞれ独立して、０または１が挙げられる。
　ｐ、ｑおよびｒとしては、０が挙げられる。 p, q, and r are each independently 0 or 1.
Examples of p, q and r include 0.
　Ｒ５aとしては、それぞれ独立して、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ５ｂとしては、それぞれ独立して、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ６aとしては、それぞれ独立して、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ６ｂとしては、それぞれ独立して、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ７としては、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ８aとしては、水素原子、または置換若しくは非置換のアルキルが挙げられる。
　Ｒ８ｂとしては、水素原子、または置換若しくは非置換のアルキルが挙げられる。 R 5a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
Examples of R 5b include independently a hydrogen atom or substituted or unsubstituted alkyl.
R 6a is independently a hydrogen atom, or substituted or unsubstituted alkyl.
Examples of R 6b include independently a hydrogen atom or substituted or unsubstituted alkyl.
R 7 includes a hydrogen atom, or substituted or unsubstituted alkyl.
R 8a includes a hydrogen atom or substituted or unsubstituted alkyl.
R 8b includes a hydrogen atom, or substituted or unsubstituted alkyl.
　－Ｙ－としては、単結合、または置換若しくは非置換のアルキレンが挙げられる。
　Ｒ３としては、水素原子、ハロゲン、カルバモイル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、または置換若しくは非置換の非芳香族複素環オキシが挙げられる。
　Ｒ３としては、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、または置換若しくは非置換の非芳香族複素環オキシが挙げられる。
　Ｒ３としては、置換若しくは非置換のフェニル、置換若しくは非置換のシクロヘキシル、置換若しくは非置換のピリジル、置換若しくは非置換のチアゾリル、置換若しくは非置換のベンゾチアゾリル、置換若しくは非置換のテトラヒドロピラニル、置換若しくは非置換のフェノキシが挙げられる。
　Ｒ３としては、置換若しくは非置換のフェニルが挙げられる。 —Y— includes a single bond or a substituted or unsubstituted alkylene.
R 3 is a hydrogen atom, halogen, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Examples include substituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy.
R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic group Heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic ring Oxy is mentioned.
R 3 includes substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted tetrahydropyranyl, substituted Or an unsubstituted phenoxy is mentioned.
R 3 includes substituted or unsubstituted phenyl.
　ｎとしては、０が挙げられる。
　ｍとしては、０または１が挙げられる。
　ｍとしては、０が挙げられる。 n may be 0.
As m, 0 or 1 is mentioned.
m may be 0.
　また、式（Ｉ）、式（ＩＩ）、式（ＩＩＩ）、式（ＩＶ）または式（Ｖ）で示される化合物またはその製薬上許容される塩としては、上記で示した各置換基の定義の一部または全部の組み合わせにより生じる化合物またはその製薬上許容される塩が挙げられる。 Further, the compound represented by the formula (I), the formula (II), the formula (III), the formula (IV) or the formula (V) or a pharmaceutically acceptable salt thereof is defined as each substituent shown above. Or a pharmaceutically acceptable salt thereof.
　式（Ｉ）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。例えば、式（Ｉ）において「－Ｙ－Ｒ６」基が水素である化合物は、以下のような互変異性体を包含する。
Figure JPOXMLDOC01-appb-C000028
 The compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof. For example, in the formula (I), the compound in which the “—Y—R 6 ” group is hydrogen includes the following tautomers.
Figure JPOXMLDOC01-appb-C000028
　式（Ｉ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
　式（Ｉ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document 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 raw materials having 14 C carbon.
　式（Ｉ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph. Various solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　式（Ｉ）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3- , PhSO 3- , p-CH 3 PhSO 3 -can be mentioned.
　上記一般式（Ｉ）で表される化合物は、Ｎａｖ１．７に対する阻害作用を有し、Ｎａｖ１．７が関与する疾患および／または状態の治療剤および／または予防剤として有用である。Ｎａｖ１．７は、疼痛に関与すると考えられており（非特許文献６～８等）、Ｎａｖ１．７が関与する疾患および／または状態として、例えば、急性疼痛、慢性疼痛、神経障害性疼痛、炎症性痛覚、内臓痛、術後疼痛を含む侵害受容性疼痛、内臓、消化管、頭蓋部、筋骨格系、脊椎、泌尿生殖器系、心血管系および中枢神経系に関連する癌性疼痛、ならびに背部痛および口腔顔面痛を含む複合的な痛みのタイプが挙げられる。 The compound represented by the above general formula (I) has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions involving Nav1.7. Nav1.7 is considered to be involved in pain (Non-Patent Documents 6 to 8 etc.), and as diseases and / or conditions in which Nav1.7 is involved, for example, acute pain, chronic pain, neuropathic pain, inflammation Pain, visceral pain, nociceptive pain, including postoperative pain, visceral, gastrointestinal tract, skull, musculoskeletal system, spine, genitourinary system, cardiovascular and central nervous system cancer pain, and back There are multiple types of pain including pain and orofacial pain.
　より好ましい本発明化合物は、選択的なＮａｖ１．７阻害作用を有する医薬組成物である。特に、サブタイプ非特異的ナトリウムチャネル阻害剤であるリドカインやメキシレチンは、心筋に発現するＮａｖ１．５に対しても抑制作用を示すことが知られており(非特許文献１０および１１)、生命維持において特に重要である心臓機能に影響を与え得るという安全性の懸念を有する。このため、特にＮａｖ１．５阻害に対するＮａｖ１．７阻害選択性を確保することが期待される。 A more preferred compound of the present invention is a pharmaceutical composition having a selective Nav1.7 inhibitory action. In particular, it is known that lidocaine and mexiletine, which are subtype non-specific sodium channel inhibitors, also show an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11). Have safety concerns that can affect cardiac function, which is particularly important in For this reason, it is expected to ensure Nav1.7 inhibition selectivity especially for Nav1.5 inhibition.
（本発明の化合物の製造法）
　本発明に係る式（Ｉ）で示される化合物は、例えば、下記に示す一般的合成法によって製造することができる。これら合成に用いる出発物質および反応試薬はいずれも、商業的に入手可能であるか、または商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。また、抽出、精製等は、通常の有機化学の実験で行う処理を行えばよい。
　本発明の化合物の合成は、当該分野において公知の手法を参酌しながら実施することができる。
　下記すべての工程において、反応の障害となる置換基（例えば、ヒドロキシ、メルカプト、アミノ、ホルミル、カルボニル、カルボキシル等）を有する場合には、Protective　Groups　in　Organic　Synthesis,　Theodora　W　Greene(John　Wiley　&　Sons)等に記載の方法で予め保護し、望ましい段階でその保護基を除去すればよい。
　また、下記すべての工程について、実施する工程の順序を適宜変更することができ、各中間体を単離して次の工程に用いてもよい。 (Method for producing the compound of the present invention)
The compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons) when all of the following steps have substituents that interfere with the reaction (eg, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.) Or the like, and the protecting group may be removed at a desired stage.
Moreover, about all the following processes, the order of the process to implement can be changed suitably, and each intermediate body may be isolated and used for the following process.
［Ａ法］
Figure JPOXMLDOC01-appb-C000029
（式中、Ｈａｌはハロゲンであり；Ｌｇ１は脱離基であり；ＲＡおよびＲＢは、それぞれ独立して、水素、もしくは置換若しくは非置換のアルキルであるか、または一緒になって置換若しくは非置換の非芳香族複素環を形成する；Ｒ４ａは、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノであり；ｍ１は、０～２の整数であり；Ｒ１、Ｒ２、Ｒ３、－Ｘ－、および－Ｙ－は、上記（１）と同意義である。）

工程１
　化合物Ａ１に、縮合剤の存在下、化合物Ａ２を反応させることにより、化合物Ａ３を得ることができる。
　縮合剤としては、ジシクロへキシルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド－Ｎ－ヒドロキシベンゾトリアゾール、ＥＤＣ、４－（４，　６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＨＡＴＵ等が挙げられ、化合物Ａ１に対して１～５モル当量用いることができる。
　反応温度は、－２０℃～６０℃、好ましくは０℃～３０℃である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、ジクロロメタン、アセトニトリル等が挙げられ、単独または混合して用いることができる。

工程２
　化合物Ａ３に、塩基を加えることにより、化合物Ａ４を得ることが出来る。
　塩基としては、カリウムｔｅｒｔ―ブトキシド、ナトリウムｔｅｒｔ―ブトキシド、水素化ナトリウム、水酸化ナトリウム、リチウムヘキサメチルジシラザン、リチウムジイソプロピルアミド、炭酸セシウム、リン酸３カリウム、等が挙げられ、化合物Ａ３に対して１～５モル当量用いることが出来る。
　反応温度は、－２０℃～６０℃、好ましくは０℃～３０℃である。
　反応時間は、０．１時間～２４時間、好ましくは０．５時間～６時間である。
　反応溶媒としては、ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。

工程３
　化合物Ａ４に、脱離基を有する化合物Ａ５、および塩基を作用させることにより、化合物Ａ６を得ることが出来る。
　脱離基としては、クロロ、ブロモ、ヨウ素、メタンスルホニル、４－トルエンスルホニル、トリフルオロメタンスルホニル等が挙げられる。
　塩基としては、カリウムｔｅｒｔ―ブトキシド、ナトリウムｔｅｒｔ―ブトキシド、水素化ナトリウム、水酸化ナトリウム、リチウムヘキサメチルジシラザン、リチウムジイソプロピルアミド、炭酸セシウム、リン酸３カリウム、等が挙げられ、化合物Ａ４に対して１～５モル当量用いることが出来る。
　反応温度は、－２０℃～６０℃、好ましくは０℃～３０℃である。
　反応時間は、０．１時間～２４時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。

工程４
　金属触媒および塩基存在下、化合物Ａ６とボロン酸またはボロン酸エステルＡ７を反応させることにより、化合物Ａ８を得ることができる。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム(ジクロロ（１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィン）フェロセン ）パラジウム（ＩＩ）)などが挙げられ、化合物Ａ６に対して、０．００１～０．５モル当量用いることができる。
　ホスフィンリガンドとしては、 (２-ビフェニル)ジシクロヘキシルホスフィン、２－ジシクロヘキシルホスフィノ-２’, ４’, ６’-トリイソプロピルビフェニル、２－ジ－ｔｅｒｔ－ブチルホスフィノ－３，４，５，６－テトラメチル－２’, ４’, ６’―トリイソプロピル－１，１’－ビフェニル、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテンなどが挙げられ、化合物ａ１に対して、０．００１～０．５モル当量用いることができる。
　また、上記の金属触媒と上記のホスフィンリガンドの複合体である［(２－ビフェニル)ジシクロヘキシルホスフィン］パラジウムなどを化合物Ａ６に対して、０．００１～０．５モル当量用いることもできる。
　塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、リン酸三ナトリウム、リン酸水素ナトリウム、リン酸三カリウム、リン酸水素カリウム等が挙げられ、化合物Ａ６に対して、１～１０モル当量用いることができる。
　ボロン酸またはボロン酸エステルＡ７は、化合物Ａ６に対して、１～１０モル当量用いることができる。
　反応温度は、２０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度、または密閉系における温度で行う。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、テトラヒドロフラン、トルエン、ＤＭＦ、ジオキサン、水、エタノール、２－プロパノール、ｔｅｒｔ-ブタノール等が挙げられ、単独または混合して用いることができる。 [Method A]
Figure JPOXMLDOC01-appb-C000029
Wherein Hal is a halogen; Lg 1 is a leaving group; R A and R B are each independently hydrogen or substituted or unsubstituted alkyl, or substituted together Or forms an unsubstituted non-aromatic heterocycle; each R 4a independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl Substituted or unsubstituted monoalkylamino, and Is substituted or unsubstituted dialkylamino; m1 is an integer from 0 to 2; R 1 , R 2 , R 3 , —X—, and —Y— are as defined above (1) .)

Process 1
Compound A3 can be obtained by reacting compound A1 with compound A2 in the presence of a condensing agent.
Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4,6-dimethoxy-1,3,5, -triazin-2-yl) -4- Examples thereof include methylmorpholinium chloride and HATU, and 1 to 5 molar equivalents can be used with respect to compound A1.
The reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.

Process 2
Compound A4 can be obtained by adding a base to compound A3.
Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
The reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.

Process 3
Compound A6 can be obtained by allowing compound A4 to react with compound A5 having a leaving group and a base.
Examples of the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl and the like.
Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium hydroxide, lithium hexamethyldisilazane, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and the like. 1 to 5 molar equivalents can be used.
The reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.

Process 4
Compound A8 can be obtained by reacting compound A6 with boronic acid or boronic ester A7 in the presence of a metal catalyst and a base.
Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound A6.
Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like. 0.001 to 0.5 molar equivalent can be used.
Further, [(2-biphenyl) dicyclohexylphosphine] palladium, which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on Compound A6.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus Examples thereof include tripotassium acid, potassium hydrogen phosphate and the like, and 1 to 10 molar equivalents can be used with respect to compound A6.
Boronic acid or boronic acid ester A7 can be used at 1 to 10 molar equivalents relative to compound A6.
The reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water, ethanol, 2-propanol, tert-butanol and the like, and these can be used alone or in combination.
［Ｂ法］
Figure JPOXMLDOC01-appb-C000030
（式中、Ｌｇ２は脱離基であり；ＲＡおよびＲＢは、それぞれ独立して、水素、もしくは置換若しくは非置換のアルキルであるか、または一緒になって置換若しくは非置換の非芳香族複素環を形成する；Ｒ４ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノであり；ｍ２は、１または２であり；Ｈａｌ、Ｌｇ１、ＲＡ、ＲＢ、Ｒ４ａ、およびｍ１は、上記Ａ法と同意義であり；Ｒ１、Ｒ２、Ｒ３、－Ｘ－、および－Ｙ－は、上記（１）と同意義である。）

工程１
　化合物Ａ６に、脱離基を有する化合物Ｂ１、および塩基を作用させることにより、化合物Ｂ２を得ることが出来る。
　脱離基としては、クロロ、ブロモ、ヨウ素、メタンスルホニル、４－トルエンスルホニル、トリフルオロメタンスルホニル、等が挙げられる。
　塩基としては、カリウムｔｅｒｔ―ブトキシド、ナトリウムｔｅｒｔ―ブトキシド、水素化ナトリウム、リチウムヘキサメチルジシラザン、リチウムジイソプロピルアミド等が挙げられ、化合物Ａ６に対して１～５モル当量用いることが出来る。
　反応温度は、－２０℃～６０℃、好ましくは０℃～３０℃である。
　反応時間は、０．１時間～２４時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。

工程２
　化合物Ａ６の代わりに化合物Ｂ２を用いて、Ａ法の第４工程に記載の方法により、化合物Ｂ３を得ることができる。
[Method B]
Figure JPOXMLDOC01-appb-C000030
Wherein Lg 2 is a leaving group; R A and R B are each independently hydrogen or substituted or unsubstituted alkyl or taken together are substituted or unsubstituted non-aromatic Each R 4b independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted Monoalkylamino or substituted or unsubstituted di M2 is 1 or 2; Hal, Lg 1 , R A , R B , R 4a , and m1 are as defined in Method A above; R 1 , R 2 , R 3 , —X— and —Y— have the same meanings as (1) above.)

Process 1
Compound B2 can be obtained by allowing compound B6 having a leaving group and a base to act on compound A6.
Examples of the leaving group include chloro, bromo, iodine, methanesulfonyl, 4-toluenesulfonyl, trifluoromethanesulfonyl, and the like.
Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium hexamethyldisilazane, lithium diisopropylamide and the like, and 1 to 5 molar equivalents can be used with respect to compound A6.
The reaction temperature is -20 ° C to 60 ° C, preferably 0 ° C to 30 ° C.
The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include dimethylformamide, tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.

Process 2
Compound B3 can be obtained by the method described in the fourth step of Method A using Compound B2 instead of Compound A6.
また、Ａ法の第４工程およびＢ法の第２工程の代わりに、以下のＣ法およびＤ法に記載の方法を用いて合成を行うことができる。
［Ｃ法］
Figure JPOXMLDOC01-appb-C000031
（式中、－Ａ－は－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－であり；Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５a、Ｒ５ｂ、Ｒ７、－Ｘ－、－Ｙ－、ｐ、ｎ、およびｍは、上記（１）と同意義である。）

　金属触媒および塩基存在下、化合物Ｃ１とアミンＣ２を反応させることにより、化合物Ｃ３を得ることができる。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム(ジクロロ（１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィン）フェロセン ）パラジウム（ＩＩ）)などが挙げられ、化合物Ｃ１に対して、０．００１～０．５モル当量用いることができる。
　ホスフィンリガンドとしては、 (２-ビフェニル)ジシクロヘキシルホスフィン、２－ジシクロヘキシルホスフィノ-２’, ４’, ６’-トリイソプロピルビフェニル、２－ジ－ｔｅｒｔ－ブチルホスフィノ－３，４，５，６－テトラメチル－２’, ４’, ６’―トリイソプロピル－１，１’－ビフェニル、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン等が挙げられ、化合物Ｃ１に対して、０．００１～０．５モル当量用いることができる。
　また、上記の金属触媒と上記のホスフィンリガンドの複合体である［(２－ビフェニル)ジシクロヘキシルホスフィン］パラジウムなどを化合物Ｃ１に対して、０．００１～０．５モル当量用いることもできる。
　塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、リン酸三ナトリウム、リン酸水素ナトリウム、リン酸三カリウム、リン酸水素カリウム、リチウムヘキサメチルジシラザン等が挙げられ、化合物Ｃ１に対して、１～１０モル当量用いることができる。
　１級もしくは２級アミンＣ２は、化合物Ｃ１に対して、１～１０モル当量用いることができる。
　反応温度は、２０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度、または密閉系における温度で行う。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、テトラヒドロフラン、トルエン、ＤＭＦ、ＤＭＡ，ＮＭＰ、ジオキサン、等が挙げられ、単独または混合して用いることができる。 Moreover, it can synthesize | combine using the method as described in the following C method and D method instead of the 4th process of A method, and the 2nd process of B method.
[Method C]
Figure JPOXMLDOC01-appb-C000031
(Wherein -A- is-(C (R 5a ) (R 5b )) p-; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 7 , -X-, -Y-, p, n, and m have the same meaning as in (1) above.)

Compound C3 can be obtained by reacting compound C1 and amine C2 in the presence of a metal catalyst and a base.
Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to Compound C1.
Examples of the phosphine ligand include (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6- And tetramethyl-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, and the like. 0.001 to 0.5 molar equivalent can be used.
Further, [(2-biphenyl) dicyclohexylphosphine] palladium, which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent based on the compound C1.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound C1.
The primary or secondary amine C2 can be used in an amount of 1 to 10 molar equivalents relative to the compound C1.
The reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
［Ｄ法］
Figure JPOXMLDOC01-appb-C000032
（式中、ＲＤは、「置換若しくは非置換の芳香族炭素環式基」の環上の置換基と同意義であり；ｔは、０から５の整数であり；Ｒ１、Ｒ２、Ｒ３、Ｒ４、－Ｙ－、ｎ、およびｍは、上記（１）と同意義である。）

　金属触媒および塩基存在下、化合物Ｄ１とフェノールＤ２を反応させることにより、化合物Ｄ３を得ることができる。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム(ジクロロ（１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィン）フェロセン ）パラジウム（ＩＩ）)などが挙げられ、化合物Ｄ１に対して、０．００１～０．５モル当量用いることができる。
　ホスフィンリガンドとしては、 (２-ビフェニル)ジシクロヘキシルホスフィン、２－ジシクロヘキシルホスフィノ-２’, ４’, ６’-トリイソプロピルビフェニル、２－ジ－ｔｅｒｔ－ブチルホスフィノ－２’, ４’, ６’―トリイソプロピル－１，１’－ビフェニル、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン等が挙げられ、化合物Ｄ１に対して、０．００１～０．５モル当量用いることができる。
　また、上記の金属触媒と上記のホスフィンリガンドの複合体である［(２－ビフェニル)ジシクロヘキシルホスフィン］パラジウムなどを化合物Ｄ１に対して、０．００１～０．５モル当量用いることもできる。
　塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、リン酸三ナトリウム、リン酸水素ナトリウム、リン酸三カリウム、リン酸水素カリウム、リチウムヘキサメチルジシラザン等が挙げられ、化合物Ｄ１に対して、１～１０モル当量用いることができる。
　フェノールＤ２は、化合物Ｄ１に対して、１～１０モル当量用いることができる。
　反応温度は、２０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度、または密閉系における温度で行う。
　反応時間は、０．１～４８時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、テトラヒドロフラン、トルエン、ＤＭＦ、ＤＭＡ，ＮＭＰ、ジオキサン、等が挙げられ、単独または混合して用いることができる。 [Method D]
Figure JPOXMLDOC01-appb-C000032
(Wherein R D is the same as the substituent on the ring of the “substituted or unsubstituted aromatic carbocyclic group”; t is an integer of 0 to 5; R 1 , R 2 , R 3 , R 4 , —Y—, n, and m are the same as defined in (1) above.)

Compound D3 can be obtained by reacting compound D1 and phenol D2 in the presence of a metal catalyst and a base.
Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium (dichloro) (1,1′-bis (di-tert-butylphosphine) ferrocene) palladium (II)) and the like, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound D1.
The phosphine ligand includes (2-biphenyl) dicyclohexylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2 ′, 4 ′, 6 ′. -Triisopropyl-1,1'-biphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, etc., and 0.001-0.5 molar equivalents relative to compound D1 Can do.
Further, [(2-biphenyl) dicyclohexylphosphine] palladium, which is a complex of the above metal catalyst and the above phosphine ligand, can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound D1.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, trisodium phosphate, sodium hydrogen phosphate, phosphorus Examples thereof include tripotassium acid, potassium hydrogen phosphate, lithium hexamethyldisilazane and the like, and can be used at 1 to 10 molar equivalents relative to compound D1.
Phenol D2 can be used at 1 to 10 molar equivalents relative to compound D1.
The reaction temperature is from 20 ° C. to the reflux temperature of the solvent, optionally under microwave irradiation, or in a closed system.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, DMA, NMP, dioxane, and the like, and these can be used alone or in combination.
　より好ましい本発明化合物は、Ｎａｖ１．７阻害作用のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有する。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）代謝安定性が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）高い溶解性を示す。
ｈ）Ｎａｖ１．７に対する高い選択性を有している。 More preferred compounds of the present invention have not only a Nav1.7 inhibitory action but also usefulness as a medicament, and have any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not exhibit irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) High selectivity for Nav1.7.
　本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、注射剤等の通常用いられるいずれの剤型でも好適に投与することができる。本発明に係る化合物は経口吸収性が高いため、経口剤として好適に使用できる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。 Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
　本発明化合物の具体的な態様としては、以下の一般式（ＩＩＩ’）において、以下に示すＲｐおよびＲｑを有する化合物が挙げられる。
Figure JPOXMLDOC01-appb-C000033
 Specific examples of the compound of the present invention include compounds having the following Rp and Rq in the following general formula (III ′).
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
（上記表中、Ｍｅはメチルを示す。）
Figure JPOXMLDOC01-appb-T000041
(In the above table, Me represents methyl.)
　以下に本発明の実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples of the present invention, but the present invention is not limited thereto.
　また、本明細書中で用いる略語は以下の意味を表す。
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＳＯ：ジメチルスルホキシド
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＥＤＣ：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド
Ｐｄ２（ｄｂａ）３：トリス（ジベンジリデンアセトン）ビスパラジウム
ＰｄＣｌ２（ｄｔｂｐｆ）：［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン付加物
ｔＢｕ：ｔｅｒｔ－ブチル
ＴＨＦ：テトラヒドロフラン
Ｘａｎｔｐｈｏｓ：４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテン
Ｘ－ｐｈｏｓ：２，４，６－トリイソプロピル－２’－（ジシクロヘキシルホスフィノ）ビフェニル
ｔＢｕ－Ｘ－ｐｈｏｓ：２，４，６－トリイソプロピル－２’－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニル Moreover, the abbreviation used in this specification represents the following meaning.
DIEA: N, N-diisopropylethylamine DMSO: dimethyl sulfoxide DMF: N, N-dimethylformamide EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Pd 2 (dba) 3 : tris (dibenzylideneacetone) bis Palladium PdCl 2 (dtbpf): [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct tBu: tert-butyl THF: tetrahydrofuran Xantphos: 4,5′-bis (diphenylphosphino) -9,9'-dimethylxanthene X-phos: 2,4,6-triisopropyl-2 '-(dicyclohexylphosphino) biphenyl tBu-X-phos: 2,4,6-triisopropyl-2'-(di -Tert Butyl phosphino) biphenyl
　各実施例で得られたＮＭＲ分析は、４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３を用いて測定した。

　下記表に示された化合物のＬＣ／ＭＳ：分析液体クロマトグラフィー／質量分析は、以下の分析条件［１］－［７］のいずれかにより測定した。各化合物の分析条件番号を、以下の表に示した。また、ＬＣ／ＭＳの分析結果を保持時間（分）および［Ｍ＋Ｈ］として、以下の別表に示した。

分析条件［１］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は１０ｍｍｏｌ／Ｌ炭酸アンモニウム水溶液、［Ｂ］はアセトニトリル
グラジエント：０分　２０％Ｂ、０．２５分　２０％Ｂ、１．５分　８０％Ｂ、２．２５分　８０％Ｂ、２．３分　２０％Ｂ、２．５分　２０％Ｂ
温度：４５度
流速：０．８３４ｍＬ／ｍiｎ
検出器：ＤＡＤ２１０－４００ｎｍ
注入量：０．５μＬ

分析条件［２］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は１０ｍｍｏｌ／Ｌ炭酸アンモニウム水溶液、［Ｂ］はアセトニトリル
グラジエント：０分　５％Ｂ、０．２５分　５％Ｂ、１．５分　６０％Ｂ、２．２５分　６０％Ｂ、２．３分　５％Ｂ、２．５分　５％Ｂ
温度：４５度
流速：０．８３４ｍＬ／ｍiｎ
検出器：ＤＡＤ２１０－４００ｎｍ
注入量：０．５μＬ

分析条件［３］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル
グラジエント：０分　５％Ｂ、０．２５分　５％Ｂ、１．５分　６０％Ｂ、２．２５分　６０％Ｂ、２．３分　５％Ｂ、２．５分　５％Ｂ
温度：４５度
流速：０．８３４ｍＬ／ｍiｎ
検出器：ＤＡＤ２１０－４００ｎｍ
注入量：０．５μＬ

分析条件［４］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル
グラジエント：０分　２０％Ｂ、０．２５分　２０％Ｂ、１．５分　８０％Ｂ、２．２５分　８０％Ｂ、２．３分　２０％Ｂ、２．５分　２０％Ｂ
温度：４５度
流速：０．８３４ｍＬ／ｍiｎ
検出器：ＤＡＤ２１０－４００ｎｍ
注入量：０．５μＬ

分析条件［５］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有メタノール
グラジエント：０分　２０％Ｂ、０．２５分　２０％Ｂ、１．５分　８０％Ｂ、２．２５分　８０％Ｂ、２．３分　２０％Ｂ、２．５分　２０％Ｂ
温度：４５度
流速：０．８３４ｍＬ／ｍiｎ
検出器：ＤＡＤ２１０－４００ｎｍ
注入量：０．５μＬ

分析条件［６］
カラム：シマヅ　Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
流速：１．６　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ

分析条件［７］
カラム：ウォーターズ　アクイティーＢＥＨ　Ｃ１８　５０×２．１ｍｍ　iｄ　１．７μｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
流速：０．８　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d 6 and CDCl 3 .

LC / MS: Analytical liquid chromatography / mass spectrometry of the compounds shown in the table below was measured under any of the following analytical conditions [1]-[7]. The analysis condition number of each compound is shown in the following table. The LC / MS analysis results are shown in the following table as retention time (minutes) and [M + H].

Analysis conditions [1]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is 10 mmol / L ammonium carbonate aqueous solution, [B] is acetonitrile gradient: 0 min 20% B, 0.25 min 20% B, 1.5 min 80% B, 2.25 min 80% B 2.3 minutes 20% B, 2.5 minutes 20% B
Temperature: 45 degrees Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [2]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is 10 mmol / L ammonium carbonate aqueous solution, [B] is acetonitrile gradient: 0 min 5% B, 0.25 min 5% B, 1.5 min 60% B, 2.25 min 60% B 2.3 minutes 5% B, 2.5 minutes 5% B
Temperature: 45 degrees Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [3]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile gradient containing 0.1% formic acid: 0 min 5% B, 0.25 min 5% B, 1.5 min 60% B, 2.25 minutes 60% B, 2.3 minutes 5% B, 2.5 minutes 5% B
Temperature: 45 degrees Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [4]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile gradient containing 0.1% formic acid: 0 min 20% B, 0.25 min 20% B, 1.5 min 80% B, 2.25 minutes 80% B, 2.3 minutes 20% B, 2.5 minutes 20% B
Temperature: 45 degrees Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [5]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing methanol gradient: 0 min 20% B, 0.25 min 20% B, 1.5 min 80% B, 2.25 minutes 80% B, 2.3 minutes 20% B, 2.5 minutes 20% B
Temperature: 45 degrees Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [6]
Column: Shima-Shim Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm)
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes. 100% solvent [B] was maintained for 5 minutes.
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm

Analysis conditions [7]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3.5 minutes 100% solvent [B] was maintained for 0.5 minutes.
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
　下記表に示された化合物の分取ＨＰＬＣによる分取精製は、ウォーターズ　サンファイアーＯＢＤフェノメネックス　ルナ　フェニルヘキシル、またはウォーターズ　エックスブリッジ　フェニル（１０μｍ、１９ｘ１５０ｍｍ）カラムを用いて、以下の条件にて実施した。
（酸性条件）
移動相：［Ａ］は０．１％ギ酸含有アセトニトリル溶液、［Ｂ］は０．１％ギ酸含有メタノール溶液
グラジェント：０～１分：５％－２０％アセトニトリル溶液のリニアグラジェント
　　　　　　　1分～２分：２０％アセトニトリル溶液の維持
　　　　　　　２分～７分：２０％から８０％アセトニトリル溶液のリニアグラジェント
　　　　　　　7分～１１分：８０％アセトニトリル溶液の維持
　　　　　　　１１分～１２分：１００％アセトニトリル溶液の維持
　　　　　　　１２分～１３．５分：５％アセトニトリル溶液の維持
流速：２０ｍＬ/分
（塩基性条件）
移動相：［Ａ］は１０ｍｍｏｌ／Ｌ アンモニア含有アセトニトリル溶液、［Ｂ］は０．１％１０ｍｍｏｌ／Ｌ アンモニア含有メタノール溶液
グラジェント：０～１分：５％－２０％アセトニトリル溶液のリニアグラジェント
　　　　　　　1分～２分：２０％アセトニトリル溶液の維持
　　　　　　　２分～７分：２０％から８０％アセトニトリル溶液のリニアグラジェント
　　　　　　　7分～１１分：８０％アセトニトリル溶液の維持
　　　　　　　１１分～１２分：１００％アセトニトリル溶液の維持
　　　　　　　１２分～１３．５分：５％アセトニトリル溶液の維持
流速：２０ｍＬ/分 Preparative purification by preparative HPLC of the compounds shown in the table below was performed using a Waters Sunfire OBD Phenomenex Luna Phenylhexyl or Waters Xbridge Phenyl (10 μm, 19 × 150 mm) column under the following conditions. .
(Acid condition)
Mobile phase: [A] is an acetonitrile solution containing 0.1% formic acid, [B] is a methanol solution containing 0.1% formic acid Gradient: 0 to 1 minute: Linear gradient of 5% -20% acetonitrile solution 1 minute to 2 minutes: maintenance of 20% acetonitrile solution 2 minutes to 7 minutes: linear gradient of 20% to 80% acetonitrile solution 7 minutes to 11 minutes: maintenance of 80% acetonitrile solution 11 minutes to 12 minutes: maintenance of 100% acetonitrile solution 12 min to 13.5 min: 5% acetonitrile solution maintenance flow rate: 20 mL / min (basic conditions)
Mobile phase: [A] is 10 mmol / L ammonia-containing acetonitrile solution, [B] is 0.1% 10 mmol / L ammonia-containing methanol solution gradient: 0 to 1 minute: linear gradient of 5% -20% acetonitrile solution 1 Min-2 min: maintenance of 20% acetonitrile solution 2 min-7 min: linear gradient of 20% to 80% acetonitrile solution 7 min-11 min: maintenance of 80% acetonitrile solution 11 min-12 min: 100% acetonitrile solution Maintenance 12 min to 13.5 min: 5% acetonitrile solution maintenance flow rate: 20 mL / min
実施例１
（１）化合物２の合成
Figure JPOXMLDOC01-appb-C000045
　化合物１（５０．００ｇ、０．２０４ｍｏｌ）とクロロ酢酸（２３．０９ｇ、０．２４４ｍｏｌ）を乾燥したジクロロメタン（１Ｌ）に懸濁し、ジイソプロピルエチルアミン（７１ｍＬ，０．４０７ｍｏｌ）を窒素雰囲気下で加えた。反応液内の固形物は室温下、１０分程度かけて溶解し、反応液はオレンジ色になった。２－ヒドロキシピリジン－Ｎ－オキシド（２７．１５ｇ、０．２４４ｍｏｌ）、ＥＤＣ塩酸塩（４６．８０ｇ、０．２４４ｍｏｌ）を順に加え、２．５時間、窒素雰囲気下、室温で攪拌した。ＬＣ／ＭＳにより原料の消失を確認した。反応液の色が暗くなり、固体が析出した。反応液を氷水で３０分冷却し、固体をろ取、ジクロロメタン（１００ｍＬ）で５回洗浄した。減圧下、４０度で５時間乾燥し、化合物２（２９．１１ｇ、収率５７％）を得た。
1H NMR δ (ppm)(DMSO-d6): 8.93 (1 H, d, J = 7.63 Hz), 8.62 (1 H, s), 8.49 (1 H, d, J = 5.31 Hz), 7.58 (1 H, d, J = 5.31 Hz), 5.30-5.22 (2 H, m), 4.21 (2 H, s), 3.76-3.61 (2 H, m). ＬＣ／ＭＳ: m/z 249, 251. Example 1
(1) Synthesis of compound 2
Figure JPOXMLDOC01-appb-C000045
Compound 1 (50.00 g, 0.204 mol) and chloroacetic acid (23.09 g, 0.244 mol) were suspended in dry dichloromethane (1 L), and diisopropylethylamine (71 mL, 0.407 mol) was added under a nitrogen atmosphere. . The solid in the reaction solution was dissolved over about 10 minutes at room temperature, and the reaction solution became orange. 2-hydroxypyridine-N-oxide (27.15 g, 0.244 mol) and EDC hydrochloride (46.80 g, 0.244 mol) were sequentially added, and the mixture was stirred for 2.5 hours at room temperature under a nitrogen atmosphere. The disappearance of the raw material was confirmed by LC / MS. The color of the reaction solution became dark and a solid precipitated. The reaction solution was cooled with ice water for 30 minutes, and the solid was collected by filtration and washed 5 times with dichloromethane (100 mL). The resultant was dried at 40 ° C. for 5 hours under reduced pressure to obtain Compound 2 (29.11 g, yield 57%).
1 H NMR δ (ppm) (DMSO-d 6 ): 8.93 (1 H, d, J = 7.63 Hz), 8.62 (1 H, s), 8.49 (1 H, d, J = 5.31 Hz), 7.58 ( 1 H, d, J = 5.31 Hz), 5.30-5.22 (2 H, m), 4.21 (2 H, s), 3.76-3.61 (2 H, m). LC / MS: m / z 249, 251.
（２）化合物３の合成
Figure JPOXMLDOC01-appb-C000046
　化合物２（３０．２１ｇ、１２１．３ｍｍｏｌ）の乾燥テトラヒドロフラン（１．３Ｌ）溶液に、窒素雰囲気下、室温で、ナトリウムヒドリド（６０％の鉱油分散体）（９．７０ｇ、２４２．５ｍｍｏｌ）を、１０分間かけて分割して加えた。当初、発熱は認められなかったが、添加終了後には反応液温は２８度まで上昇した。氷水浴を用いて、反応液温を２５度以下に冷却した。反応液温が２０～２５度に下がると、氷水浴を外し、室温下１時間攪拌した。ＬＣ／ＭＳにより、原料の消失と目的化合物の生成を確認した。反応液を氷水浴で冷却し、飽和塩化アンモニウム水溶液（２５０ｍＬ）を、反応液温を１０度程度に維持しながら滴下し、反応を停止した。有機層を分離し、水層は酢酸エチル（２５０ｍＬ）で３回洗浄した。まとめた有機層を硫酸マグネシウムにより乾燥し、減圧濃縮した。得られた残渣にイソヘキサン（２００ｍＬ程度）を加えて固体化した。固体をろ取、イソヘキサン（１００ｍＬ）で２度洗浄した。減圧下４０度で４時間乾燥し、化合物３（２４．０２ｇ、収率９３％）を得た。
1H NMR δ (ppm) (DMSO-d6): 8.62 (1 H, s), 8.56 (1 H, d, J = 5.31 Hz), 8.54 (1 H, br s), 7.64 (1 H, d, J = 5.31 Hz), 5.03 (1 H, q, J = 3.68 Hz), 4.26 (1 H, d, J = 16.40 Hz), 4.17 (1 H, d, J = 16.40 Hz), 4.09 (1 H, dd, J = 11.81, 3.97 Hz), 3.76 (1 H, dd, J = 11.81, 4.66 Hz). ＬＣ／ＭＳ： m/z 213, 215. (2) Synthesis of compound 3
Figure JPOXMLDOC01-appb-C000046
Sodium hydride (60% mineral oil dispersion) (9.70 g, 242.5 mmol) was added to a solution of compound 2 (30.21 g, 121.3 mmol) in dry tetrahydrofuran (1.3 L) at room temperature under a nitrogen atmosphere. Added in portions over 10 minutes. Initially, no exotherm was observed, but the temperature of the reaction solution rose to 28 ° C after the end of the addition. The reaction liquid temperature was cooled to 25 degrees C or less using an ice water bath. When the reaction solution temperature dropped to 20-25 ° C., the ice water bath was removed and the mixture was stirred at room temperature for 1 hour. LC / MS confirmed the disappearance of the starting materials and the formation of the target compound. The reaction solution was cooled in an ice-water bath, and a saturated aqueous ammonium chloride solution (250 mL) was added dropwise while maintaining the reaction solution temperature at about 10 degrees to stop the reaction. The organic layer was separated and the aqueous layer was washed 3 times with ethyl acetate (250 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. Isohexane (about 200 mL) was added to the obtained residue to solidify it. The solid was collected by filtration and washed twice with isohexane (100 mL). It was dried at 40 ° C. under reduced pressure for 4 hours to obtain Compound 3 (24.02 g, yield 93%).
1 H NMR δ (ppm) (DMSO-d 6 ): 8.62 (1 H, s), 8.56 (1 H, d, J = 5.31 Hz), 8.54 (1 H, br s), 7.64 (1 H, d , J = 5.31 Hz), 5.03 (1 H, q, J = 3.68 Hz), 4.26 (1 H, d, J = 16.40 Hz), 4.17 (1 H, d, J = 16.40 Hz), 4.09 (1 H , dd, J = 11.81, 3.97 Hz), 3.76 (1 H, dd, J = 11.81, 4.66 Hz). LC / MS: m / z 213, 215.
（３）化合物４の合成
　化合物４は、以下のスキームおよび反応操作に従って合成することができる。
Figure JPOXMLDOC01-appb-C000047
［式中、Rａは、ベンジル、メチル、２-メトキシエチル、２-フルオロベンジル、３-メトキシベンジル、２-ピリジルメチル、４-クロロベンジル、４-メチルベンジル、シクロプロピルメチル、(２-メチルチアゾール-４-イル)メチルまたは(ピペリジニル)エチル］
　化合物３（１０．６３ｇ、５０．０ｍｍｏｌ）の乾燥ＤＭＦ（２００ｍＬ）溶液に、窒素雰囲気下、室温で、１．０ｍｏｌ／Ｌのカリウム－ｔｅｒｔ－ブトキシドのテトラヒドロフラン溶液（７５ｍＬ、７５ｍｍｏｌ、１．５～３当量）を滴下する。得られた赤褐色の溶液を室温下２０分攪拌する。反応液を氷水浴により冷却し、アルキルハライド（７５ｍｍｏｌ、１．５当量）を、反応液温を１０～１５度に維持しながら、１０分間かけて加える。氷水浴を取り外し、室温下で攪拌する。ＬＣ／ＭＳにより反応進行を確認し、原料３が消失することを確認後、反応液を氷水浴で冷却し、水（５０ｍＬ）で反応停止する。反応液を減圧濃縮し、ＤＭＦを除いた。得られた残渣に酢酸エチル（４００ｍＬ）、飽和食塩水（１００ｍＬ），水（１００ｍＬ）を加え、分液する。水層は酢酸エチル（４００ｍＬ）で４度洗浄し、まとめた有機層を無水硫酸マグネシウムで乾燥、減圧濃縮する。得られた残渣をジエチルエーテル中で固化してろ取精製するか、または、シリカゲルカラムクロマトグラフィー（１００％ジクロロメタンから５％メタノール-９５％ジクロロメタン、または８０％酢酸エチル-イソヘキサンから１００％酢酸エチル）により精製して、化合物４を得ることができる。 (3) Synthesis of Compound 4 Compound 4 can be synthesized according to the following scheme and reaction procedure.
Figure JPOXMLDOC01-appb-C000047
[In the formula, Ra is benzyl, methyl, 2-methoxyethyl, 2-fluorobenzyl, 3-methoxybenzyl, 2-pyridylmethyl, 4-chlorobenzyl, 4-methylbenzyl, cyclopropylmethyl, (2-methylthiazole, -4-yl) methyl or (piperidinyl) ethyl]
To a solution of compound 3 (10.63 g, 50.0 mmol) in dry DMF (200 mL) at room temperature under a nitrogen atmosphere, 1.0 mol / L potassium-tert-butoxide in tetrahydrofuran (75 mL, 75 mmol, 1.5- 3 equivalents) is added dropwise. The resulting reddish brown solution is stirred at room temperature for 20 minutes. The reaction is cooled with an ice-water bath and alkyl halide (75 mmol, 1.5 eq) is added over 10 minutes while maintaining the reaction temperature at 10-15 degrees. Remove the ice-water bath and stir at room temperature. After confirming the progress of the reaction by LC / MS and confirming that the raw material 3 has disappeared, the reaction solution is cooled in an ice-water bath and quenched with water (50 mL). The reaction solution was concentrated under reduced pressure to remove DMF. To the obtained residue are added ethyl acetate (400 mL), saturated brine (100 mL), and water (100 mL), and the mixture is separated. The aqueous layer is washed four times with ethyl acetate (400 mL), and the combined organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is solidified in diethyl ether and purified by filtration or by silica gel column chromatography (100% dichloromethane to 5% methanol-95% dichloromethane, or 80% ethyl acetate-isohexane to 100% ethyl acetate). Purification can give compound 4.
例えば、化合物 ４ｂ（反応時間３．５時間、収率７１％）を得た。
Figure JPOXMLDOC01-appb-C000048
1H NMR δ (ppm)(CDCl3): 8.52 (1 H, d, J = 5.29 Hz), 8.47 (1 H, s), 7.39 (1 H, d, J = 5.29 Hz), 4.91 (1 H, dd, J = 3.63, 2.80 Hz), 4.40 (1 H, d, J = 16.71 Hz), 4.29 (1 H, d, J = 16.69 Hz), 4.12 (1 H, dd, J = 12.09, 3.73 Hz), 3.94 (1 H, dd, J = 12.09, 2.76 Hz), 2.92 (3 H, s).

例えば化合物４ｃ（アルキルハライドとして2-ブロモエチルメチルエーテル (１．２当量) を使用。反応時間１６．５時間、収率７０％）を得た。
Figure JPOXMLDOC01-appb-C000049
1H NMR δ (ppm)(CDCl3): 8.50 (1 H, d, J = 5.29 Hz), 8.45 (1 H, s), 7.37 (1 H, d, J = 5.29 Hz), 5.24 (1 H, dd, J = 3.29, 2.22 Hz), 4.40 (1 H, d, J = 16.81 Hz), 4.31 (1 H, d, J = 16.81 Hz), 4.14-4.07 (2 H, m), 3.95 (1 H, dd, J = 12.04, 2.14 Hz), 3.66 (1 H, ddd, J = 10.25, 8.80, 3.31 Hz), 3.46 (1 H, ddd, J = 8.28, 6.08, 3.98 Hz), 3.29 (3 H, s), 2.84 (1 H, ddd, J = 14.37, 8.80, 3.61 Hz).

例えば化合物４ｄ（アルキルハライドとして2-フルオロベンジルブロミド (１．２当量)を使用。反応時間１６時間、収率７２％）を得た。
Figure JPOXMLDOC01-appb-C000050
1H NMR δ (ppm)(CDCl3): 8.48 (1 H, d, J = 5.29 Hz), 8.46 (1 H, s), 7.37-7.31 (2 H, m), 7.37-7.16 (1 H, m), 7.12 (1 H, ddd, J = 7.61, 7.40, 1.19 Hz), 6.99 (1 H, ddd, J = 10.05, 8.25, 1.17 Hz), 5.25 (1 H, d, J = 14.75 Hz), 4.91 (1 H, dd, J = 3.37, 2.44 Hz), 4.47 (1 H, d, J = 16.85 Hz), 4.33 (1 H, d, J = 16.85 Hz), 4.05-3.86 (3 H, m). For example, Compound 4b (reaction time 3.5 hours, yield 71%) was obtained.
Figure JPOXMLDOC01-appb-C000048
1 H NMR δ (ppm) (CDCl 3 ): 8.52 (1 H, d, J = 5.29 Hz), 8.47 (1 H, s), 7.39 (1 H, d, J = 5.29 Hz), 4.91 (1 H , dd, J = 3.63, 2.80 Hz), 4.40 (1 H, d, J = 16.71 Hz), 4.29 (1 H, d, J = 16.69 Hz), 4.12 (1 H, dd, J = 12.09, 3.73 Hz ), 3.94 (1 H, dd, J = 12.09, 2.76 Hz), 2.92 (3 H, s).

For example, Compound 4c (using 2-bromoethyl methyl ether (1.2 equivalents) as the alkyl halide, reaction time 16.5 hours, yield 70%) was obtained.
Figure JPOXMLDOC01-appb-C000049
1 H NMR δ (ppm) (CDCl 3 ): 8.50 (1 H, d, J = 5.29 Hz), 8.45 (1 H, s), 7.37 (1 H, d, J = 5.29 Hz), 5.24 (1 H , dd, J = 3.29, 2.22 Hz), 4.40 (1 H, d, J = 16.81 Hz), 4.31 (1 H, d, J = 16.81 Hz), 4.14-4.07 (2 H, m), 3.95 (1 H, dd, J = 12.04, 2.14 Hz), 3.66 (1 H, ddd, J = 10.25, 8.80, 3.31 Hz), 3.46 (1 H, ddd, J = 8.28, 6.08, 3.98 Hz), 3.29 (3 H , s), 2.84 (1 H, ddd, J = 14.37, 8.80, 3.61 Hz).

For example, Compound 4d (using 2-fluorobenzyl bromide (1.2 equivalents) as the alkyl halide, reaction time 16 hours, yield 72%) was obtained.
Figure JPOXMLDOC01-appb-C000050
1 H NMR δ (ppm) (CDCl 3 ): 8.48 (1 H, d, J = 5.29 Hz), 8.46 (1 H, s), 7.37-7.31 (2 H, m), 7.37-7.16 (1 H, m), 7.12 (1 H, ddd, J = 7.61, 7.40, 1.19 Hz), 6.99 (1 H, ddd, J = 10.05, 8.25, 1.17 Hz), 5.25 (1 H, d, J = 14.75 Hz), 4.91 (1 H, dd, J = 3.37, 2.44 Hz), 4.47 (1 H, d, J = 16.85 Hz), 4.33 (1 H, d, J = 16.85 Hz), 4.05-3.86 (3 H, m) .
例えば、化合物４ｆ（アルキルハライドとして2-(ブロモメチル)ピリジン　ハイドロブロミド (１．２当量)を使用。反応時間２１時間、収率７４％）を得た。
Figure JPOXMLDOC01-appb-C000051
1H NMR δ (ppm)(CDCl3): 8.53-8.46 (3 H, m), 7.65 (1 H, ddd, J = 8.64, 6.88, 0.71 Hz), 7.34 (1 H, d, J = 5.29 Hz), 7.30 (1 H, d, J = 7.83 Hz), 7.19 (1 H, dd, J = 7.53, 4.94 Hz), 5.38 (1 H, d, J = 15.00 Hz), 5.19 (1 H, dd, J = 3.33, 2.25 Hz), 4.48 (1 H, d, J = 16.87 Hz), 4.36 (1 H, d, J = 16.87 Hz), 4.11 (1 H, dd, J = 12.98, 11.50 Hz), 3.98 (1 H, dd, J = 12.05, 2.19 Hz), 3.83 (1 H, d, J = 15.00 Hz).

例えば、化合物４ｈ（アルキルハライドとして4-メチルベンジルブロミド (１．２当量)を使用。反応時間１６時間、収率４９％）を得た。
Figure JPOXMLDOC01-appb-C000052
1H NMR δ (ppm)(CDCl3): 8.53-8.48 (2 H, m), 7.36 (1 H, d, J = 5.29 Hz), 7.09 (4 H, dd, J = 24.25, 7.84 Hz), 5.50 (1 H, d, J = 14.51 Hz), 4.81 (1 H, dd, J = 3.27, 2.41 Hz), 4.48 (1 H, d, J = 16.83 Hz), 4.33 (1 H, d, J = 16.83 Hz), 3.93 (1 H, dd, J = 12.08, 3.43 Hz), 3.88 (1 H, dd, J = 12.08, 2.37 Hz), 3.43 (1 H, d, J = 14.53 Hz), 2.33 (3 H, s)

例えば、化合物４ｉ（収率７４％）を得た。
Figure JPOXMLDOC01-appb-C000053
1H NMR δ (ppm)(CDCl3): 8.50 (1 H, d, J = 5.30 Hz), 8.48 (1 H, s), 7.37 (1 H, d, J = 5.30 Hz), 5.22 (1 H, dd, J = 3.33, 2.29 Hz), 4.42 (1 H, d, J = 16.77 Hz), 4.31 (1 H, d, J = 16.76 Hz), 4.12 (1 H, dd, J = 12.04, 3.49 Hz), 4.00-3.89 (2 H, m), 2.56 (1 H, dd, J = 14.23, 7.74 Hz), 0.93-0.82 (1 H, m), 0.58-0.49 (1 H, m), 0.45-0.36 (1 H, m), 0.18-0.05 (2 H, m). For example, Compound 4f (2- (bromomethyl) pyridine hydrobromide (1.2 eq) was used as the alkyl halide. Reaction time 21 hours, yield 74%) was obtained.
Figure JPOXMLDOC01-appb-C000051
1 H NMR δ (ppm) (CDCl 3 ): 8.53-8.46 (3 H, m), 7.65 (1 H, ddd, J = 8.64, 6.88, 0.71 Hz), 7.34 (1 H, d, J = 5.29 Hz ), 7.30 (1 H, d, J = 7.83 Hz), 7.19 (1 H, dd, J = 7.53, 4.94 Hz), 5.38 (1 H, d, J = 15.00 Hz), 5.19 (1 H, dd, J = 3.33, 2.25 Hz), 4.48 (1 H, d, J = 16.87 Hz), 4.36 (1 H, d, J = 16.87 Hz), 4.11 (1 H, dd, J = 12.98, 11.50 Hz), 3.98 (1 H, dd, J = 12.05, 2.19 Hz), 3.83 (1 H, d, J = 15.00 Hz).

For example, compound 4h (4-methylbenzyl bromide (1.2 equivalents) was used as the alkyl halide. Reaction time 16 hours, yield 49%) was obtained.
Figure JPOXMLDOC01-appb-C000052
1 H NMR δ (ppm) (CDCl 3 ): 8.53-8.48 (2 H, m), 7.36 (1 H, d, J = 5.29 Hz), 7.09 (4 H, dd, J = 24.25, 7.84 Hz), 5.50 (1 H, d, J = 14.51 Hz), 4.81 (1 H, dd, J = 3.27, 2.41 Hz), 4.48 (1 H, d, J = 16.83 Hz), 4.33 (1 H, d, J = 16.83 Hz), 3.93 (1 H, dd, J = 12.08, 3.43 Hz), 3.88 (1 H, dd, J = 12.08, 2.37 Hz), 3.43 (1 H, d, J = 14.53 Hz), 2.33 (3 H, s)

For example, Compound 4i (yield 74%) was obtained.
Figure JPOXMLDOC01-appb-C000053
1 H NMR δ (ppm) (CDCl 3 ): 8.50 (1 H, d, J = 5.30 Hz), 8.48 (1 H, s), 7.37 (1 H, d, J = 5.30 Hz), 5.22 (1 H , dd, J = 3.33, 2.29 Hz), 4.42 (1 H, d, J = 16.77 Hz), 4.31 (1 H, d, J = 16.76 Hz), 4.12 (1 H, dd, J = 12.04, 3.49 Hz) ), 4.00-3.89 (2 H, m), 2.56 (1 H, dd, J = 14.23, 7.74 Hz), 0.93-0.82 (1 H, m), 0.58-0.49 (1 H, m), 0.45-0.36 (1 H, m), 0.18-0.05 (2 H, m).
（４）化合物Ｉ－２３１の合成
Figure JPOXMLDOC01-appb-C000054
　６：１(v/v)のジオキサン-水溶液（溶液Ａ）を窒素でバブリングしながら、激しく脱気を２時間行った。トリチオシアヌル酸（３６０ｍｇ）、塩化ナトリウム（１．４ｇ）、アンモニア（０．８８ＳＧ）のエタノール（４５ｍＬ）/水（５０ｍＬ）溶液（溶液Ｂ）を調整した。４０ｍＬサイズの反応バイアルに、化合物４ｂ（０．５０ｍｍｏｌ、１当量）、ピリジン－３－ボロン酸（１．００ｍｍｏｌ、２当量）、炭酸セシウム（４８９ｍｇ、１．５０ｍｍｏｌ、３当量）、(２-ビフェニル)ジシクロヘキシルホスフィン(２７ｍｇ、０．０７５ｍｍｏｌ、０．１５当量）、酢酸パラジウム(ＩＩ)（６ｍｇ、０．０２５ｍｍｏｌ、０．０５当量）を順に加えた。脱気した溶液Ａ（４ｍＬ）を加え、反応液を震とう、または攪拌した。反応液を窒素バブリングにより３０秒間、脱気した。反応バイアルを３０秒間窒素置換し、密閉した。反応液を１００度で２０時間、震とう、または攪拌した。反応液を室温まで冷却後、ＬＣ／ＭＳにより反応進行を確認した。溶媒を減圧留去し、残渣にＤＭＦ（２ｍＬ）、溶液Ｂ（１ｍＬ）を加え、３０分間震とうまたは攪拌した。混合物をろ過し、ろ液を分取ＨＰＬＣにより精製し、化合物Ｉ－２３１を得た。
1H NMR δ (ppm)(CDCl3): 8.75 (1 H, dd, J = 4.87, 1.68 Hz), 8.69 (1 H, s), 8.68 (1 H, s), 8.56 (1 H, d, J = 2.28 Hz), 7.60 (1 H, ddd, J = 7.82, 2.33, 1.69 Hz), 7.47 (1 H, ddd, J = 7.81, 4.85, 0.90 Hz), 7.21 (1 H, d, J = 4.99 Hz), 4.57 (1 H, dd, J = 4.25, 3.99 Hz), 4.36 (1 H, d, J = 16.63 Hz), 4.24 (1 H, d, J = 16.63 Hz), 3.95 (1 H, dd, J = 12.06, 4.05 Hz), 3.73 (1 H, dd, J = 12.06, 4.24 Hz), 2.82 (3 H, s).  (4) Synthesis of compound I-231
Figure JPOXMLDOC01-appb-C000054
A 6: 1 (v / v) dioxane-water solution (solution A) was vigorously degassed for 2 hours while bubbling with nitrogen. A solution (solution B) of trithiocyanuric acid (360 mg), sodium chloride (1.4 g), and ammonia (0.88 SG) in ethanol (45 mL) / water (50 mL) was prepared. In a 40 mL size reaction vial, compound 4b (0.50 mmol, 1 eq), pyridine-3-boronic acid (1.00 mmol, 2 eq), cesium carbonate (489 mg, 1.50 mmol, 3 eq), (2-biphenyl) ) Dicyclohexylphosphine (27 mg, 0.075 mmol, 0.15 eq) and palladium (II) acetate (6 mg, 0.025 mmol, 0.05 eq) were added in turn. Degassed solution A (4 mL) was added and the reaction was shaken or stirred. The reaction was degassed by nitrogen bubbling for 30 seconds. The reaction vial was purged with nitrogen for 30 seconds and sealed. The reaction was shaken or stirred at 100 degrees for 20 hours. After the reaction solution was cooled to room temperature, the progress of the reaction was confirmed by LC / MS. The solvent was distilled off under reduced pressure, DMF (2 mL) and solution B (1 mL) were added to the residue, and the mixture was shaken or stirred for 30 minutes. The mixture was filtered and the filtrate was purified by preparative HPLC to give compound I-231.
1 H NMR δ (ppm) (CDCl 3 ): 8.75 (1 H, dd, J = 4.87, 1.68 Hz), 8.69 (1 H, s), 8.68 (1 H, s), 8.56 (1 H, d, J = 2.28 Hz), 7.60 (1 H, ddd, J = 7.82, 2.33, 1.69 Hz), 7.47 (1 H, ddd, J = 7.81, 4.85, 0.90 Hz), 7.21 (1 H, d, J = 4.99 Hz), 4.57 (1 H, dd, J = 4.25, 3.99 Hz), 4.36 (1 H, d, J = 16.63 Hz), 4.24 (1 H, d, J = 16.63 Hz), 3.95 (1 H, dd , J = 12.06, 4.05 Hz), 3.73 (1 H, dd, J = 12.06, 4.24 Hz), 2.82 (3 H, s).
（５）化合物Ｉ－１９０の合成
Figure JPOXMLDOC01-appb-C000055
　４０ｍＬサイズの反応バイアルに、化合物３（０．５０ｍｍｏｌ、１当量）、フェノール（１・００ｍｍｏｌ、２当量）、炭酸セシウム（４０７．５ｍｇ、１．２５ｍｍｏｌ、２．５当量）を順に加えた。乾燥したＤＭＦ（２．５ｍＬ）を加え、反応液を震とう、または攪拌した。反応バイアルを３０秒間窒素置換し、密閉した。反応液を１２０度で２０時間、震とう、または攪拌した。反応液を室温まで冷却後、ＬＣ／ＭＳにより反応進行を確認した。反応混合物をろ過し、ろ液を分取ＨＰＬＣにより精製し、化合物Ｉ－１９０を得た。
1H NMR δ (ppm)(CDCl3): 8.61 (1 H, s), 8.40 (1 H, d, J = 5.68 Hz), 7.49-7.43 (2 H, m), 7.36-7.21 (2 H, m), 7.10-7.06 (2 H, m), 6.59 (1 H, d, J = 5.68 Hz), 5.26-5.21 (1 H, m), 4.30 (2 H, s), 4.19 (1 H, dd, J = 11.80, 3.98 Hz), 3.92 (1 H, dd, J = 11.80, 5.60 Hz).  (5) Synthesis of Compound I-190
Figure JPOXMLDOC01-appb-C000055
Compound 3 (0.50 mmol, 1 equivalent), phenol (1.00 mmol, 2 equivalents), cesium carbonate (407.5 mg, 1.25 mmol, 2.5 equivalents) were sequentially added to a 40 mL size reaction vial. Dry DMF (2.5 mL) was added and the reaction was shaken or stirred. The reaction vial was purged with nitrogen for 30 seconds and sealed. The reaction was shaken or stirred at 120 degrees for 20 hours. After the reaction solution was cooled to room temperature, the progress of the reaction was confirmed by LC / MS. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to give compound I-190.
1 H NMR δ (ppm) (CDCl 3 ): 8.61 (1 H, s), 8.40 (1 H, d, J = 5.68 Hz), 7.49-7.43 (2 H, m), 7.36-7.21 (2 H, m), 7.10-7.06 (2 H, m), 6.59 (1 H, d, J = 5.68 Hz), 5.26-5.21 (1 H, m), 4.30 (2 H, s), 4.19 (1 H, dd , J = 11.80, 3.98 Hz), 3.92 (1 H, dd, J = 11.80, 5.60 Hz).
（６－Ａ）化合物Ｉ－１４０の合成
Figure JPOXMLDOC01-appb-C000056
　乾燥したジオキサンを、窒素バブリングにより２時間激しく脱気した。乾燥した１７ｍｍサイズの反応チューブに攪拌子を入れ、炭酸セシウム（３３０ｍｇ、１．０１２５ｍｍｏｌ、２．２５当量）を加えた。ジクロロメタン（１ｍＬ）に溶解したキサントホス（４０ｍｇ、０．０６７５ｍｍｏｌ、０．１５当量）をそれぞれの反応チューブに加え、溶媒を減圧留去した。中間体４（０．４５ｍｍｏｌ、１当量）の脱気した無水ジオキサン（２ｍＬ）溶液、及び３－メトキシアニリン（１．３５ｍｍｏｌ、３当量）の脱気した無水ジオキサン（１ｍＬ）溶液を順に加えた。最後に、酢酸パラジウム(ＩＩ)（１０ｍｇ、０．０４５ｍｍｏｌ、０．１ 当量）の脱気した無水ジオキサン（１ｍＬ）溶液を、それぞれの反応チューブに加え、３０秒間窒素バブリングにより脱気した。各バイアルを３０秒間窒素置換、密閉し、９０度で１８時間、攪拌した。反応液を室温まで冷却後、ＬＣ／ＭＳにより反応進行を確認した。反応終了後、室温まで冷却し、溶媒を減圧留去した。残渣に酢酸エチル（４ｍＬ）と飽和炭酸水素ナトリウム水溶液（４ｍＬ）を加え、超音波処理、ピペット攪拌により、抽出した。有機層を一旦ピペットにより除き、水層を酢酸エチル（４ｍＬ）で２度、抽出した。有機層をまとめて、別の新しい反応チューブに移し、減圧濃縮した。残渣をＤＭＦ（１．５ｍＬ）に溶解、ろ過し、ろ液を分取ＨＰＬＣにより精製し、化合物Ｉ－１４０を得た。 (6-A) Synthesis of Compound I-140
Figure JPOXMLDOC01-appb-C000056
The dried dioxane was degassed vigorously by nitrogen bubbling for 2 hours. A stir bar was placed in a dry 17 mm size reaction tube, and cesium carbonate (330 mg, 1.0125 mmol, 2.25 equivalents) was added. Xanthophos (40 mg, 0.0675 mmol, 0.15 equiv) dissolved in dichloromethane (1 mL) was added to each reaction tube and the solvent was removed in vacuo. A solution of Intermediate 4 (0.45 mmol, 1 eq) in degassed anhydrous dioxane (2 mL) and 3-methoxyaniline (1.35 mmol, 3 eq) in degassed anhydrous dioxane (1 mL) were added sequentially. Finally, palladium (II) acetate (10 mg, 0.045 mmol, 0.1 eq) in degassed anhydrous dioxane (1 mL) was added to each reaction tube and degassed by nitrogen bubbling for 30 seconds. Each vial was purged with nitrogen for 30 seconds, sealed, and stirred at 90 degrees for 18 hours. After the reaction solution was cooled to room temperature, the progress of the reaction was confirmed by LC / MS. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate (4 mL) and saturated aqueous sodium hydrogen carbonate solution (4 mL) were added to the residue, and extraction was performed by sonication and pipetting. The organic layer was once removed by pipette and the aqueous layer was extracted twice with ethyl acetate (4 mL). The organic layers were combined, transferred to another new reaction tube, and concentrated under reduced pressure. The residue was dissolved in DMF (1.5 mL) and filtered, and the filtrate was purified by preparative HPLC to give Compound I-140.
（６－Ｂ）化合物Ｉ－０７３の合成
Figure JPOXMLDOC01-appb-C000057
　５ｍＬのマイクロウェーブ反応バイアルに化合物４ｃ（０．４０ｍｍｏｌ、１当量）およびモルホリン（２ｍＬ）を加えた。バイアルを密閉し、マイクロウェーブ照射下、２００度で１４時間反応した。反応後、室温まで冷却し、ＬＣ／ＭＳにより反応進行を確認した。反応液を、メタノール（約５ｍＬ）を用いて別のチューブに移し、溶媒を減圧留去した。得られた残渣にＤＭＦ（１．５ｍＬ）を加え、ろ過した。ろ液を分取ＨＰＬＣにより精製し、化合物Ｉ－０７３を得た。
1H NMR δ (ppm)(CDCl3): 8.52 (1 H, d, J = 5.41 Hz), 8.41 (1 H, s), 7.01 (1 H, d, J = 5.43 Hz), 5.31 (1 H, dd, J = 3.65, 2.94 Hz), 4.38 (1 H, d, J = 16.72 Hz), 4.30 (1 H, d, J = 16.71 Hz), 4.16-4.08 (2 H, m), 3.87-3.80 (5 H, m), 3.67 (1 H, td, J = 9.77, 2.87 Hz), 3.46 (1 H, dt, J = 10.03, 3.53 Hz), 3.29 (3 H, s), 3.20-3.10 (2 H, m), 2.86-2.78 (2 H, m), 2.73 (1 H, ddd, J = 14.44, 9.55, 3.29 Hz).
(6-B) Synthesis of Compound I-073
Figure JPOXMLDOC01-appb-C000057
Compound 4c (0.40 mmol, 1 eq) and morpholine (2 mL) were added to a 5 mL microwave reaction vial. The vial was sealed and reacted at 200 degrees for 14 hours under microwave irradiation. After the reaction, the reaction mixture was cooled to room temperature, and the progress of the reaction was confirmed by LC / MS. The reaction solution was transferred to another tube using methanol (about 5 mL), and the solvent was distilled off under reduced pressure. DMF (1.5 mL) was added to the obtained residue and filtered. The filtrate was purified by preparative HPLC to give Compound I-073.
1 H NMR δ (ppm) (CDCl 3 ): 8.52 (1 H, d, J = 5.41 Hz), 8.41 (1 H, s), 7.01 (1 H, d, J = 5.43 Hz), 5.31 (1 H , dd, J = 3.65, 2.94 Hz), 4.38 (1 H, d, J = 16.72 Hz), 4.30 (1 H, d, J = 16.71 Hz), 4.16-4.08 (2 H, m), 3.87-3.80 (5 H, m), 3.67 (1 H, td, J = 9.77, 2.87 Hz), 3.46 (1 H, dt, J = 10.03, 3.53 Hz), 3.29 (3 H, s), 3.20-3.10 (2 H, m), 2.86-2.78 (2 H, m), 2.73 (1 H, ddd, J = 14.44, 9.55, 3.29 Hz).
実施例２　化合物Ｉ－２６２の合成
Figure JPOXMLDOC01-appb-C000058
工程１
　２－アミノ－２－（５－ブロモピリジン－３－イル）エタノール塩酸塩（１０ｇ、３９．４ｍｍｏｌ）およびクロロ酢酸（４．５ｇ、４７．３ｍｍｏｌ）のジクロロメタン（２００ｍＬ）溶液に、ＤＩＥＡ（６．９ｍＬ，３９．４ｍｍｏｌ）を加えた。室温にて１０分間攪拌した後、２－ヒドロキシピリジン－１－オキシド（５．３ｇ、４７．３ｍｍｏｌ）およびＥＤＣ（９．１ｇ、４７．３ｍｍｏｌ）を加え、室温にて４時間攪拌した。酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥した。ろ過、減圧濃縮により、粗製の化合物６（８．３ｇ、収率７２％）を固体として得た。
1H-NMR (400 MHz, DMSO-d6)δ8.71 (1 H, d, J = 7.8 Hz), 8.59 (1 H, s), 8.52 (1 H,s), 7.98 (1 H, s), 5.09 (1 H, t, J = 5.4 Hz), 4.89 (1 H, dd, J = 13.1, 6.0 Hz), 4.15 (2 H, s), 3.63 (2 H, t, J = 5.5 Hz).

工程２
　粗製の化合物６（８．３ｇ、２８．３ｍｍｏｌ）のＴＨＦ（２３０ｍＬ）溶液に、氷冷下にて水素化ナトリウム（２．２６ｇ、５６．６ｍｍｏｌ）を加え、１時間攪拌した。酢酸エチルを加え、飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥した。ろ過、減圧濃縮後、得られた残渣にヘキサンを加え固体とした。ろ取、乾燥し、粗製の化合物７（７．２２ｇ、収率９９％）を固体として得た。
1H-NMR (400 MHz, DMSO-d6)δ8.68 (1 H, s), 8.56 (1 H, s), 8.49 (1 H, s), 8.04 (1 H, s), 4.72 (1 H, brs), 4.12 (2 H, dd, J = 16.1 Hz), 3.99 (1 H, J = 11.8, 3.8 Hz), 3.70 (1 H, dd, J = 11.7, 5.6 Hz).

工程３
　化合物７（３．０ｇ、１１．７ｍｍｏｌ）をＤＭＦ（４５ｍＬ）に溶解し、氷冷下にてカリウムｔｅｒｔ－ブトキシド（１．９６ｇ、１７．５ｍｍｏｌ）および４－メチルベンジルブロミド（３．２ｇ、１７．５ｍｍｏｌ）を加えた。室温にて４時間攪拌した後、酢酸エチルを加え、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、ろ過、濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物８（３．２１ｇ、収率７６％）を得た。
1H-NMR (400 MHz, DMSO-d6)δ8.64 (1 H, s), 8.46 (1 H, s), 7.89 (1 H, s), 7.07 (4 H, dd, J = 18.7, 7.7 Hz), 4.96 (1 H, d, J = 15.1 Hz), 4.57 (1 H, s), 4.40 (1 H, d, J = 16.6 Hz), 4.26 (1 H, d, J = 16.6 Hz), 4.04 (1 H, m), 3.78 (2 H, t, J = 15.3 Hz), 2.26 (3 H, s).

工程４
　２－（トリフルオロメトキシ）フェニルボロン酸（２６ｍｇ、０．１２５ｍｍｏｌ）、化合物８（３０ｍｇ、０．０８３ｍｍｏｌ）およびＰｄＣｌ２（ｄｔｂｐｆ）（３ｍｇ、０．００５ｍｍｏｌ）のＴＨＦ（０．５ｍＬ）溶液に、２ｍｏｌ／Ｌ炭酸カリウム水溶液（０．１２ｍＬ）を加えた。窒素雰囲気下、およびマイクロウェーブ照射下で、１２０℃にて２０分間攪拌した。酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄し、有機層を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物Ｉ－２６２（３２ｍｇ、収率８７％）を得た。
1H-NMR (400 MHz, DMSO-d6)δ8.63 (1 H, s), 8.53 (1 H, s), 7.78 (1 H, s), 7.62-7.53 (4 H, m), 7.08 (4 H, dd, J = 22.6, 7.5 Hz), 5.08 (1 H, d, J = 15.1 Hz), 4.64 (1 H, s), 4.32 (2 H, dd, J = 30.0, 16.4 Hz), 4.04 (1 H, m), 3.84 (1 H, d, J = 11.8 Hz), 3.65 (1 H, d, J = 14.8 Hz), 2.26 (3 H, s).
Example 2 Synthesis of Compound I-262
Figure JPOXMLDOC01-appb-C000058
Process 1
To a solution of 2-amino-2- (5-bromopyridin-3-yl) ethanol hydrochloride (10 g, 39.4 mmol) and chloroacetic acid (4.5 g, 47.3 mmol) in dichloromethane (200 mL) was added DIEA (6. 9 mL, 39.4 mmol) was added. After stirring at room temperature for 10 minutes, 2-hydroxypyridine-1-oxide (5.3 g, 47.3 mmol) and EDC (9.1 g, 47.3 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over sodium sulfate. Filtration and concentration under reduced pressure gave crude compound 6 (8.3 g, yield 72%) as a solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.71 (1 H, d, J = 7.8 Hz), 8.59 (1 H, s), 8.52 (1 H, s), 7.98 (1 H, s ), 5.09 (1 H, t, J = 5.4 Hz), 4.89 (1 H, dd, J = 13.1, 6.0 Hz), 4.15 (2 H, s), 3.63 (2 H, t, J = 5.5 Hz) .

Process 2
Sodium hydride (2.26 g, 56.6 mmol) was added to a THF (230 mL) solution of the crude compound 6 (8.3 g, 28.3 mmol) under ice cooling, and the mixture was stirred for 1 hour. Ethyl acetate was added, washed with saturated brine, and the organic layer was dried over sodium sulfate. After filtration and concentration under reduced pressure, hexane was added to the resulting residue to obtain a solid. Filtration and drying gave crude compound 7 (7.22 g, 99% yield) as a solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.68 (1 H, s), 8.56 (1 H, s), 8.49 (1 H, s), 8.04 (1 H, s), 4.72 (1 H, brs), 4.12 (2 H, dd, J = 16.1 Hz), 3.99 (1 H, J = 11.8, 3.8 Hz), 3.70 (1 H, dd, J = 11.7, 5.6 Hz).

Process 3
Compound 7 (3.0 g, 11.7 mmol) was dissolved in DMF (45 mL), and potassium tert-butoxide (1.96 g, 17.5 mmol) and 4-methylbenzyl bromide (3.2 g, 17 mL) were cooled with ice. 0.5 mmol) was added. After stirring at room temperature for 4 hours, ethyl acetate was added and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 8 (3.21 g, yield 76%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.64 (1 H, s), 8.46 (1 H, s), 7.89 (1 H, s), 7.07 (4 H, dd, J = 18.7, 7.7 Hz), 4.96 (1 H, d, J = 15.1 Hz), 4.57 (1 H, s), 4.40 (1 H, d, J = 16.6 Hz), 4.26 (1 H, d, J = 16.6 Hz) , 4.04 (1 H, m), 3.78 (2 H, t, J = 15.3 Hz), 2.26 (3 H, s).

Process 4
To a THF (0.5 mL) solution of 2- (trifluoromethoxy) phenylboronic acid (26 mg, 0.125 mmol), Compound 8 (30 mg, 0.083 mmol) and PdCl 2 (dtbpf) (3 mg, 0.005 mmol) A 2 mol / L potassium carbonate aqueous solution (0.12 mL) was added. The mixture was stirred at 120 ° C. for 20 minutes in a nitrogen atmosphere and under microwave irradiation. Ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound I-262 (32 mg, yield 87%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.63 (1 H, s), 8.53 (1 H, s), 7.78 (1 H, s), 7.62-7.53 (4 H, m), 7.08 (4 H, dd, J = 22.6, 7.5 Hz), 5.08 (1 H, d, J = 15.1 Hz), 4.64 (1 H, s), 4.32 (2 H, dd, J = 30.0, 16.4 Hz), 4.04 (1 H, m), 3.84 (1 H, d, J = 11.8 Hz), 3.65 (1 H, d, J = 14.8 Hz), 2.26 (3 H, s).
実施例３　化合物Ｉ－２６６の合成
Figure JPOXMLDOC01-appb-C000059
　化合物８（１００ｍｇ、０．２７ｍｍｏｌ）、フェノール（３１ｍｇ、０．３３ｍｍｏｌ）、リン酸３カリウム（１１７ｍｇ、０．５４ｍｍｏｌ）、ｔＢｕ－Ｘ－ｐｈｏｓ（３ｍｇ、０．００７ｍｍｏｌ）、Ｐｄ２（ｄｂａ）３（３ｍｇ、０．００３ｍｍｏｌ）にトルエン（０．６ｍＬ）を加え、窒素雰囲気下、およびマイクロウェーブ照射下で、１１０℃にて３０分間攪拌した。酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥した。ろ過、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物Ｉ－２６６（３７ｍｇ、収率３６％）を得た。
1H-NMR (400 MHz, DMSO-d6)δ8.29 (2 H, s), 7.44 (2 H, t, J = 7.7 Hz), 7.33 (1 H, brs), 7.20 (1 H, t, J = 7.3 Hz), 7.12-7.08 (2 H, m), 7.05-7.02 (4 H, m), 5.00 (1 H, d, J = 14.9 Hz), 4.55 (1 H, brs), 4.28 (1 H, d, J = 12.5 Hz), 4.00 (1 H, m), 3.79 (1 H, d, J = 12.2 Hz), 3.70 (1 H, d, J = 14.9 Hz), 2.27 (3 H, s).
Example 3 Synthesis of Compound I-266
Figure JPOXMLDOC01-appb-C000059
Compound 8 (100 mg, 0.27 mmol), phenol (31 mg, 0.33 mmol), tripotassium phosphate (117 mg, 0.54 mmol), tBu-X-phos (3 mg, 0.007 mmol), Pd 2 (dba) 3 Toluene (0.6 mL) was added to (3 mg, 0.003 mmol), and the mixture was stirred at 110 ° C. for 30 minutes in a nitrogen atmosphere and under microwave irradiation. Ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over sodium sulfate. Filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain compound I-266 (37 mg, yield 36%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.29 (2 H, s), 7.44 (2 H, t, J = 7.7 Hz), 7.33 (1 H, brs), 7.20 (1 H, t , J = 7.3 Hz), 7.12-7.08 (2 H, m), 7.05-7.02 (4 H, m), 5.00 (1 H, d, J = 14.9 Hz), 4.55 (1 H, brs), 4.28 ( 1 H, d, J = 12.5 Hz), 4.00 (1 H, m), 3.79 (1 H, d, J = 12.2 Hz), 3.70 (1 H, d, J = 14.9 Hz), 2.27 (3 H, s).
実施例４　化合物Ｉ－２８０の合成
Figure JPOXMLDOC01-appb-C000060
　化合物８（１００ｍｇ、０．２７ｍｍｏｌ）、２－フルオロベンジルアミン（５２ｍｇ、０．４２ｍｍｏｌ）、炭酸セシウム（１８０ｍｇ、０．５５ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（６．６ｍｇ、０．０１２ｍｍｏｌ）、Ｐｄ２（ｄｂａ）３（６．４ｍｇ、０．００６ｍｍｏｌ）に１，４－ジオキサン（１．１ｍＬ）を加え、窒素雰囲気下、およびマイクロウェーブ照射下で、１２０℃にて４時間攪拌した。酢酸エチルを加え、飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥した。ろ過、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物Ｉ－２８０（３７ｍｇ、収率３３％）を得た。
1H-NMR (400 MHz, DMSO-d6)δ7.94 (1 H, s), 7.66 (1 H, s), 7.40 (1 H, t, J = 7.5 Hz), 7.33 (1 H, dd, J = 13.7, 7.0 Hz), 7.23-7.00 (6 H, m), 6.81 (1 H, s), 6.58 (1 H, t, J = 5.7 Hz), 5.13 (1 H, d, J = 14.9 Hz), 4.33-4.24 (5 H, m), 3.94 (1 H, d, J = 12.0 Hz), 3.70 (1 H, d, J = 9.8 Hz), 2.27 (3 H, s).
Example 4 Synthesis of Compound I-280
Figure JPOXMLDOC01-appb-C000060
Compound 8 (100 mg, 0.27 mmol), 2-fluorobenzylamine (52 mg, 0.42 mmol), cesium carbonate (180 mg, 0.55 mmol), Xantphos (6.6 mg, 0.012 mmol), Pd 2 (dba) 3 1,4-Dioxane (1.1 mL) was added to (6.4 mg, 0.006 mmol), and the mixture was stirred at 120 ° C. for 4 hours under a nitrogen atmosphere and under microwave irradiation. Ethyl acetate was added, washed with saturated brine, and the organic layer was dried over sodium sulfate. Filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain compound I-280 (37 mg, yield 33%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ7.94 (1 H, s), 7.66 (1 H, s), 7.40 (1 H, t, J = 7.5 Hz), 7.33 (1 H, dd , J = 13.7, 7.0 Hz), 7.23-7.00 (6 H, m), 6.81 (1 H, s), 6.58 (1 H, t, J = 5.7 Hz), 5.13 (1 H, d, J = 14.9 Hz), 4.33-4.24 (5 H, m), 3.94 (1 H, d, J = 12.0 Hz), 3.70 (1 H, d, J = 9.8 Hz), 2.27 (3 H, s).
実施例５　化合物Ｉ－２７５の合成
Figure JPOXMLDOC01-appb-C000061
　実施例２と同様の反応を経て得られた化合物９（４０ｍｇ、０．１２ｍｍｏｌ）のＤＭＦ（０．３ｍＬ）溶液に、カリウムｔｅｒｔ－ブトキシド（２０ｍｇ、０．１７ｍｍｏｌ）、ブロモメチルシクロヘキサン（１７ｍｇ、０．１７ｍｍｏｌ）を加えた。室温にて一晩攪拌した後、酢酸エチルを加え、飽和食塩水で洗浄し、有機層を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物Ｉ－２７５（４２ｍｇ、収率８２％）を得た。
1H-NMR (400 MHz, DMSO-d6)δ8.91 (1 H, s), 8.54 (1 H, s), 7.99 (1 H, s), 7.87 (2 H, d, J = 8.4 Hz), 7.52 (2 H, d, J = 8.2 Hz), 4.78 (1 H, brs), 4.32 (1 H, d, J = 16.3 Hz), 4.22 (1 H, d, J = 16.4 Hz), 4.12 (1 H, dd, J = 11.9, 2.6 Hz), 3.89 (1 H, d, J =11.9 Hz), 3.72 (1 H, dd, J = 13.4, 8.1 Hz), 2.33 (1 H, dd, J = 13.4, 6.7 Hz), 1.64-1.56 (6 H, m), 1.19-1.08 (3 H, m), 0.99-0.78 (2 H, m).
Example 5 Synthesis of Compound I-275
Figure JPOXMLDOC01-appb-C000061
To a solution of compound 9 (40 mg, 0.12 mmol) obtained in the same manner as in Example 2 in DMF (0.3 mL) was added potassium tert-butoxide (20 mg, 0.17 mmol), bromomethylcyclohexane (17 mg, 0 mL). .17 mmol) was added. After stirring at room temperature overnight, ethyl acetate was added, washed with saturated brine, and the organic layer was concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound I-275 (42 mg, yield: 82%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ8.91 (1 H, s), 8.54 (1 H, s), 7.99 (1 H, s), 7.87 (2 H, d, J = 8.4 Hz ), 7.52 (2 H, d, J = 8.2 Hz), 4.78 (1 H, brs), 4.32 (1 H, d, J = 16.3 Hz), 4.22 (1 H, d, J = 16.4 Hz), 4.12 (1 H, dd, J = 11.9, 2.6 Hz), 3.89 (1 H, d, J = 11.9 Hz), 3.72 (1 H, dd, J = 13.4, 8.1 Hz), 2.33 (1 H, dd, J = 13.4, 6.7 Hz), 1.64-1.56 (6 H, m), 1.19-1.08 (3 H, m), 0.99-0.78 (2 H, m).
　上記実施例に従い、以下の化合物を合成した。 The following compounds were synthesized according to the above examples.
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
　以下に、本発明化合物の生物試験例を記載する。 Hereinafter, biological test examples of the compounds of the present invention will be described.
試験例１：Ｎａｖ１．７阻害活性の評価
　以下の方法により、本発明化合物がＮａｖ１．７機能を阻害する程度を評価した。 Test Example 1: Evaluation of Nav1.7 inhibitory activity The degree to which the compound of the present invention inhibits Nav1.7 function was evaluated by the following method.
　ヒトＮａｖ１．７を安定発現したHEK293細胞を384 ウェルマイクロタイタープレートに8000個/ウェルで播種し、37℃、5％CO2インキュベーター内で24時間培養後、アッセイプレートとして使用した。アッセイプレートの各ウェル内をアッセイバッファー(10mmol/L HEPES、10mmol/L Glucose, 137mmol/L NaCl, 4 mmol/L KCl, 1 mmol/L MgCl2, 1.8 mmol/L CaCl2, pH7.4)で洗浄した。20μLのアッセイバッファーを残したウェル内に10μLの蛍光指示薬溶液（7.5μmol/L Asante Natrium Green-2（TEFLABS社）、0.08% Pluronic F-127、アッセイバッファーに溶解）を添加し、室温で1時間静置した（Asante Natrium Green-2の最終濃度：2.5μmol/L）。各ウェル内をアッセイバッファーで洗浄後、20μLのアッセイバッファーを残し、室温で5分間静置した。アッセイプレートをカイネティック蛍光測定装置FLIPR TETRA (Molecular devices社)にセットし、励起波長：488nm、測定波長：510-570nmで各ウェルの蛍光指示薬由来の蛍光強度を１秒ないし10秒間隔で測定した。各ウェル内にFLIPR TETRA内蔵のピペッターを用いて、測定開始直後にアッセイバッファーで希釈した10μLの本発明化合物溶液を添加し、さらに測定開始から約5分後にアッセイバッファーで希釈した10μLのナトリウムチャネル開口剤Veratridine溶液を添加し、混合した（Veratridineの最終濃度：40μmol/L）。FLIPR TETRAによる蛍光強度測定はVeratridine添加から約3分後まで継続した。 HEK293 cells stably expressing human Nav1.7 were seeded at 8000 cells / well in a 384-well microtiter plate, cultured for 24 hours in a 37 ° C., 5% CO 2 incubator and used as an assay plate. Each well of the assay plate was washed with assay buffer (10 mmol / L HEPES, 10 mmol / L Glucose, 137 mmol / L NaCl, 4 mmol / L KCl, 1 mmol / L MgCl2, 1.8 mmol / L CaCl2, pH 7.4). . Add 10 μL of fluorescent indicator solution (7.5 μmol / L Asante Natrium Green-2 (TEFLABS), 0.08% Pluronic F-127, dissolved in assay buffer) to the well with 20 μL of assay buffer remaining, and then at room temperature for 1 hour It was allowed to stand (final concentration of Asante Natrium Green-2: 2.5 μmol / L). After washing each well with assay buffer, 20 μL of assay buffer was left, and the well was allowed to stand at room temperature for 5 minutes. The assay plate was set in a kinetic fluorescence measurement apparatus FLIPR TETRA (Molecular devices), and the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm. . Using a pipetter with built-in FLIPR TETRA in each well, add 10 μL of the compound solution of the present invention diluted with assay buffer immediately after the start of measurement, and further open 10 μL of sodium channel diluted with assay buffer approximately 5 minutes after the start of measurement. The agent Veratridine solution was added and mixed (final concentration of Veratridine: 40 μmol / L). The fluorescence intensity measurement by FLIPR TETRA was continued until about 3 minutes after the addition of Veratridine.
　本発明化合物のＮａｖ１．７阻害活性（IC50値）の算出方法を以下に示す。各ウェルについてVeratridine溶液の添加直前から3分後までの蛍光強度値の最大値と最小値の差によって表される変化量を算出した。本発明化合物の抑制率は、本発明化合物の溶媒であるDMSOを添加したウェルを陰性対照とし、Mexiletineを添加したウェル(Mexiletineの最終濃度：500μmol/L )を陽性対照として次式より算出した。
　抑制率＝(1-(本発明化合物による変化量－陽性対照による変化量)/(陰性対照による変化量－陽性対象による変化量))x100
本発明化合物濃度0.156、0.312、0.625、1.25、2.50、5.00、10.0、20.0μmol/L(8点)について抑制率を求め、ロジスティック近似法によりIC50値(μmol/L)を算出した。
本発明化合物の試験結果を以下の表に示す。 The calculation method of Nav1.7 inhibitory activity (IC50 value) of the compound of the present invention is shown below. For each well, the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity value from immediately before the addition of Veratridine solution to 3 minutes later was calculated. The inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO as a solvent of the compound of the present invention as a negative control and a well added with mexiletine (final concentration of mexiletine: 500 μmol / L) as a positive control.
Inhibition rate = (1- (change amount by the compound of the present invention−change amount by positive control) / (change amount by negative control−change amount by positive object)) × 100
The inhibition rate was determined for the compound concentrations of the present invention of 0.156, 0.312, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 μmol / L (8 points), and the IC50 value (μmol / L) was calculated by the logistic approximation method.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
試験例２：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価する。 Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始する。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止する。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量する。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. To start. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) , Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。
The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
試験例３：ＢＡ試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはＳＤラットを使用する。
（２）飼育条件：マウスあるいはＳＤラットは、固形飼料および滅菌水道水を自由摂取させる。
（３）投与量、群分けの設定：所定の投与量で経口投与および静脈内投与する。以下のように群を設定する。（化合物ごとで投与量は変更有）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液または懸濁液として投与する。静脈内投与は可溶化して投与する。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与する。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与する。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定する。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群の投与量比およびＡＵＣ比から本発明化合物のバイオアベイラビリティ（ＢＡ）を算出する。
Test Example 3: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration liquid: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with a needle.
(6) Evaluation item: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.
試験例４：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価する。 Test Example 4: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させる（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心する。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算する。
In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%.
試験例５：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価する。 Test Example 5: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定する。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とする。
A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC 50 by inverse estimation using a logistic model. The case where the difference in IC 50 value is 5 μmol / L or more is (+), and the case where it is 3 μmol / L or less is (−).
試験例６：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価する。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は７．７０ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去する。７．７０ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１２０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加する。ＴＡ１００株は３．４２ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１３０ｍＬに添加し試験菌液を調製する。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養する。本発明化合物を曝露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し、５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養する。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。
Test Example 6: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL of Micro F buffer (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: The cells are suspended in 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacterial growth wells that changed to yellow in 48 wells per dose was counted. Evaluate compared to negative control group. The negative mutagenicity is indicated as (−) and the positive mutagenicity is indicated as (+).
試験例７：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャネルを発現させたＨＥＫ２９３細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討する。
　全自動パッチクランプシステム（ＰａｔｃｈＸｐｒｅｓｓ　７０００Ａ、ＡｘｏｎＩｎｓｔｒｕｍｅｎｔｓ　Ｉｎｃ．）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持し、－５０ｍＶのリーク電位を与えた後、＋４０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録する。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１３５　ｍｍｏｌ／Ｌ、ＫＣｌ：５．４　ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．３ｍｍｏｌ／Ｌ、ＣａＣｌ２・２Ｈ２Ｏ：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２・６Ｈ２Ｏ：１ｍｍｏｌ／Ｌ、グルコース：１０ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温条件下で、１０分間細胞に適用させる。得られたＩＫｒから、解析ソフト（ＤａｔａＸｐｒｅｓｓ　ｖｅｒ．２、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価する。

試験例７－２：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャネルを発現させたＣＨＯ細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討する。
　全自動パッチクランプシステム（ＱＰａｔｃｈ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持し、－５０ｍＶのリーク電位を与えた後、＋２０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録する。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１４５　ｍｍｏｌ／Ｌ、ＫＣｌ：４　ｍｍｏｌ／Ｌ、ＣａＣｌ２：２　ｍｍｏｌ／Ｌ、ＭｇＣｌ２：１　ｍｍｏｌ／Ｌ、グルコース：１０　ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温条件下で、１０分間細胞に適用させる。得られたＩＫｒから、解析ソフト（Ｆａｌｓｔｅｒ　Ｐａｔｃｈ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価する。
Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing human ether-a-go-related gene (hERG) channels are used for ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ) that plays a role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cell was held at a membrane potential of −80 mV by the whole cell patch clamp method, and after applying a leak potential of −50 mV, depolarization stimulation of +40 mV was applied. Record the I Kr elicited for 2 seconds, followed by a -50 mV repolarization stimulus for 2 seconds. After the generated current is stabilized, an extracellular solution (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration) CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine etheric acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.

Test Example 7-2: hERG Test Ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role in the process, is examined.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by a whole cell patch clamp method, and after applying a leak potential of −50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol) in which the compound of the present invention is dissolved at a desired concentration. / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7. 4) is applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current is measured from the obtained I Kr using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
試験例８：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定する。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとした）５９４μＬに添加する。２５℃で１６時間静置させた後、混液を吸引濾過する。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣまたはＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定する。
Test Example 8: Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) To 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.
試験例９：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとする）を２００μＬずつ添加する。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加する。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないかを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量する。
Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１　錠剤
　　本発明化合物　　　　　　　　　１５ｍｇ
　　乳糖　　　　　　　　　　　　　１５ｍｇ
　　ステアリン酸カルシウム　　　　　３ｍｇ
　ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２　カプセル剤
　　本発明化合物　　　　　　　　　１０ｍｇ
　　ステアリン酸マグネシウム　　　１０ｍｇ
　　乳糖　　　　　　　　　　　　　８０ｍｇ
を均一に混合して粉末又は細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
製剤例３　顆粒剤
　　本発明化合物　　　　　　　　　　　３０ｇ
　　乳糖　　　　　　　　　　　　　　２６５ｇ
　　ステアリン酸マグネシウム　　　　　　５ｇ
をよく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.
　本発明に係る化合物は、Ｎａｖ１．７に対する阻害作用を有し、Ｎａｖ１．７が関与する疾患または状態の治療剤および／または予防剤として有用であると考えられる。 The compound according to the present invention has an inhibitory action against Nav1.7, and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving Nav1.7.

Claims (12)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、　
    　Ｒ１は、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基；
    　－Ｘ－は、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、－Ｓ－（Ｃ（Ｒ６a）（Ｒ６ｂ））ｑ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；
    　Ｒ５aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　Ｒ５ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　Ｒ６aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　Ｒ６ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　Ｒ７は、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、または置換若しくは非置換のアルキルカルボニル；
    　Ｒ８aは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　Ｒ８ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、または置換若しくは非置換のアルキニル；
    　ｐ、ｑおよびｒは、それぞれ独立して、０～５の整数；
    　Ｒ２は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
    　ｎは、０または１；
    　－Ｙ－は、単結合、置換若しくは非置換のアルキレン、置換若しくは非置換のアルケニレン、または置換若しくは非置換のアルキニレン；
    　Ｒ３は、水素原子、ハロゲン、カルバモイル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、または置換若しくは非置換の非芳香族複素環オキシ；
    　Ｒ４は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のモノアルキルアミノ、または置換若しくは非置換のジアルキルアミノ；
    　ｍは、０～２の整数）
    で示される化合物またはその製薬上許容される塩。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group A heterocyclic group;
    -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, -S- (C (R 6a ) (R 6b )) q-, or -N (R 7 )- (C (R 8a ) (R 8b )) r-;
    Each R 5a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    Each R 5b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    Each R 6a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    Each R 6b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    R 7 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkylcarbonyl;
    Each R 8a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    Each R 8b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    p, q and r are each independently an integer of 0 to 5;
    Each R 2 is independently halogen, hydroxy, carboxy, amino, carbamoyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino Or substituted or unsubstituted dialkylamino;
    n is 0 or 1;
    -Y- is a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
    R 3 is a hydrogen atom, halogen, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted A non-aromatic carbocyclic oxy, a substituted or unsubstituted aromatic heterocyclic oxy, or a substituted or unsubstituted non-aromatic heterocyclic oxy;
    Each R 4 independently represents halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, or substituted or Unsubstituted dialkylamino;
    m is an integer from 0 to 2)
    Or a pharmaceutically acceptable salt thereof.
  2. 　Ｒ１が、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基である、請求項１記載の化合物またはその製薬上許容される塩。
    The compound according to claim 1, wherein R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group. Or a pharmaceutically acceptable salt thereof.
  3. 　－Ｘ－が、単結合、－Ｏ－（Ｃ（Ｒ５a）（Ｒ５ｂ））ｐ－、または－Ｎ（Ｒ７）－（Ｃ（Ｒ８a）（Ｒ８ｂ））ｒ－；ｐおよびｒが、それぞれ独立して、０または１；Ｒ５a、Ｒ５ｂ、Ｒ７、Ｒ８a、およびＲ８ｂが、請求項１と同意義である、請求項１または２に記載の化合物またはその製薬上許容される塩。
    -X- is a single bond, -O- (C (R 5a ) (R 5b )) p-, or -N (R 7 )-(C (R 8a ) (R 8b )) r-; p and r Are each independently 0 or 1; R 5a , R 5b , R 7 , R 8a , and R 8b are as defined in claim 1 or a pharmaceutically acceptable salt thereof Acceptable salt.
  4. 　－Ｘ－が、単結合、－Ｏ－（ＣＨ２）ｐ－、または－Ｎ（Ｈ）－（ＣＨ２）ｒ－であり；ｐおよびｒが、それぞれ独立して、０または１である、請求項１または２に記載の化合物またはその製薬上許容される塩。
    -X- is a single bond, -O- (CH 2 ) p-, or -N (H)-(CH 2 ) r-; p and r are each independently 0 or 1, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  5. 　ｎが、０である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein n is 0.
  6. 　－Ｙ－が、単結合または置換若しくは非置換のアルキレンである、請求項１～５のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein -Y- is a single bond or substituted or unsubstituted alkylene.
  7. 　Ｒ３が、水素原子、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族複素環式基、または置換若しくは非置換の芳香族炭素環オキシである、請求項１～６のいずれかに記載の化合物またはその製薬上許容される塩。
    R 3 is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is a group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic oxy.
  8. 　ｍが、０である、請求項１～７のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein m is 0.
  9. 　請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
    A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　Ｎａｖ１．７阻害作用を有する請求項９記載の医薬組成物。
    The pharmaceutical composition according to claim 9, which has a Nav1.7 inhibitory action.
  11. 　Ｎａｖ１．７が関与する疾患の治療および／または予防に使用するための、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving Nav1.7.
  12. 　請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、Ｎａｖ１．７が関与する疾患の治療および／または予防方法。 A method for treating and / or preventing a disease involving Nav1.7, which comprises administering the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
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