WO2013161928A1 - Dérivé oxazolotriazole et composition médicamenteuse contenant celui-ci - Google Patents

Dérivé oxazolotriazole et composition médicamenteuse contenant celui-ci Download PDF

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Publication number
WO2013161928A1
WO2013161928A1 PCT/JP2013/062181 JP2013062181W WO2013161928A1 WO 2013161928 A1 WO2013161928 A1 WO 2013161928A1 JP 2013062181 W JP2013062181 W JP 2013062181W WO 2013161928 A1 WO2013161928 A1 WO 2013161928A1
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substituted
unsubstituted
aromatic
aromatic heterocyclic
aromatic carbocyclic
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PCT/JP2013/062181
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English (en)
Japanese (ja)
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一成 服部
健二 高谷
一穂 川瀬
夏枝 青木
義人 石田
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塩野義製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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).
  • Non-patent Document 9 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 Documents 10 and 11 it is known that it also shows an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11), and safety that can affect heart function that is particularly important in life support.
  • a Nav1.7 selective inhibitor having a weak inhibitory activity against Nav1.5 exhibits a strong analgesic action and is very useful as a therapeutic agent for various pain pathologies overcoming safety concerns. It is done.
  • Non-Patent Documents 12, 13, and 14 and Patent Documents 3 and 4 describe a compound having a structure similar to that of the compound of the present invention, but do not describe the Nav1.7 inhibitory action.
  • Patent Documents 1 and 2 describe compounds having a Nav1.7 inhibitory action, but differ in structure from the compounds of the present invention.
  • 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 (22) and (1 ′) to (8 ′).
  • R 1a is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted dialkylamino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-substituted 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 aromatic The compound according to the above (1) or a pharmaceutically acceptable salt thereof, which is heterocyclic oxy, or substituted or unsubstituted aromatic carbocyclic alkyloxy.
  • R 7 is a group represented by — (C (R 9 ) (R 10 )) pR 11 , represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a Or a pharmaceutically acceptable salt thereof according to (1) or (2) above, which is a group or a group represented by —C (R 3a ) (R 4a ) —O—Y a —R 6a .
  • R 9 is independently a hydrogen atom or halogen
  • R 10 is independently a hydrogen atom or halogen, or a pharmaceutical product thereof Top acceptable salt.
  • R 6a is a hydrogen atom, halogen, hydroxy, carboxy, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted dialkylamino, 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 aromatic carbocyclic amino, or substituted or unsubstituted non-aromatic carbocyclic amino; or “—R 5a ” and “—Y a -R 6a ” groups to which they are attached The compound according to any one of (1) to (9) above or a product thereof, which forms a substituted
  • R 8 is a substituted or unsubstituted aromatic carbocyclic group; or a group represented by — (C (R 13 ) (R 14 )) qR 15 , —C (R 16 ) (R 17 ) —N (R 18 ) —X—R 19 or a group represented by —C (R 16 ) (R 17 ) —O—X—R 19 above (1) to (10) Or a pharmaceutically acceptable salt thereof.
  • R 13 is each independently a hydrogen atom, halogen, or alkyl
  • R 14 is each independently a hydrogen atom, halogen, or alkyl. Or a pharmaceutically acceptable salt thereof.
  • R 19 is a hydrogen atom, halogen, hydroxy, carboxy, carbamoyl, sulfo, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxy Carbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic amino, or a substituted or unsubstitute
  • R 1 is a hydrogen atom, halogen, 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 aromatic carbocyclic alkyl, substituted or unsubstituted aromatic carbocyclic alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic A group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted
  • R 1 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic heterocyclic group, or substituted or unsubstituted aromatic carbocyclic oxy ;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic alkyl, or substituted or unsubstituted aromatic carbocyclic group;
  • R 3 and R 4 taken together are oxo;
  • R 5 is a hydrogen atom, or substituted or unsubstituted alkyl;
  • -Y- is a single bond or substituted or unsubstituted alkylene;
  • R 6 is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted dialkylamino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsub
  • a pharmaceutical composition comprising the compound according to any one of (1) to (18) and (1 ′) to (8 ′) or a pharmaceutically acceptable salt thereof.
  • a disease associated with Nav1.7 comprising administering the compound according to any one of (1) to (18) 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.
  • Different embodiments include 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 2 or more rings also includes those in which the ring in the above “aromatic carbocyclic group” is condensed with a monocyclic or 2 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, dihydroindenyl, 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, dihydrobenzofuryl, dihydrobenzodioxinyl 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.
  • 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 carbonylamino” means a group in which the following “aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic carbocyclic carbonyl for example, phenylcarbonylamino, naphthylcarbonylamino and the like can be mentioned.
  • Non-aromatic carbocyclic carbonylamino means a group in which the above “non-aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples thereof include cyclopropylcarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino and the like.
  • “Aromatic heterocyclic carbonylamino” means a group in which the above “aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic carbonyl for example, pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.
  • Non-aromatic heterocyclic carbonylamino means a group in which the above “non-aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like can be mentioned.
  • “Aromatic carbocyclic sulfonylamino” means a group in which the following “aromatic carbocyclic sulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic carbocyclic sulfonyl for example, phenylsulfonylamino, naphthylsulfonylamino and the like can be mentioned.
  • Non-aromatic carbocyclic sulfonylamino means a group in which the above “non-aromatic carbocyclic sulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylsulfonylamino, cyclohexylsulfonylamino, cyclohexenylsulfonylamino and the like can be mentioned.
  • “Aromatic heterocyclic sulfonylamino” means a group in which the above “aromatic heterocyclic sulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic sulfonyl for example, pyridylsulfonylamino, oxazolylsulfonylamino and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonylamino means a group in which the above “non-aromatic heterocyclic sulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • non-aromatic heterocyclic sulfonyl For example, piperidinylsulfonylamino, tetrahydrofurylsulfonylamino 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 substituent group A.
  • Substituent group A 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,
  • substituents of “substituted or unsubstituted alkyl” and “substituted or unsubstituted alkyloxy” include the following substituent group B.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituent group B.
  • Substituent group B 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 , Alkynylsulfonyl, monoalky
  • the atom at any position on the ring may be bonded to one or more groups selected from the following substituent group C.
  • Substituent group C 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,
  • 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.
  • Substituted or unsubstituted aromatic carbocyclic alkyl and “substituted or unsubstituted aromatic carbocyclic alkyloxy” are aromatic carbons of the above “aromatic carbocyclic alkyl” and “aromatic carbocyclic alkyloxy”.
  • the ring portion may be substituted with one or more groups selected from the above substituent group C, and / or the alkyl portion of the “aromatic carbocyclic alkyl” and “aromatic carbocyclic alkyloxy” is The case where it is substituted with one or more groups selected from Substituent Group B is included.
  • Substituted or unsubstituted non-aromatic carbocyclic alkyl and “substituted or unsubstituted non-aromatic carbocyclic alkyloxy” are the above-mentioned “non-aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyloxy”.
  • non-aromatic carbocyclic moiety may be substituted with one or more groups selected from the above substituent group C, and / or the above-mentioned “non-aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyloxy”
  • the alkyl part of "is substituted with one or more groups selected from the above substituent group B is included.
  • “Substituted or unsubstituted aromatic heterocyclic alkyl” and “substituted or unsubstituted aromatic heterocyclic alkyloxy” are aromatic carbons of the above “aromatic heterocyclic alkyl” and “aromatic heterocyclic alkyloxy”.
  • the ring part may be substituted with one or more groups selected from the above substituent group C, and / or the alkyl part of the “aromatic heterocyclic alkyl” and “aromatic heterocyclic alkyloxy” is The case where it is substituted with one or more groups selected from Substituent Group B is included.
  • “Substituted or unsubstituted non-aromatic heterocyclic alkyl” and “substituted or unsubstituted non-aromatic heterocyclic alkyloxy” are the above-mentioned “non-aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyloxy”.
  • non-aromatic carbocyclic moiety may be substituted with one or more groups selected from the above-mentioned substituent group C, and / or the above-mentioned “non-aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyloxy”
  • substituent group C substituent group C
  • non-aromatic heterocyclic alkyl and “non-aromatic heterocyclic alkyloxy”
  • alkyl part of "is substituted with one or more groups selected from the above substituent group B is included.
  • the “—R 5 ” group and the “—YR 6 ” group together with the nitrogen atom to which they are bonded form a substituted or unsubstituted non-aromatic heterocycle “Includes the case where the“ —R 5 ”group and the“ —Y—R 6 ”group form a non-aromatic heterocyclic ring containing the nitrogen atom.
  • Examples include thiazole, tetrahydroisothiazole, hexahydroazepine, diazepan, indoline, and isoindoline.
  • the “—R 5a ” group and the “—Y a -R 6a ” group together with the nitrogen atom to which they are bonded form a substituted or unsubstituted non-aromatic heterocycle “Includes the case where the“ —R 5a ”group and the“ —Y a -R 6a ”group form a non-aromatic heterocyclic ring containing the nitrogen atom.
  • Examples include thiazole, tetrahydroisothiazole, tetrahydroquinoline, tetrahydroisoquinoline, hexahydroazepine, diazepan, indoline, and isoindoline.
  • the “—R 18 ” group and the “—XR 19 ” group together with the nitrogen atom to which they are bonded form a substituted or unsubstituted non-aromatic heterocycle ” This includes the case where the “—R 18 ” group and the “—XR 19 ” group form a non-aromatic heterocyclic ring containing the nitrogen atom.
  • Examples include thiazole, tetrahydroisothiazole, tetrahydroquinoline, tetrahydroisoquinoline, hexahydroazepine, diazepan, indoline, and isoindoline.
  • R 1a includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted dialkylamino, 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 fragrance Group heterocyclic oxy, or substituted or unsubstituted aromatic carbocyclic alkyloxy.
  • R 1a includes a hydrogen atom, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, substituted or non-substituted A substituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy, or a substituted or unsubstituted aromatic heterocyclic oxy may be mentioned.
  • R 1a includes a hydrogen atom, halogen, alkyloxy substituted with substituted or unsubstituted phenyl, substituted or unsubstituted dialkylamino, substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexenyl, or substituted or unsubstituted Substituted phenyloxy.
  • R 1a include a hydrogen atom, substituted or unsubstituted phenyl, or substituted or unsubstituted phenyloxy.
  • R 7 is a group represented by-(C (R 9 ) (R 10 )) p-R 11 , represented by -C (R 3a ) (R 4a ) -N (R 5a ) -Y a -R 6a Or a group represented by —C (R 3a ) (R 4a ) —O—Y a —R 6a .
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a , or —C (R 3a ) (R 4a ) —O—Y a —R Examples include the group represented by 6a .
  • R 9 includes a hydrogen atom.
  • R 10 includes each independently a hydrogen atom or halogen.
  • R 10 includes a hydrogen atom.
  • R 11 includes a hydrogen atom or halogen.
  • R 11 includes a hydrogen atom. Examples of p include 1 or 2. Examples of p include 1.
  • R 3a and R 4a include a hydrogen atom, or oxo together.
  • examples of R 3a and R 4a include a hydrogen atom.
  • R 3a and R 4a together include oxo.
  • examples of R 5a include a hydrogen atom or substituted or unsubstituted alkyl.
  • R 5a includes a hydrogen atom or methyl.
  • R 6a is a hydrogen atom, halogen, hydroxy, carboxy, carbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted dialkylamino, 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 aromatic carbocyclic amino, or substituted or unsubstituted non-aromatic carbocyclic amino.
  • R 6a includes a hydrogen atom, 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 group A non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic oxy.
  • R 6a is a hydrogen atom, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted dihydroindenyl, substituted or unsubstituted phenyl, substituted or unsubstituted Naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted Substituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzothiazo
  • the “—R 5a ” group and the “—Y a —R 6a ” group together with the nitrogen atom to which they are attached form a substituted or unsubstituted non-aromatic heterocycle.
  • the groups “—R 5a ” and “—Y a -R 6a ”, together with the nitrogen atom to which they are attached, are substituted or unsubstituted pyrrolidine, substituted or unsubstituted indoline, substituted or unsubstituted iso Forms indoline, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisoquinoline, or substituted or unsubstituted diazepane.
  • R 8 is a substituted or unsubstituted aromatic carbocyclic group; or a group represented by — (C (R 13 ) (R 14 )) qR 15 , —C (R 16 ) (R 17 ) —N (R 18 ) —X—R 19 , or —C (R 16 ) (R 17 ) —O—X—R 19 .
  • R 8 includes substituted or unsubstituted phenyl; or a group represented by — (C (R 13 ) (R 14 )) q—R 15 .
  • R 8 is a group represented by —C (R 16 ) (R 17 ) —N (R 18 ) —XR 19 , or —C (R 16 ) (R 17 ) —O—X—R 19 And the groups shown.
  • R 13 includes each independently a hydrogen atom, halogen, or alkyl. Examples of R 13 include independently a hydrogen atom or alkyl. Examples of R 14 include independently a hydrogen atom, halogen, or alkyl. Examples of R 14 include independently a hydrogen atom or alkyl. R 15 includes a hydrogen atom, halogen, or a substituted or unsubstituted aromatic carbocyclic group. Examples of R 15 include a hydrogen atom or substituted or unsubstituted phenyl. q includes 1 or 2. As q, 1 may be mentioned.
  • the “—R 18 ” group and the “—XR 19 ” group together with the nitrogen atom to which they are attached form a substituted or unsubstituted non-aromatic heterocycle.
  • the “—R 18 ” group and the “—XR 19 ” group, together with the nitrogen atom to which they are attached, are substituted or unsubstituted pyrrolidine, substituted or unsubstituted indoline, substituted or unsubstituted isoindoline. , Substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, or substituted or unsubstituted piperidine.
  • a “—R 18 ” group and a “—XR 19 ” group, together with the nitrogen atom to which they are attached, are substituted or unsubstituted pyrrolidine, substituted or unsubstituted indoline, or substituted or unsubstituted piperidine Form.
  • R 19 is a hydrogen atom, halogen, hydroxy, carboxy, carbamoyl, sulfo, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocycle Group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic
  • R 19 is a hydrogen atom, 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 group And non-aromatic heterocyclic groups.
  • R 19 includes substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted phenyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted piperidinyl.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof includes a compound or a pharmaceutically acceptable salt thereof generated by a combination of a part or all of the definitions of each substituent shown above. It is done.
  • R 1a is a hydrogen atom
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a ; -Y a -is a single bond or substituted or unsubstituted alkylene
  • R 6a is 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 Or a “—R 5a ” group and a “—Y a —R 6a ” group, together with the nitrogen atom to which they are attached, a substituted or unsubstituted non-aromatic heterocyclic group;
  • R 1a is a hydrogen atom
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a
  • —Y a — is a single bond or substituted or unsubstituted alkylene
  • R 6a is 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; or a “—R 5a ” group and a “—Y a —R 6a ” group, together with the nitrogen atom to which they are attached, substituted or unsubstituted pyrrolidine, substituted or unsubstituted Indoline, or substituted or unsubstituted piperidine; R 8 is substituted or un
  • R 1a is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic carbocyclic oxy
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a , or —C (R 3a ) (R 4a ) —O—Y a —R 6a
  • R 6a is 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; or a “—R 5a ” group and a “—Y a —
  • R 1a is substituted or unsubstituted phenyl, or substituted or unsubstituted phenyloxy
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a , or —C (R 3a ) (R 4a ) —O—Y a —R 6a
  • R 6a is 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; or a “—R 5a ” group and a “—Y a —R 6a ” group, together
  • R 1a is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic carbocyclic oxy
  • R 7 is a group represented by —C (R 9 ) (R 10 ) —R 11
  • R 9 , R 10 , and R 11 are each independently a hydrogen atom or halogen
  • R 8 is a group represented by —C (R 16 ) (R 17 ) —N (R 18 ) —XR 19 , or represented by —C (R 16 ) (R 17 ) —O—X—R 19
  • a group -X- is a single bond or substituted or unsubstituted alkylene
  • R 19 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 unsubstitute
  • R 1a is substituted or unsubstituted phenyl, or substituted or unsubstituted phenyloxy;
  • R 7 is a group represented by —CH 3 ;
  • R 8 is a group represented by —C (R 16 ) (R 17 ) —N (R 18 ) —XR 19 , or represented by —C (R 16 ) (R 17 ) —O—X—R 19
  • a group -X- is a single bond or substituted or unsubstituted alkylene;
  • R 19 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 Or a “—R 18 ” group and a “—XR 19 ” group, together with the nitrogen atom to which they are attached, are
  • R 1a is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic carbocyclic oxy
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a , or —C (R 3a ) (R 4a ) —O—Y a —R 6a
  • R 6a is a hydrogen atom, 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 group A non-aromatic heterocyclic group
  • R 8 is a group represented by —C (R 16
  • R 1a is substituted or unsubstituted phenyl, or substituted or unsubstituted phenyloxy
  • R 7 is a group represented by —C (R 3a ) (R 4a ) —N (R 5a ) —Y a —R 6a , or —C (R 3a ) (R 4a ) —O—Y a —R 6a
  • R 6a is a hydrogen atom, 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 group A non-aromatic heterocyclic group
  • R 8 is a group represented by —C (R 16 ) (R 17 )
  • 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.
  • R A and R B are each independently hydrogen, or substituted or unsubstituted alkyl, or taken together form a substituted or unsubstituted non-aromatic heterocycle;
  • R 1a , R 5a , R 6a , R 8 , and —Y a — have the same meanings as in (1) above.
  • Process 1 Compound A3 can be obtained by allowing compound A1 and a base to act on compound A1. Examples of the base include triethylamine, DIEA, sodium carbonate, potassium carbonate, cesium carbonate, DBU and the like, and 1 to 10 molar equivalents can be used with respect to compound A1.
  • the reaction temperature is 0 ° C. to 120 ° C., preferably 60 ° C.
  • Process 2 Compound A5 can be obtained by reacting compound A3 and boronic acid or boronic ester A4 in the presence of a metal catalyst and a base.
  • metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to compound A3.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, trisodium phosphate, sodium hydrogen phosphate, tripotassium phosphate And potassium hydrogen phosphate can be used, and 1 to 10 molar equivalents can be used with respect to Compound A3.
  • Boronic acid or boronic ester A4 can be used at 1 to 10 molar equivalents relative to compound A3.
  • the reaction temperature is 20 ° C. to the reflux temperature of the solvent, and optionally under microwave irradiation.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include tetrahydrofuran, toluene, DMF, dioxane, water and the like, and these can be used alone or in combination.
  • Process 3 Compound A6 can be obtained by allowing a hydroxide to act on compound A5.
  • the hydroxide include sodium hydroxide, lithium hydroxide, barium hydroxide and the like, and 1 to 10 molar equivalents can be used with respect to the compound A5.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • Step 4-1 A halide can be obtained by reacting Compound A6 with a halogenating agent.
  • the halogenating agent include thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine and the like, and 1 to 5 molar equivalents can be used with respect to compound A6.
  • the reaction temperature is ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent acetonitrile, tetrahydrofuran, toluene, dichloromethane, dimethylacetamide and the like can be used.
  • a sulfonyl compound can be obtained by reacting compound A6 with a sulfonylating agent in the presence of a base such as triethylamine, DIEA, or pyridine.
  • a base such as triethylamine, DIEA, or pyridine.
  • the sulfonylating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like, and 1 to 5 molar equivalents can be used with respect to Compound A6.
  • the reaction temperature is ⁇ 80 ° C.
  • Step 4-2 Compound A8 can be obtained by reacting compound A7 with the resulting halide or sulfonyl compound in the presence of a base.
  • the base include pyridine, DIEA, triethylamine, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include acetonitrile, tetrahydrofuran, toluene, dichloromethane, dimethylacetamide and the like.
  • R A and R B are each independently hydrogen, or substituted or unsubstituted alkyl, or taken together to form a substituted or unsubstituted non-aromatic heterocycle; R 1a , R 7 , R 18 , R 19 , and —X— have the same meanings as (1) above.
  • Process 1 Using compound B1 and compound B2, compound B3 can be obtained by the same method as described in Method A, first step.
  • Process 2 Using compound B3 and compound B4, compound B5 can be obtained by the same method as described in Method A, second step.
  • Process 3 Using compound B5, compound B6 can be obtained in the same manner as described in Method A, third step.
  • Compound B8 can be obtained in the same manner as described in Method A, Step 4-1 and Step 4-2, using Compound B6 and Compound B7. Moreover, it is possible to perform the same synthesis by using Compound B9 shown below as a nucleophile instead of Compound B7.
  • Process 1 Compound C1 can be obtained by reacting compound A5 with a reducing agent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like.
  • the reducing agent can be used at 1 to 10 molar equivalents relative to Compound A5.
  • the reaction temperature is 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • Step 2-1 A halide can be obtained by reacting compound C1 with a halogenating agent and a base.
  • the halogenating agent include phosphorus pentachloride, phosphorus oxychloride, methanesulfonyl chloride, 4-toluenesulfonyl chloride, and the like, and 1 to 10 molar equivalents can be used with respect to compound C1.
  • Examples of the base include triethylamine, DIEA, pyridine, DMAP, DBU and the like, and 1 to 10 molar equivalents can be used with respect to compound C1.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • Examples of the reaction solvent include acetonitrile, tetrahydrofuran, dichloromethane, toluene and the like, and these can be used alone or in combination.
  • a sulfonyl compound can be obtained by reacting compound C1 with a sulfonylating agent and a base.
  • Examples of the sulfonylating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like, and 1 to 5 molar equivalents can be used with respect to Compound C1.
  • Examples of the base include triethylamine, DIEA, pyridine, DMAP, DBU and the like, and 1 to 10 molar equivalents can be used with respect to compound C1.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • Step 2-2 A compound C3 can be obtained by allowing a nucleophile C2 and a base to act on the obtained halide or sulfonyl compound.
  • the nucleophilic agent can be used in an amount of 1 to 10 molar equivalents relative to the obtained halide or sulfonyl compound.
  • Examples of the base include triethylamine, DIEA, pyridine, DMAP, DBU and the like, and 1 to 10 molar equivalents can be used with respect to the obtained halide or sulfonyl compound.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • the reaction solvent include acetonitrile, tetrahydrofuran, toluene, dichloromethane, dimethylformamide and the like, and these can be used alone or in combination.
  • Method D (In the formula, R 1a , R 7 , R 18 , R 19 , and —X— have the same meaning as the above (1).)
  • Process 1 Using compound B5, compound D1 can be obtained in the same manner as described in Method C, first step.
  • Process 2 Using compound D1 and nucleophile D2, compound D3 can be obtained in the same manner as described in Method C, step 2-1 and step 2-2.
  • Method E (In the formula, Hal is a halogen; R 1a , R 5a , R 6a , R 18 , R 19 , —X—, and —Y a — have the same meanings as (1) above.)
  • Process 1 Compound E2 can be obtained by allowing a halogenating agent and a radical initiator to act on compound E1 obtained by the same method as described in the first step and the second step of Method A.
  • the halogenating agent include N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, bromine, iodine and the like, and 1 to 10 molar equivalents can be used with respect to compound E1.
  • radical initiator examples include azobisisobutyronitrile, di-tert-butyl peroxide, benzoyl peroxide and the like, and 1 to 10 molar equivalents can be used with respect to compound E1.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • Examples of the reaction solvent include carbon tetrachloride and benzene.
  • Process 2 Using compound E2 and nucleophile D3, compound E3 can be obtained by the same method as described in Method D, third step.
  • Process 3 Using compound E3, compound E4 can be obtained in the same manner as described in Method A, third step.
  • Process 4 Using compound E4 and compound A7, compound E5 can be obtained in the same manner as described in Method A, Step 4-1 and Step 4-2.
  • Process 1 Compound F2 can be obtained by a method similar to that described in Method E, Step 1, using Compound F1 obtained by a method similar to that described in Method B, Step 1 and Step 2.
  • Process 2 Compound F3 can be obtained in the same manner as described in Method C, step 3, using compound F2 and nucleophile C3.
  • Process 3 Compound F4 can be obtained in the same manner as described in Method A, Step 3, using Compound F3.
  • Process 4 Using compound F4 and compound B7, a compound can be obtained by the same method as described in Method A, Step 4-1 and Step 4-2.
  • 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 Rr, Rp and Rq in the following general formula (II ′).
  • AIBN azobisisobutyronitrile
  • DMSO dimethyl sulfoxide
  • DMF N, N-dimethylformamide
  • DIEA N, N-diisopropylethylamine
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3 3-tetramethyluronium hexafluorophosphate
  • IBX 2-iodoxybenzoic acid
  • NBS N-bromosuccinimide
  • PdCl 2 (dtbpf) [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct
  • THF tetrahydrofuran
  • Example 1 (1) Synthesis of Compounds 5, 7 and 9 (1-1-A) Synthesis of Compound 1b Diethyl ether (200 mL) was added to diethyl oxalate (0.4 mol) and cooled to -70 ° C. Under a nitrogen atmosphere, benzylmagnesium chloride (0.4 mol) was added dropwise while maintaining the liquid temperature at ⁇ 50 ° C. or lower. The temperature was raised to 0 ° C. and hydrochloric acid was added. The organic layer was separated and the aqueous layer was washed with diethyl ether. The organic layer was dried and concentrated under reduced pressure to obtain Compound 1b (47.5 g, yield 62%).
  • the mixture is filtered, methanol is distilled off under reduced pressure, and the pH is adjusted to 2 with dilute hydrochloric acid. Concentrate the solvent to about 20 mL.
  • the obtained solid can be filtered and washed with water to obtain crude compound 8.
  • the reaction mixture is filtered through celite and concentrated under reduced pressure.
  • Example 2 Process 1 To a solution of methyl 2-chloro-3-oxobutanoate (2.07 g, 13.7 mmol) in acetonitrile (40 mL) was added compound 18 (3.0 g, 12.5 mmol), and DIEA (6.55 mL, 37.5 mmol). ) And stirred at 95 ° C. for 3 hours. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over sodium sulfate. After filtration and concentration, the resulting residue was purified by silica gel column chromatography to obtain compound 19 (1.07 g, yield 31%).
  • Example 3 Process 1 To a solution of compound 21 (600 mg, 2.06 mmol) in THF (6 mL), diisobutylaluminum hydride (4.3 mL, 1 mol / L hexane solution) was added dropwise under ice cooling. After stirring at room temperature for 4 hours, ethyl acetate was added to the reaction mixture, and the mixture was washed with an aqueous potassium sodium tartrate solution and saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound 22 (469 mg, yield 86%).
  • Example 4 To a solution of 1- (4-fluorophenyl) -N-methylmethanamine (22.2 mg, 0.16 mmol) in DMF (0.3 mL) was added DIEA (37 ⁇ L, 0.21 mmol) and compound I-295 (30 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, washed with saturated brine, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound I-300 (37.2 mg, yield 91%).
  • Example 5 To a solution of compound I-295 (30.0 mg, 0.106 mmol) in DMF (1 mL) was added phenol (12.0 mg, 0.128 mmol) and potassium carbonate (29.4 mg, 0.213 mmol) at room temperature. Stir for 2 hours. Water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain compound I-361 (32.2 mg, yield 89%).
  • Example 6 Process 1 NBS (1.34 g, 7.54 mmol) and AIBN (225 mg, 1.37 mmol) were added to a solution of compound 21 (2.0 g, 6.86 mmol) in carbon tetrachloride (25 mL). The mixture was stirred at 80 ° C. for 3 days under a nitrogen atmosphere. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 23 (1.91 g, yield 75%).
  • Example 7 Synthesis of Compound I-292 To a solution of compound 23 (40 mg, 0.108 mmol) in DMF (0.3 mL) was added 50% aqueous dimethylamine solution (30 ⁇ L, 0.32 mmol), and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was concentrated under reduced pressure. To the obtained residue, THF (0.5 mL), 2 mol / L aqueous sodium hydroxide solution (65 ⁇ L, 0.13 mmol) were added, and the mixture was stirred at room temperature for 2 hours.
  • THF 0.5 mL
  • 2 mol / L aqueous sodium hydroxide solution 65 ⁇ L, 0.13 mmol
  • Example 8 Process 1 4- (4-Fluorophenoxy) piperidine (23.7 mg, 0.121 mmol) was mixed with Compound 24 (30.0 mg, 0.081 mmol) obtained in the same manner as Compound 23 described in Example 6 in THF (0. 6 mL) solution and DIEA (28 ⁇ L, 0.162 mmol) were added and stirred at room temperature for 4 hours. A sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative HPLC (10 mmol / L ammonium carbonate-containing aqueous solution-acetonitrile) to obtain Compound 25 (15.5 mg, yield 39%).
  • Example 9 Process 1 To a solution of compound 26 (5.5 g, 21.1 mmol) in carbon tetrachloride (82 mL), NBS (4.14 g, 23.3 mmol) and AIBN (347 mg, 2.1 mmol) were added, and 75 ° C. under a nitrogen atmosphere. And heated at reflux for 12 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 27 (5.96 g, yield 83%) as a white solid.
  • Example 10 Synthesis of Compound I-335 Process 1 Bromine (1.76 g, 11.0 mmol) was added to a solution of compound 32 (1.0 g, 5.52 mmol) in carbon tetrachloride (40 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 33 (489 mg, yield 34%).
  • 1 H-NMR (CDCl 3 ) ⁇ : 4.10 (s, 3H), 4.86 (s, 2H), 8.05 (s, 1H).
  • Example 11 Process 1 Step 1-1 Sodium hydride (129 mg, 3.23 mmol) was added to 2-chlorophenylmethanol (253 mg, 1.77 mmol) in THF (1.5 mL) under ice cooling. The mixture was stirred at room temperature for 1 hour, and a solution of compound 36 (500 mg, 1.61 mmol) in THF (3.5 mL) was added dropwise under ice cooling. After stirring overnight at room temperature, methanol was added. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated.
  • Step 1-2 4-Toluenesulfonic acid (10.2 g, 59.04 mmol) was added to a solution of compound 37 (11.0 g, 29.52 mmol) in methanol (50 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain compound 38 (6.2 g, yield 72.7%).
  • Example 12 Process 1 To a solution of compound I-326 (130 mg, 0.35 mmol) in DMSO (3 mL) was added IBX (778 mg, 2.78 mmol) at room temperature, and the mixture was stirred at 100 ° C. overnight. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, and the organic layer was dried over sodium sulfate. After filtration and concentration, the resulting residue was purified by preparative TLC to obtain Compound 41 (80 mg, yield 59%) as a solid.
  • 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

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Dans ladite formule, R1a est un atome d'hydrogène ou analogue; R7 est le groupe représenté par -C(R3a)(R4a)-N(R5a)-Y­ a-R6a ou analogue; R3a et R4a sont tous deux des atomes d'hydrogène ou forment ensemble un oxo ou analogue; R5a est un atome d'hydrogène ou analogue; -Ya- est une liaison simple ou analogue; R6a est un atome d'hydrogène ou analogue; R8 est le groupe représenté par -C(R16)(R17)-N(R18)-X-R19 ou analogue; R16 et R17 sont tous deux des atomes d'hydrogène ou forment ensemble un oxo ou analogue; R18 est un atome d'hydrogène ou analogue; -X- représente une liaison simple ou analogue; et R19 est un atome d'hydrogène ou analogue).
PCT/JP2013/062181 2012-04-26 2013-04-25 Dérivé oxazolotriazole et composition médicamenteuse contenant celui-ci WO2013161928A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2020054657A1 (fr) 2018-09-10 2020-03-19 科研製薬株式会社 Dérivé d'amide hétéroaromatique et médicament le contenant
KR20210057008A (ko) 2018-09-10 2021-05-20 가껭세이야꾸가부시기가이샤 신규한 헤테로방향족 아미드 유도체 및 이를 함유하는 약제

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