WO2017204316A1 - Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante - Google Patents

Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante Download PDF

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WO2017204316A1
WO2017204316A1 PCT/JP2017/019634 JP2017019634W WO2017204316A1 WO 2017204316 A1 WO2017204316 A1 WO 2017204316A1 JP 2017019634 W JP2017019634 W JP 2017019634W WO 2017204316 A1 WO2017204316 A1 WO 2017204316A1
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substituted
unsubstituted
aromatic
group
aromatic heterocyclic
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Japanese (ja)
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浩幸 甲斐
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds useful for treating diseases or conditions involving P2X receptors, particularly P2X 3 and / or P2X 2/3 receptors, and pharmaceutical compositions containing the compounds.
  • Adenosine triphosphate is known as an intracellular energy source and phosphorylated substrate. On the other hand, it is also known to work as an extracellular information transmission substance. Furthermore, ATP is released to the outside of cells by various stimuli such as cell damage, inflammation, nociceptive stimulation, reduction of blood oxygen concentration, and released from the primary sensory nerve ending together with other neurotransmitters. It is known. ATP released to the outside of the cell performs various extracellular information transmission via the ATP receptor (Non-patent Documents 4 and 5).
  • ATP receptors are roughly classified into an ion channel type P2X family and a G protein coupled type P2Y family. Seven types of subtypes have been reported in the P2X receptor family, and function as non-selective cation channels by forming homotrimers or heterotrimers with other P2X subtypes (Non-patent Document 6). ).
  • Non-Patent Document 1 Non-Patent Document 1
  • A-317491 was reported as an antagonist specific for the P2X 3 and P2X 2/3 receptors.
  • A-317491 has the following formula: Is a tri-substituted -N-[(1S) -1,2,3,4-tetrahydro-1-taphthalenyl] benzamide derivative (Patent Document 1), which antagonizes P2X 3 and P2X 2/3 receptors It has been reported that it showed activity and showed analgesic action in a rat neuropathic pain model and inflammatory pain model (Non-patent Document 7). This indicates that it pain via the P2X 3 or P2X 2/3 receptor is transmitted, and P2X 3 or P2X 2/3 compounds with receptor antagonistic activity are useful as analgesics .
  • Non-patent Document 2 a compound having a P2X 3 receptor antagonistic action is used in the treatment of diseases accompanied by abnormal dysuria. It also suggests that it is useful.
  • Non-Patent Document 9 neuroepithelial bodies (NEB) of the lungs
  • Non-Patent Document 10 ATP-induced cough
  • P2X 3 receptors It has been suggested that it is involved in information transmission in the respiratory organs (Non-patent Document 11).
  • Patent Document 9 a compound called A-317491 known as a P2X 3 and P2X 2/3 receptor antagonist has been reported to inhibit the activity of vagal afferent A fibers in lung diseases.
  • Patent Document 10 biphenyl and phenyl-pyridine derivatives have been reported as P2X 3 and / or P2X 2/3 receptor antagonists, suggesting that they have an action to improve respiratory diseases in asthma and lung function models.
  • Patent Document 11 describes a compound having a 1,2,4-triazine skeleton similar to the compound of the present invention, but does not describe analgesic action and P2X 3 or P2X 2/3 receptor antagonistic action.
  • Non-Patent Documents 8 and 14 describe compounds having a 1,3,5-triazine skeleton similar to the compounds of the present invention and exhibiting analgesic activity, but P2X 3 or P2X 2/3 receptors. No antagonism has been described.
  • Patent Documents 2 to 8, 15 and 16 and Non-Patent Documents 12 and 13 also describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonistic activity, but the structure is different from the compounds of the present invention.
  • Patent Documents 12 to 14 and 17 describe compounds having a P2X 3 or P2X 2/3 receptor antagonistic activity having a 1,3,5-triazine skeleton similar to the compounds of the present invention.
  • Patent Document 18 describes a compound having a 1,2,4-triazine skeleton and having a P2X 3 or P2X 2/3 receptor antagonistic action, but has a structure different from that of the compound of the present invention.
  • Patent Document 19 describes a compound having a 1,2,4-triazine skeleton and an analgesic action, but does not describe a P2X 3 or P2X 2/3 receptor antagonistic action.
  • the present invention provides novel P2X 3 and / or P2X 2/3 receptor antagonistic compounds. Further, to provide a pharmaceutical composition having a P2X 3 and / or P2X 2/3 receptor antagonism.
  • the present inventors have found that a novel compound that specifically binds to the P2X 3 and / or P2X 2/3 receptor and exhibits an antagonism, and P2X 3 and / or Alternatively, a novel compound that specifically binds to the P2X 2/3 receptor was found. Also found a pharmaceutical composition having P2X 3 and / or P2X 2/3 receptor antagonism.
  • the pharmaceutical compositions encompassed by the compounds or the present invention included in the present invention, P2X 3 receptor inhibiting activity, a rat serum albumin (hereinafter, RSA) good results in P2X 3 receptor inhibitory activity and the like in the presence of Indicated.
  • the compound included in the present invention or the pharmaceutical composition included in the present invention is a CYP enzyme inhibition confirmation test, FAT test, solubility confirmation test, metabolic stability confirmation test, hERG inhibitory activity confirmation test, pharmacokinetic test.
  • bioavailability confirmation test the whole body clearance confirmation test, etc. and / or the protein binding confirmation test, good results were also shown.
  • the present invention relates to the following (1) to (25).
  • Adjacent ring member atoms are unsubstituted), substituted or unsubstituted non-aromatic heterocyclic groups (however, the ring member atom adjacent to the ring atom to which X is attached is unsubstituted), substituted Or an unsubstituted aromatic carbocyclic group (wherein the ring atom adjacent to the ring atom to which X is bonded is unsubstituted), or a substituted or unsubstituted aromatic heterocyclic group (wherein The ring atom adjacent to the ring atom to which X is attached is unsubstituted);
  • Each R 4a is independently a hydrogen atom or substituted or unsubstituted alkyl;
  • R 4b is each independently a hydrogen atom, or substituted or unsubstituted alkyl, or R 4a and R 4b taken together are oxo;
  • n is an integer of 0 to 4) or a pharmaceutically acceptable salt thereof.
  • n is an integer of 1 to 4
  • R 2 represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic A heterocyclic group
  • R 3 is a substituted or unsubstituted non-aromatic carbocyclic group (wherein the ring atom adjacent to the ring atom to which X is bonded is unsubstituted), substituted or unsubstituted non-aromatic heterocycle A cyclic group (wherein the ring atom adjacent to the ring atom to which X is bonded is unsubstituted), a substituted or unsubstituted aromatic carbocyclic group (however, the ring structure to which X is bonded) The ring atom adjacent to the atom is unsubstituted), or a
  • R 2 represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic A heterocyclic group
  • R 3 is a substituted or unsubstituted non-aromatic carbocyclic group (wherein the ring atom adjacent to the ring atom to which X is bonded is unsubstituted), substituted or unsubstituted non-aromatic heterocycle A cyclic group (wherein the ring atom adjacent to the ring atom to which X is bonded is unsubstituted), a substituted or unsubstituted aromatic carbocyclic group (however, the ring structure to which X is bonded) The ring atom adjacent to the atom is unsubstituted), or a substituted or unsubstituted, or
  • R 1 is a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino Or a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4) or (2A) above, which is a substituted or unsubstituted aromatic heterocyclic group.
  • R 3 is represented by the formula: Wherein ring A is an aromatic carbocycle or aromatic heterocycle; Ring B is an aromatic heterocycle; R 6 to R 10 are each independently a hydrogen atom, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted acyl, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyl
  • R 3 is represented by the formula: Wherein R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R 12 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, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6) or (2A) above, which is a
  • (16A) The compound according to (15) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of neuropathic pain or inflammatory pain.
  • (17) A P2X 3 and / or P2X 2/3 receptor, comprising administering the compound according to any one of (1) to (11) or (2A) above or a pharmaceutically acceptable salt thereof.
  • (18) The treatment and / or prevention method according to the above (17) for chronic pain, dysuria or respiratory disease.
  • (18A) The treatment and / or prevention method according to (17) above for neuropathic pain or inflammatory pain.
  • (22) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures
  • (23) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrups, soft capsules, microcapsules or sustained-release capsules
  • (24) A pharmaceutical composition for parenteral administration comprising the compound according to any one of (1) to (11) or (2A) above, or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention have an antagonistic effect on P2X 3 and / or P2X 2/3 receptor and are useful for the disease or condition P2X 3 and / or P2X 2/3 receptors are involved.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes linear 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. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and 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, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • 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. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • aromatic carbocyclic group means a cyclic aromatic hydrocarbon group having one or more rings.
  • aromatic carbocyclic group includes phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, 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 monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • non-aromatic heterocyclic group having two or more rings is the same as the above-mentioned “non-aromatic carbocyclic group” and / or “non-aromatic heterocyclic group”. Also included are those in which each ring in the “group” is condensed. Furthermore, the “non-aromatic heterocyclic group” includes a group that 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.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • 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. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • 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 “halogen” is bonded to the “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. Preferable embodiments of “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. Preferable embodiments of “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. Preferable embodiments of “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.
  • Alkylamino means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N, N-diisopropylamino, N-methyl-N-ethylamino and the like can be mentioned.
  • Preferable embodiments of “alkylamino” include methylamino and ethylamino.
  • 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.
  • Preferable embodiments of “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.
  • Alkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Alkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Preferable embodiments of “alkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • 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. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like. Preferable embodiments of “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.
  • Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, 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.
  • Alkylcarbamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
  • Alkylsulfamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyl groups 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, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “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 portion 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, phenylpropyloxy, 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, phenylpropyloxycarbonyl, 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, phenylpropyloxymethyl, 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”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” 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 “ Also included are “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, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • aromatic carbocyclic oxy means a group in which “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. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • aromatic heterocycle part 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 “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.
  • Acyl means “formyl”, “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic carbonyl”, “aromatic heterocyclic carbonyl” and Includes “non-aromatic heterocyclic carbonyl”.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkeny
  • An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkylcarbonyl, alkyl,
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • Examples of the substituent of “substituted or unsubstituted alkyl” in R 1 include halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted alkenyl” in R 1 include halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted alkyloxycarbonyl” in R 1 include halogen. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted carbamoyl” in R 1 include alkyl; haloalkyl; hydroxyalkyl; non-aromatic heterocyclic group; aromatic heterocyclic group. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted amino” in R 1 include acyl. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 1 include alkyl; haloalkyl; hydroxyalkyl; carboxy; It may be substituted with one or more groups selected from these.
  • R 1 examples include alkyl; haloalkyl; hydroxyalkyl; carboxy; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted non-aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted non-aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; It may be substituted with one or more groups selected from these.
  • substituents of the “substituted or unsubstituted aromatic carbocyclic group” in R 3 include, for example, Unsubstituted or substituted (substituents include, for example, halogen; alkyloxy, which may be substituted with one or more groups selected from these) alkyloxy; Unsubstituted or substituted (substituents include, for example, halogen; alkyloxy, which may be substituted with one or more groups selected from these) alkenyloxy; Unsubstituted or substituted (substituents include, for example, halogen; alkyloxy, which may be substituted with one or more groups selected from these) alkynyloxy; Unsubstituted or substituted (substituents include, for example, halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl, which may be substituted with one or more groups selected from these) aromatic heterocyclic oxy;
  • substituents of “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, and “substituted or unsubstituted alkynyloxy” in R 6 to R 10 include, for example, halogen; alkyloxy . It may be substituted with one or more groups selected from these.
  • Substituted or unsubstituted aromatic heterocyclic oxy “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted aromatic carbocyclic oxy” or “substituted or unsubstituted” in R 6 to R 10
  • substituent of “substituted non-aromatic carbocyclic oxy” include halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl. It may be substituted with one or more groups selected from these.
  • substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, or “substituted or unsubstituted alkynyl” in R 11 include, for example, halogen; alkyloxy. It may be substituted with one or more groups selected from these.
  • Substituted or unsubstituted aromatic heterocycle “substituted or unsubstituted nonaromatic heterocycle”, “substituted or unsubstituted aromatic carbocycle” or “substituted or unsubstituted nonaromatic carbocycle” in R 11
  • substituents include “halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl”. It may be substituted with one or more groups selected from these.
  • R 7 and R 8 together with the ring atoms to which they are attached are substituted or unsubstituted aromatic carbocycles, substituted or unsubstituted non-aromatic carbocycles, substituted or unsubstituted aromatics. May form a heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring " Wherein ring C and ring D are each independently a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, An unsubstituted non-aromatic heterocycle) It is included.
  • R 9 and R 10 together with the ring atoms to which they are attached are substituted or unsubstituted aromatic carbocycles, substituted or unsubstituted non-aromatic carbocycles, substituted or unsubstituted aromatic May form a heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring "
  • ring E represents a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted nonaromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted nonaromatic heterocyclic ring. Is) It is included.
  • —X— includes —N (R 5 ) —.
  • R 1 include a hydrogen atom.
  • R 1 includes halogen.
  • R 1 includes carboxy.
  • R 1 includes substituted or unsubstituted alkyl.
  • R 1 includes substituted or unsubstituted alkenyl.
  • R 1 includes substituted or unsubstituted alkyloxycarbonyl.
  • Examples of R 1 include substituted or unsubstituted carbamoyl.
  • R 1 includes substituted or unsubstituted amino.
  • R 1 includes a substituted or unsubstituted aromatic heterocyclic group.
  • R 2 includes a substituted or unsubstituted aromatic carbocyclic group.
  • R 2 includes substituted or unsubstituted phenyl.
  • R 3 includes a substituted or unsubstituted aromatic carbocyclic group.
  • R 3 includes substituted or unsubstituted phenyl.
  • R 4a include a hydrogen atom.
  • R 4b include a hydrogen atom.
  • R 5 includes a hydrogen atom.
  • Ring A includes benzene.
  • R 6 to R 10 are each independently a hydrogen atom.
  • R 6 to R 10 each independently include halogen.
  • R 6 to R 10 each independently include a substituted or unsubstituted alkyloxy.
  • Examples of R 6 to R 10 each independently include substituted or unsubstituted aromatic heterocyclic oxy.
  • R 11 includes substituted or unsubstituted alkyl.
  • R 11 includes a substituted or unsubstituted aromatic heterocyclic group.
  • R 12 includes a hydrogen atom.
  • R 12 includes halogen.
  • R 1 , R 2 , R 11 and R 12 are shown below.
  • Examples of the compound represented by the formula (IA) include all combinations of these specific examples.
  • R 1 is a hydrogen atom, halogen, carboxy, cyano, 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 acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbo
  • R 1 is a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted Alternatively, it is an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-2).
  • R 1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted or unsubstituted aromatic Group heterocyclic group (hereinafter referred to as A-3).
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-4).
  • R 1 is substituted or unsubstituted amino (hereinafter referred to as A-5).
  • R 1 is substituted or unsubstituted alkyl (hereinafter referred to as A-6).
  • R 1 is substituted or unsubstituted carbamoyl (hereinafter referred to as A-7).
  • R 1 is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-8).
  • R 1 is substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted pyridyl, substituted or unsubstitutedazinyl, substituted or unsubstituted Pyrimidinyl or substituted or unsubstituted pyrazinyl (hereinafter referred to as A-9).
  • R 1 is substituted or unsubstituted oxadiazolyl or substituted or unsubstituted oxazolyl (hereinafter referred to as A-10).
  • R 1 is alkyl or unsubstituted alkyl substituted with one or more groups selected from (halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; alkylsulfonyl; carboxy), (alkyl; haloalkyl; hydroxy Carbamoyl or unsubstituted carbamoyl substituted with one or more groups selected from alkyl; non-aromatic heterocyclic group; aromatic heterocyclic group) or (alkyl; haloalkyl; hydroxyalkyl; carboxy) An aromatic heterocyclic group substituted with one or more groups or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-11).
  • R 1 is alkyl substituted with one or more groups selected from (halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; alkylsulfonyl; carboxy) or unsubstituted alkyl (hereinafter referred to as A- 12).
  • R 1 is carbamoyl substituted with one or more groups selected from (alkyl; haloalkyl; hydroxyalkyl; non-aromatic heterocyclic group; aromatic heterocyclic group) or unsubstituted carbamoyl (hereinafter, A-13).
  • R 1 is an aromatic heterocyclic group substituted with one or more groups selected from (alkyl; haloalkyl; hydroxyalkyl; carboxy) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-14). And).
  • R 1 is substituted (as the substituent, one or more groups selected from the following: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted furyl, substituted (as the substituent, one or more selected from the following: Group: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted thienyl, substituted (as the substituent, one or more groups selected from: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted pyrrolyl, Substituted (substituent is one or more groups selected from: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted pyrazolyl, substituted (substituent is one or more groups selected from: alkyl Haloalkyl; hydroxyalkyl; carboxy) or unsubstituted An imidazolyl, substituted
  • R 1 represents one or more groups selected from substituted (one or more groups selected from the following: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted oxadiazolyl or a substituted substituent.
  • R 2 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , A substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as B-1).
  • R 2 represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic A heterocyclic group (hereinafter referred to as B-2).
  • R 2 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as B-3).
  • R 2 is a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as B-4).
  • R 2 is substituted or unsubstituted phenyl (hereinafter referred to as B-5).
  • R 2 is an aromatic carbocyclic group substituted with one or more groups selected from (halogen; alkyloxy), or an unsubstituted aromatic carbocyclic group (hereinafter referred to as B-6).
  • B-6 an unsubstituted aromatic carbocyclic group
  • B-7 phenyl substituted with one or more groups selected from (halogen; alkyloxy) or unsubstituted phenyl (hereinafter referred to as B-7).
  • R 11 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , A substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-1).
  • R 11 is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or A substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-2).
  • R 11 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-3).
  • R 11 is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-4).
  • R 11 is substituted or unsubstituted alkyl (hereinafter referred to as C-5).
  • R 11 is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-6).
  • R 11 is substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted pyridyl, substituted or unsubstitutedazinyl, substituted or unsubstituted Pyrimidinyl or substituted or unsubstituted pyrazinyl (hereinafter referred to as C-7).
  • R 11 is substituted or unsubstituted pyridyl (hereinafter referred to as C-8).
  • R 11 is alkyl substituted with one or more groups selected from (halogen; alkyloxy) or unsubstituted alkyl, or one or more selected from (halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl)
  • An aromatic heterocyclic group substituted with a group or an unsubstituted aromatic heterocyclic group hereinafter referred to as C-9.
  • R 11 is alkyl substituted with one or more groups selected from (halogen; alkyloxy) or unsubstituted alkyl (hereinafter referred to as C-10).
  • An aromatic heterocyclic group substituted with one or more groups selected from (halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl) or an unsubstituted aromatic heterocyclic group hereinafter referred to as C-11). To do).
  • R 11 is substituted (as the substituent, one or more groups selected from the following: alkyl; halogen; alkyloxy; haloalkyloxy; haloalkyl) or unsubstituted furyl, substituted (the substituent is selected from the following: One or more groups: alkyl; halogen; alkyloxy; haloalkyloxy; haloalkyl) or unsubstituted thienyl, substituted (as substituents, one or more groups selected from: alkyl; halogen; alkyloxy; haloalkyloxy Haloalkyl) or unsubstituted pyrrolyl, substituted (as substituents, one or more groups selected from: alkyl; halogen; alkyloxy; haloalkyloxy; haloalkyl) or unsubstituted pyrazolyl, substituted (as substituents One or more groups selected from: alkyl; Alkyloxy;
  • R 11 is pyridyl or unsubstituted pyridyl substituted with one or more groups selected from (halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl) (hereinafter referred to as C-12).
  • R 12 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, or substituted or unsubstituted Substituted alkynyloxy (hereinafter referred to as D-1).
  • D-1 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as D-2).
  • R 12 is halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C1-C3 alkyloxy (hereinafter referred to as D-3).
  • R 12 is a hydrogen atom or halogen (hereinafter referred to as D-4).
  • R 12 is a hydrogen atom (hereinafter referred to as D-5).
  • R 12 is halogen (hereinafter referred to as D-6).
  • R 1 , R 2 , R 6 , R 7 and R 8 are shown below. Examples of the compound represented by the formula (IB) include all combinations of these specific examples.
  • R 1 is a hydrogen atom, halogen, carboxy, cyano, 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 acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbo
  • R 1 is a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted Alternatively, it is an unsubstituted aromatic heterocyclic group (hereinafter referred to as E-2).
  • R 1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted or unsubstituted aromatic Group heterocyclic group (hereinafter referred to as E-3).
  • R 1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted carbamoyl, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as E-4).
  • R 1 is substituted or unsubstituted amino (hereinafter referred to as E-5).
  • R 1 is substituted or unsubstituted alkyl (hereinafter referred to as E-6).
  • R 1 is substituted or unsubstituted carbamoyl (hereinafter referred to as E-7).
  • R 1 is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as E-8).
  • R 1 is substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted pyridyl, substituted or unsubstitutedazinyl, substituted or unsubstituted Pyrimidinyl or substituted or unsubstituted pyrazinyl (hereinafter referred to as E-9).
  • R 1 is substituted or unsubstituted oxadiazolyl or substituted or unsubstituted oxazolyl (hereinafter referred to as E-10).
  • R 1 is alkyl or unsubstituted alkyl substituted with one or more groups selected from (halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; alkylsulfonyl; carboxy), (alkyl; haloalkyl; hydroxy Carbamoyl or unsubstituted carbamoyl substituted with one or more groups selected from alkyl; non-aromatic heterocyclic group; aromatic heterocyclic group) or (alkyl; haloalkyl; hydroxyalkyl; carboxy) An aromatic heterocyclic group substituted with one or more groups or an unsubstituted aromatic heterocyclic group (hereinafter referred to as E-11).
  • R 1 is alkyl substituted with one or more groups selected from (halogen; alkyloxycarbonyl; hydroxy; acyl; amino; alkylamino; alkylsulfonyl; carboxy) or unsubstituted alkyl (hereinafter referred to as E- 12).
  • R 1 is carbamoyl substituted with one or more groups selected from (alkyl; haloalkyl; hydroxyalkyl; non-aromatic heterocyclic group; aromatic heterocyclic group) or unsubstituted carbamoyl (hereinafter, E-13).
  • R 1 is an aromatic heterocyclic group substituted with one or more groups selected from (alkyl; haloalkyl; hydroxyalkyl; carboxy) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as E-14). And).
  • R 1 is substituted (as the substituent, one or more groups selected from the following: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted furyl, substituted (as the substituent, one or more selected from the following: Group: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted thienyl, substituted (as the substituent, one or more groups selected from: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted pyrrolyl, Substituted (substituent is one or more groups selected from: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted pyrazolyl, substituted (substituent is one or more groups selected from: alkyl Haloalkyl; hydroxyalkyl; carboxy) or unsubstituted An imidazolyl, substituted
  • R 1 represents one or more groups selected from substituted (one or more groups selected from the following: alkyl; haloalkyl; hydroxyalkyl; carboxy) or unsubstituted oxadiazolyl or a substituted substituent.
  • R 2 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , A substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as F-1).
  • R 2 represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic A heterocyclic group (hereinafter referred to as F-2).
  • R 2 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as F-3).
  • R 2 is a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as F-4).
  • R 2 is substituted or unsubstituted phenyl (hereinafter referred to as F-5).
  • R 2 is an aromatic carbocyclic group substituted with one or more groups selected from (halogen; alkyloxy), or an unsubstituted aromatic carbocyclic group (hereinafter referred to as F-6).
  • F-6 an unsubstituted aromatic carbocyclic group
  • R 2 is phenyl substituted with one or more groups selected from (halogen; alkyloxy) or unsubstituted phenyl (hereinafter referred to as F-7).
  • R 6 to R 8 are each independently a hydrogen atom, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted acyl, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • R 6 to R 8 are each independently a hydrogen atom, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl Oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted acyl, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • R 6 to R 8 are each independently a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or An unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic oxy, or a substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as G). -2).
  • R 6 to R 8 are each independently a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as G-3).
  • R 7 represents substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic ring Oxy, substituted or unsubstituted aromatic carbocyclic oxy, or substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-1).
  • R 7 is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, or substituted or Unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-2).
  • R 7 is substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic oxy, or substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-3).
  • R 7 is substituted or unsubstituted alkyloxy, or substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-4).
  • R 7 is substituted or unsubstituted alkyloxy (hereinafter referred to as H-5).
  • R 7 is a substituted or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-6).
  • R 7 is alkyloxy substituted or unsubstituted with one or more groups selected from (halogen; alkyloxy), or Aromatic heterocyclic oxy substituted with one or more groups selected from (halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl) or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H-7) .
  • R 7 is alkyloxy substituted with one or more groups selected from (halogen; alkyloxy) or unsubstituted alkyloxy (hereinafter referred to as H-8).
  • R 7 is an aromatic heterocyclic oxy substituted with one or more groups selected from (halogen; haloalkyl; haloalkyloxy; alkyloxy; alkyl) or unsubstituted aromatic heterocyclic oxy (hereinafter referred to as H- 9).
  • R 6 and R 8 are each independently a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Or substituted or unsubstituted alkynyloxy (hereinafter referred to as I-1).
  • R 6 and R 8 are each independently a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as I-2).
  • R 6 and R 8 are each independently halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C1-C3 alkyloxy (hereinafter referred to as I-3).
  • R 6 and R 8 are each independently a hydrogen atom or halogen (hereinafter referred to as I-4).
  • Ring A is an aromatic carbocyclic ring or an aromatic heterocyclic ring (hereinafter referred to as J-1).
  • Ring A is benzene (hereinafter referred to as J-2).
  • Ring A is pyridine (hereinafter referred to as J-3).
  • the compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.
  • the compound in which X is —NH— includes the following tautomers.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
  • 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 catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • the 14 C-labeled compound can be prepared by using a raw material 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, hydrate etc.), a co-crystal and / or a crystal polymorph. Also encompasses such various solvates, co-crystals and polymorphs.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
  • 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.
  • a method for selecting and producing an appropriate prodrug derivative is described in, for example, “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 reacting with a condensing agent.
  • 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 compounds of the present invention can be synthesized with reference to techniques known in the art. For example, it can synthesize
  • the compound represented by the formula (I) of the present invention can be produced, for example, by the following synthesis route.
  • Compound (iii) is produced by reacting Compound (ii) in a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., at 0 ° C. to heating under reflux, preferably 50 ° C. to heating under reflux. can do.
  • Compound (iii) can be used in the next step as a crude product or reaction solution.
  • Compound (iii) is -10 ° C to 60 ° C in a solvent such as THF, dioxane, methanol, ethanol, isopropanol, acetonitrile, etc. in the presence of a base such as sodium hydroxide, triethylamine, N, N-diisopropylethylamine, preferably 0
  • a base such as sodium hydroxide, triethylamine, N, N-diisopropylethylamine, preferably 0
  • Compound (v) can be produced by reacting compound (iv) at from 30 ° C. to 30 ° C.
  • Compound (v) can be used in the next step as a crude product or reaction solution.
  • the compound (vii) can be produced by reacting the compound (vi) at ⁇ 10 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C. (4th process) Compound (vii) in a solvent such as t-butanol in the presence of an acid such as acetic acid at 60 ° C. to 150 ° C., preferably 80 ° C.
  • base such as potassium carbonate, cesium carbonate, sodium hydroxide, triethylamine, N, N-diisopropylethylamine in a solvent such as THF, dioxane, dichloromethane, NMP, DMF, DMA, DMSO, acetone, acetonitrile
  • the compound (vii) can be produced by reacting the compound (vi) at ⁇ 10 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C. (4th process) Compound (vii) in a solvent such as t-butanol in
  • a compound represented by compound (ix) can be produced by reacting with compound (viii) in the presence of a base such as potassium oxide or sodium hydride at ⁇ 10 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C. it can.
  • the compound (v) is oxidized with m-chloroperbenzoic acid in a solvent such as dichloromethane and then reacted with the compound (viii) at ⁇ 10 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C.
  • a compound represented by (ix) can be produced.
  • R 18 is hydrogen or substituted or unsubstituted alkyl
  • R 19 is substituted or unsubstituted alkyl or substituted or unsubstituted non-aromatic heterocyclic group
  • u is an integer of 0 to 4, The symbol of is the same as above.
  • Compound (x ′) in a solvent such as THF, DMF, NMP and the like, 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and other condensing agents and triethylamine
  • Compound (xv) can be produced by reacting compound (xiv) in the presence of a base such as diisipropylethylamine or sodium carbonate.
  • Compound (xvi) can be produced by reacting compound (x ′) with diphenyl phosphate azide in a solvent such as THF, t-butanol, dioxane or the like or a mixed solvent thereof.
  • the compound represented by the above formula (I) has an antagonistic action on the P2X 3 and / or P2X 2/3 receptor, and is useful as a therapeutic agent for diseases involving P2X 3 and / or P2X 2/3. .
  • P2X 3 and / or P2X 2/3 receptor is believed to be involved in pain, urinary system diseases, and respiratory diseases (Nature 407, 26, 1011-1015 ( 2000), Nature, Vol.407, No.26 , 1015-1017 (2000), Non-Patent Document 1, Non-Patent Document 2, Non-Patent Documents 9 to 11, etc.), and is useful as a pharmaceutical composition having an analgesic action or an urination disorder improving action.
  • pain associated with rheumatoid arthritis pain associated with osteoarthritis, headache, migraine, oral and facial pain, toothache, glossodynia, pain associated with temporomandibular disorders, trigeminal neuralgia, shoulder pain, pain associated with disc herniation, Pain associated with degenerative cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus withdrawal syndrome, shoulder-hand syndrome, pain associated with whiplash, chest pain, abdominal pain, colic, cholelithiasis Pain associated with pancreatitis, pain associated with urolithiasis, pain associated with irritable bowel syndrome, low back pain, sciatica, pain associated with fracture, pain associated with osteoporosis, joint pain, pain associated with gout, Pain associated with cauda equina syndrome, pain associated with ankylosing spinal inflammation, muscle pain, painful spasm, myofascial pain syndrome, fibromyalg
  • the “pharmaceutical composition having an urination disorder improving effect” includes a pharmaceutical composition used for treatment, prevention and / or improvement of urination disorder.
  • the compound of the present invention has not only P2X 3 and / or P2X 2/3 receptor antagonistic activity but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • composition of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections, drops, external preparations eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas
  • Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered.
  • the injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
  • the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • 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.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d 6 and CDCl 3 . Moreover, when NMR data is shown, there are cases where not all measured peaks are described.
  • the LC / MS data of the compound of the present invention was measured under the following conditions and showed the retention time (minutes) and m / z.
  • reaction solution was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 2- (4-chlorobenzyl) -6- (ethoxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino. ] -1,2,4-Triazin-5 (2H) -one (432 mg, yield: 24%) was obtained as a pale yellow powder.
  • reaction solution was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 6-bromo-2- (4-chlorobenzyl) -3- [4- (2-pyridyloxy) phenylamino] -1 , 2,4-Triazin-5 (2H) -one (190 mg, yield: 25%) was obtained as a white powder.
  • Test example 3000 cells per well and stably expressing cell lines by introducing the evaluation of Test Example 1 Human P2X 3 receptor inhibitory activity human P2X 3 receptor gene (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates In a medium (7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution, DMEM containing 2.0% glutamine) at 37 ° C., 5% Cultivation was carried out for 2 days under carbon dioxide.
  • a medium 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution, DMEM containing 2.0% glutamine
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5
  • washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Filled with 20 ⁇ L per wash buffer.
  • the microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices).
  • Fluorescence intensity measurement by FLIPR 384 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid , 0.1% Pluronic F-127, pH 7.5)
  • dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid , 0.1% Pluronic F-127, pH 7.5.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • the concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity and IC 50 were calculated using software from Spotfire (Science Technology Systems). The test results of the compounds of the present invention are shown in the following table.
  • HSA Human serum albumin
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.37 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0. 5% BSA, 0.04% Pluronic F-127, pH 7.5) and incubate at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.37 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0. 5% BSA, 0.04% Pluronic F-127, pH 7.5
  • wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 ⁇ L of wash buffer.
  • the microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% using a solution to which human serum albumin has been added to dilute the compound DMSO solution of the present invention to different concentrations per well Dispense 40 ⁇ L at a time using an automatic dispensing device built in FDSS 3000.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).
  • Rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells were seeded such that 3000 cells per well, media ( 7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) and cultured at 37 ° C. under 5% carbon dioxide for 2 days.
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5
  • washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Filled with 20 ⁇ L per wash buffer.
  • the microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices).
  • Fluorescence intensity measurement by FLIPR 384 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid , 0.1% Pluronic F-127, pH 7.5), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FLIPR 384, 20 ⁇ L per well. did.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • the concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity and IC 50 were calculated using software from Spotfire (Science Technology Systems). The test results of the compounds of the present invention are shown in the following table.
  • the compounds described herein exhibited inhibitory activity against P2X 3 receptor.
  • the compound of the present invention acts on the P2X 3 subtype, it is considered that the compound of the present invention also shows an inhibitory activity against the P2X 2/3 receptor which is also composed of the P2X 2 subtype.
  • Test Example 4 rat serum albumin (RSA) Evaluation of rat P2X 3 receptor inhibitory activity in the presence of rat P2X 3 receptor gene (GenBank Accession sequence NM_031075) 1 hole per stably expressing cells introduced into C6BU-1 cells 8000 In a medium (7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. Incubate for days.
  • a medium 7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution
  • the medium was supplemented with 4 ⁇ M Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide.
  • 4 ⁇ M Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5
  • wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 ⁇ L of wash buffer.
  • the microplate is installed in the high-throughput screening system FDSS 7000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 7000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Dispense 40 ⁇ L per unit with an automatic dispenser built in FDSS 7000.
  • dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 is calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).
  • Test Example 5 Evaluation of drug efficacy by Seltzer model Rat Partial sciatic nerve ligation model (rat sciatic nerve partial ligation model) Model preparation Rats are anesthetized with isoflurane and the left leg is shaved. An incision is made in the upper thigh skin and the muscle is broken to expose the sciatic nerve. 1/3 to 1/2 of the sciatic nerve is tightly ligated with a thread, and the muscle and skin are sutured. This is the operation side. For the right foot, perform the same procedure except for sciatic nerve ligation, and make it the sham operation side. Evaluation (1) Two weeks after surgery, the effect on tactile allodynia is assessed by von Frey filament.
  • the rats are habituated to a plastic cage placed on a wire mesh.
  • the von Frey filament (0.4-26 g) is pressed against the back of the rat foot from the wire mesh side, and the pressure value of the von Frey fiber at which the rat begins to show escape behavior is taken as the pain threshold.
  • the pain threshold is evaluated for the left and right hind limbs, and set as a pretreatment pain threshold. Animals with an operating pain threshold of 0.6 to 2 g and a sham surgical pain threshold of 8 to 15 g are employed. In order to train the animal, the same operation is performed before measuring the pre-treatment pain threshold.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is crushed using a mortar and pestle, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value.
  • Test Example 6 Preparation of model animal for evaluation of drug efficacy using cauda equina nerve compression model
  • the lower back of the rat is incised under anesthesia to expose the fourth, fifth and sixth lumbar vertebrae. Incisions are made on the 4th-5th and 5th-6th lumbar vertebral joints. Silicon rubber is inserted into the 4th and 6th lumbar spinal canals from the vertebral joint incision and placed, and the incision is sutured.
  • the above-described operation is subjected to an operation excluding silicon rubber insertion and indwelling operations.
  • the compound of the present invention is crushed using a mortar and pestle, a suspension or solution is prepared using 0.5% methylcellulose solution as a medium, and is orally administered to the adopted animal using an oral sonde.
  • the pressure value of the von Frey filament at which the rat begins to show escape behavior by the same operation is measured and set as a pain threshold after administration.
  • % reversal value (logarithm of pain threshold after administration of model animal-logarithm of pain threshold before administration of model animal) / (logarithm of pain threshold before administration of sham-operated animal-logarithm of pain threshold before administration of model animal)
  • 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 110 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 120 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).
  • hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using CHO cells in which human ether-a-go-related gene (hERG) channels are expressed, it is important for the ventricular repolarization process.
  • hERG human ether-a-go-related gene
  • 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 Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, and add 2 ⁇ L of the compound solution of the present invention to JP-2 solution (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL) Add 1 volume of water to 1 volume) and add to 198 ⁇ L. After shaking for 1 hour at room temperature, the mixture is filtered with suction.
  • Medium concentration (C) is measured.
  • 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 Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium
  • the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution.
  • the dilution factor was changed as necessary.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsome, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 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 the compound of the present invention was added at each concentration was calculated.
  • Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value. If the Shifted IC is 1.5 or more, it is Positive, and if the Shifted IC is 1.0 or less, it is Negative.
  • Test Example 12 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the metabolite production amount 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 microsomes 0.2 mg protein / mL; drug concentration of the present invention, 1.0, 5.0, 10, 20 ⁇ mol / L ( 4 points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the supernatant was collected using a fluorescent multilabel counter or LC / MS / MS with tolbutamide hydroxide (CYP2C9 metabolite) and mephenytoin 4 ′ hydroxylated.
  • the body CYP2C19 metabolite
  • dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • a control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and calculating the residual activity (%) at each concentration to which the drug solution of the present invention was added. Used to calculate IC 50 by inverse estimation with a logistic model.
  • Test Example 13 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound is reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • SPE solid phase extraction
  • Test Example 14 Protein Binding Test Serum protein non-binding rate of the inventive compound is measured using rat serum.
  • Reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 2 ⁇ g / mL.
  • a test solution is added to rat serum and stirred to prepare a serum sample having the above compound concentration.
  • a serum sample is added to one of the equilibrium dialysis cells, and phosphate buffered saline (PBS) is added to the other, followed by equilibrium dialysis for 24 hours at 37 ° C.
  • PBS phosphate buffered saline
  • the amount of compound in the sample collected from each cell is measured by LC / MS / MS or solid phase extraction (SPE) / MS.
  • SPE solid phase extraction
  • Test Example 14-2 Protein Binding Test
  • the serum protein non-binding rate of the compound of the invention is measured using rat or human serum.
  • the reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 4 ⁇ mol / L.
  • a test solution is added to rat or human serum and stirred to prepare a serum sample having the above compound concentration.
  • a serum sample is added to one of the equilibrium dialysis cells, and phosphate buffered saline (PBS) is added to the other, followed by equilibrium dialysis for 24 hours at 37 ° C.
  • the amount of compound in the sample collected from each cell is measured by LC / MS / MS or solid phase extraction (SPE) / MS.
  • SPE solid phase extraction
  • Test Example 15 Pharmacokinetic Test Experimental Materials and Methods
  • Animals used SD rats were used.
  • Breeding conditions SD rats were allowed to freely take solid feed and sterilized tap water.
  • Test Example 16 Brain transfer test The compound of the present invention is intravenously administered to rats at a dose of 1 ⁇ mol / kg, and 30 minutes later, the blood is exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. Thereafter, the brain is removed and 20-25% homogenate is prepared with distilled water. On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
  • Test Example 17 P-gp Substrate Test A compound according to the present invention is added to one side of a transwell (registered trademark, CORNING) in which human MDR1-expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time. The Efflux Ratio (ER value) of the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate.
  • a transwell registered trademark, CORNING
  • ER value Efflux Ratio
  • Membrane permeability coefficient in the axial direction from the axial side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A) is calculated, and the Efflux Ratio (ER; B ⁇ A and A ⁇ B) of the MDR1-expressing cell and the parent cell. The ratio of the membrane permeation coefficient) is calculated.
  • Test Example 18 mdr1a ( ⁇ / ⁇ ) B6 mouse P-gp substrate
  • Test material animal mdr1a ( ⁇ / ⁇ ) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse)
  • Animals may be fed before administration of the compounds of the present invention. 2.
  • the compound of the present invention is administered to three animals at each time point, and blood and brain samples are given at predetermined time points after administration (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 24 hours). Time). Blood (0.3-0.7 mL) is collected with a syringe containing anticoagulants (EDTA and heparin).
  • EDTA and heparin anticoagulants
  • Blood and tissue (such as brain) samples should be ice-cold immediately. 3.
  • the blood sample is centrifuged (1780 ⁇ g, 10 minutes) to remove cells and obtain plasma.
  • the plasma sample is then transferred to a tube and stored at -70 ° C. 4).
  • Plasma and tissue (such as brain) samples are prepared using deproteinization and analyzed by LC / MS / MS. For the measurement, a quality control sample is used to confirm the accuracy and accuracy of the measurement method using a calibration curve prepared from blank plasma or blank brain. 6).
  • Plasma and brain concentration values (ng / mL and ng / g) are analyzed with an appropriate method for determining pharmacokinetic parameters, such as the WinNonlin® pharmacokinetic analysis software program.
  • 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 After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
  • Formulation Example 4 Orally Disintegrating Tablets
  • the compound of the present invention and crystalline cellulose are mixed and compressed after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
  • Formulation Example 9 Ointment
  • the compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.
  • Compounds of formula (I) has an antagonistic effect on P2X 3 and / or P2X 2/3 receptor, diseases or conditions P2X 3 and / or P2X 2/3 receptor is involved, such as chronic pain, It is considered useful for urination disorders, respiratory diseases and the like.

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Abstract

La présente invention concerne un nouveau composé antagoniste du récepteur P2X3 et/ou P2X2/3. L'invention porte sur un composé représenté par la formule (I) : (dans laquelle R1 représente alkyle substitué ou non substitué ou analogue, R2 représente un groupe carboné cyclique aromatique substitué ou non substitué ou analogue, R3 représente un groupe carboné cyclique aromatique substitué ou non substitué ou analogue, chaque R4a représente, indépendamment, un atome d'hydrogène ou analogue, chaque R4b représente, indépendamment, un atome d'hydrogène ou analogue, n représente un entier de 0-4, X représente -N(R5)- ou analogue, R5 représente un atome d'hydrogène ou analogue) ou sur un sel pharmaceutiquement acceptable correspondant.
PCT/JP2017/019634 2016-05-27 2017-05-26 Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante Ceased WO2017204316A1 (fr)

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WO2018074565A1 (fr) * 2016-10-21 2018-04-26 塩野義製薬株式会社 Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
WO2022253270A1 (fr) * 2021-06-04 2022-12-08 上海海雁医药科技有限公司 Dérivé d'acide triazinylméthylcycloalkylcarboxylique, composition pharmaceutique et utilisation de celui-ci
WO2024114663A1 (fr) * 2022-11-30 2024-06-06 上海海雁医药科技有限公司 Forme cristalline d'un dérivé d'acide triazinyl méthyl cycloalkyl carboxylique et son utilisation
WO2024114665A1 (fr) * 2022-11-30 2024-06-06 上海海雁医药科技有限公司 Intermédiaire dérivé de triazine-2,4-dione substitué et son procédé de préparation

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US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11124486B2 (en) 2015-04-24 2021-09-21 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
US11685740B2 (en) 2016-10-17 2023-06-27 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
WO2018074565A1 (fr) * 2016-10-21 2018-04-26 塩野義製薬株式会社 Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant
WO2022253270A1 (fr) * 2021-06-04 2022-12-08 上海海雁医药科技有限公司 Dérivé d'acide triazinylméthylcycloalkylcarboxylique, composition pharmaceutique et utilisation de celui-ci
WO2024114663A1 (fr) * 2022-11-30 2024-06-06 上海海雁医药科技有限公司 Forme cristalline d'un dérivé d'acide triazinyl méthyl cycloalkyl carboxylique et son utilisation
WO2024114665A1 (fr) * 2022-11-30 2024-06-06 上海海雁医药科技有限公司 Intermédiaire dérivé de triazine-2,4-dione substitué et son procédé de préparation

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