WO2018074565A1 - Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant - Google Patents

Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant Download PDF

Info

Publication number
WO2018074565A1
WO2018074565A1 PCT/JP2017/037919 JP2017037919W WO2018074565A1 WO 2018074565 A1 WO2018074565 A1 WO 2018074565A1 JP 2017037919 W JP2017037919 W JP 2017037919W WO 2018074565 A1 WO2018074565 A1 WO 2018074565A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
aromatic
aromatic heterocyclic
aromatic carbocyclic
Prior art date
Application number
PCT/JP2017/037919
Other languages
English (en)
Japanese (ja)
Inventor
啓一朗 平井
雄貴 緒方
尚武 小林
徳文 中橋
浩幸 甲斐
Original Assignee
塩野義製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Publication of WO2018074565A1 publication Critical patent/WO2018074565A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds useful for treating diseases or conditions P2X 7 receptor is involved, and to pharmaceutical compositions containing such compounds.
  • Adenosine triphosphate acts as an energy source and phosphorylation substrate inside the cell, while acting as an information transmitter outside the cell. It is known that ATP is released from cells by various stimuli such as cell damage, inflammation, noxious stimuli, reduction of blood oxygen concentration, and is released from nerve endings like other neurotransmitters. (Non-Patent Document 1). ATP released to the outside of the cell is responsible for various extracellular information transmission through the ATP receptor.
  • ATP receptors are roughly classified into an ion channel type P2X family and a G protein coupled type P2Y family. Seven subtypes are known in the P2X family, and function as channels by forming homotrimers or heterotrimers with other P2X subtypes.
  • P2X 7 receptors are nonselective cation channel belonging to the P2X family, exhibits a function as a homo trimer. Cations are opened by extracellular ATP and flow into the cell. During repeated stimulation, intracellular signals are enhanced, and small pores are formed in a membrane via hemichannels such as pannexin (Non-patent Document 2). This induces the release of small molecules such as ATP out of the cell and induces further activation of the cell.
  • P2X 7 receptors are macrophages, mast cells, microglia, and expression was observed like astrocytes. In knockout mice P2X 7 receptors have been reported to pain following inflammation or nerve damage is attenuated (Non-Patent Document 4). In addition, genetic polymorphism analysis in mice reveals that the 451st amino acid is involved in pore formation after receptor activation and correlates with pain intensity after nerve injury (Non-patent Document 5). . Similar loss-of-function mutations have also been reported in human genetic polymorphism analysis in patients with chronic pain, and inhibition of this receptor is associated with chronic pain such as rheumatoid arthritis, osteoarthritis, and neuropathic pain. It is considered to be a therapeutic drug.
  • Non-Patent Document 6 Body involvement has been reported and its inhibitors may be therapeutic.
  • Patent Documents 2 to 5 the compounds showing analgesic action are described, different structure from the compounds of the present invention, not described or suggested about P2X 7 inhibiting effect.
  • Patent Documents 6 and 7 a compound having a similar structure as the present invention compound are described to exhibit analgesic activity, no mention or suggest about P2X 7 inhibiting effect.
  • Patent Document 8 and 9 although a compound having a P2X 7 inhibiting effect have been described, those having a structure that is different from the compound according to the present invention.
  • An object of the present invention is to provide novel compounds and pharmaceutical compositions having a P2X 7 receptor inhibitory action having P2X 7 receptor inhibitory action.
  • the present invention relates to the following (1 ′′), (1 ′), (1) to (49), (50 ′), (51 ′′) to (56 ′′) and (1001) to (1007). .
  • (1 ′′) Formula (I): (Where Y 1 N (R Y ), O or S; R Y Is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted A non
  • R 10e are each independently a halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy);
  • R 5 Is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,
  • R Y Is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted A non-aromatic heterocyclic group of R 1 Is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group
  • R 10e are each independently a halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy);
  • R 5 Is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,
  • R Y Is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted A non-aromatic heterocyclic group of R 1 Is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group,
  • R 10e are each independently a halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy);
  • R 5 Is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,
  • R 6 represents a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, 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 alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or un
  • R 3 is (Wherein R 9a , R 10a and p1 are as defined above (1); ring B ′ is as defined above (2)), ), (1 ′) and (1) to (6), or a pharmaceutically acceptable salt thereof.
  • R 10a and R 10b are each independently halogen, hydroxy, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbon
  • R 10a and R 10b are each independently halogen, hydroxy, carbamoyl, sulfamoyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbon Cyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-ar
  • R 10a and R 10b are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Substituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted nonaromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic oxy
  • R 10a and R 10b are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (1 ′′), (1 ′) and (1) to The compound according to any one of (10) or a pharmaceutically acceptable salt thereof.
  • R 3 is (Wherein R 9a has the same meaning as (1) above; ring B ′ and R 10ac have the same meaning as (2) above; R 10ad is halogen, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted
  • R 10ad is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted
  • the compound according to (15) above which is alkynyloxy, or a pharmaceutically acceptable salt thereof.
  • R 10ad is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof.
  • R 10ad is halogen, or a pharmaceutically acceptable salt thereof.
  • R 3 is (Wherein, R 9a is as defined the above (1), R lOaa, R 10 ab and R 10ac, the above (2) and is as defined) is a group represented by the above (1 '' ), (1 ′), (1) and (3) to (6), or a pharmaceutically acceptable salt thereof.
  • R 3 is (Wherein, R 9a is as defined the above (1), R lOaa, R 10 ab and R 10ac, the above (2) and is as defined) is a group represented by the above (1 '' ), (1 ′) and (1) to (6), or a pharmaceutically acceptable salt thereof.
  • R 10aa and R 10ab are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Or a pharmaceutically acceptable salt thereof.
  • R 10aa and R 10ab are each independently halogen, or substituted or unsubstituted alkyl, or the compound according to any one of the above (2) and (19) to (20), or a pharmaceutically acceptable salt thereof Salt.
  • R 10ac is halogen, hydroxy, carboxy, carbamoyl, sulfamoyl, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyls
  • R 10ac is halogen, hydroxy, carbamoyl, sulfamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle Cyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted
  • R 10ac is halogen, carbamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted nonaromatic heterocyclic
  • R 10ac is halogen, carbamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic group
  • R 10ac is halogen, carbamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic group
  • R 9a and R 9b are each independently substituted or unsubstituted alkyl, or a compound thereof Pharmaceutically acceptable salt.
  • R 9a and R 10a bonded to adjacent ring member atoms, or R 9b and R 10b bonded to adjacent ring member atoms are taken together to form a substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted Forming a non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted non-aromatic heterocycle;
  • Two R 10a bonded to adjacent ring member atoms or two R 10b bonded to adjacent ring member atoms together form a substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic Forming an aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring,
  • R 9a and R 10aa bonded to adjacent atoms taken together are a substituted or
  • R 9a and R 10a bonded to adjacent ring member atoms, or R 9b and R 10b bonded to adjacent ring member atoms, together, are substituted or unsubstituted aromatic heterocycles, or substituted or unsubstituted A non-aromatic heterocycle of Two R 10a bonded to adjacent ring member atoms, or two R 10b bonded to adjacent ring member atoms, together are a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted non-substituted ring.
  • R 1 is (Wherein R 1a , R 1b and R 1c are each independently halogen) of the above (1 ′′), (1 ′) and (1) to (31) A compound according to any one of the above, or a pharmaceutically acceptable salt thereof.
  • R 5 is a hydrogen atom, halogen, hydroxy, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkenyl
  • Compounds according to the present invention has an inhibitory effect on P2X 7 receptors are useful as therapeutic and / or prophylactic agent for a disease or condition P2X 7 is 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 straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. 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, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • “Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned. A preferred embodiment of the “aromatic carbocycle” includes a benzene ring.
  • the “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • non-aromatic carbocycle means a monocyclic ring or two or more cyclic saturated hydrocarbon rings or cyclic non-aromatic unsaturated hydrocarbon rings.
  • the two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
  • the “non-aromatic carbocycle” includes a ring that is bridged as follows, or a spiro ring.
  • the monocyclic non-aromatic carbocycle 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 cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
  • the two or more non-aromatic carbocycles include indane, indene, acenaphthalene, tetrahydronaphthalene, and fluorene.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the non-aromatic carbocyclic group having 2 or more rings includes a monocyclic ring or a non-aromatic carbocyclic group having 2 or more rings condensed with the ring in the above “aromatic carbocyclic group”.
  • 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 heterocycle” means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • Two or more aromatic heterocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
  • the monocyclic aromatic heterocyclic ring is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples thereof include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
  • bicyclic aromatic heterocycle examples include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, Benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine, etc.
  • 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.
  • 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 heterocycle means a monocyclic or bicyclic or more cyclic non-aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring .
  • the non-aromatic heterocyclic ring having two or more rings is the above-mentioned “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” in addition to a single ring or two or more non-aromatic heterocyclic rings. Also included are those in which each ring is condensed.
  • the two or more non-aromatic heterocycles include those in which the ring in the above “non-aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
  • the “non-aromatic heterocyclic ring” includes a ring that is bridged as follows, or a spiro ring.
  • the monocyclic non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Examples include dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thio
  • 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 includes those in which the ring in the above-mentioned “non-aromatic carbocyclic group” is condensed to a monocyclic or two or more aromatic heterocyclic group.
  • 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.
  • Alkyloxy means a group wherein 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.
  • vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like can be mentioned.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • 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.
  • Alkylamino means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylamino, ethylamino, isopropylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Preferable embodiments of “alkylamino” include methylamino and ethylamino.
  • Alkenylamino means a group in which the above “alkenyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenyl For example, ethylenylamino, propenylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkynylamino means a group in which the above “alkynyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynyl For example, ethynylamino, propynylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • 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.
  • 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.
  • 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.
  • Alkylsulfonyloxy means a group in which the above “alkylsulfonyl” is bonded to an oxygen atom. Examples thereof include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, tert-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy and the like. Preferable embodiments of “alkylsulfonyloxy” include methylsulfonyloxy and ethylsulfonyloxy.
  • Alkenylsulfonyloxy means a group in which the above “alkenylsulfonyl” is bonded to an oxygen atom.
  • alkenylsulfonyloxy ethylenylsulfonyloxy, propenylsulfonyloxy and the like can be mentioned.
  • Alkynylsulfonyloxy means a group in which the above “alkynylsulfonyl” is bonded to an oxygen atom.
  • alkynylsulfonyloxy ethynylsulfonyloxy, propynylsulfonyloxy and the like can be mentioned.
  • Alkyloxysulfonyl means a group in which the above “alkyloxy” is bonded to a sulfonyl group. Examples include methyloxysulfonyl, ethyloxysulfonyl, propyloxysulfonyl, isopropyloxysulfonyl, tert-butyloxysulfonyl, isobutyloxysulfonyl, sec-butyloxysulfonyl, pentyloxysulfonyl, isopentyloxysulfonyl, hexyloxysulfonyl and the like. It is done. Preferable embodiments of “alkyloxysulfonyl” include methyloxysulfonyl, ethyloxysulfonyl, and propyloxysulfonyl.
  • Alkenyloxysulfonyl means a group in which the above “alkenyloxy” is bonded to a sulfonyl group.
  • alkenyloxy ethylenyloxysulfonyl, propenyloxysulfonyl and the like can be mentioned.
  • Alkynyloxysulfonyl means a group in which the above “alkynyloxy” is bonded to a sulfonyl group.
  • alkynyloxy ethynyloxysulfonyl, propynyloxysulfonyl and the like can be mentioned.
  • Alkylcarbamoyl means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl. Further, the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkenylcarbamoyl means a group in which the above “alkenyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • alkenyl ethylenylcarbamoyl, propenylcarbamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkynylcarbamoyl means a group in which the above “alkynyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • alkynyl ethynylcarbamoyl, propynylcarbamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkylsulfamoyl means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned. Further, the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • Alkenylsulfamoyl means a group in which the above “alkenyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • alkenyl ethylenyl sulfamoyl, propenyl sulfamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkynylsulfamoyl means a group in which the above “alkynyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • alkynyl ethynyl sulfamoyl, propynyl sulfamoyl, etc. are mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Preferable embodiments of “alkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Alkenylcarbonylamino means a group in which the above “alkenylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenylcarbonyl For example, ethylenylcarbonylamino, propenylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkynylcarbonylamino means a group in which the above “alkynylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynylcarbonyl For example, ethynylcarbonylamino, propynylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Preferable embodiments of “alkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Alkenylsulfonylamino means a group in which the above “alkenylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenylsulfonyl For example, ethylenylsulfonylamino, propenylsulfonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkynylsulfonylamino means a group in which the above “alkynylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynylsulfonyl For example, ethynylsulfonylamino, propynylsulfonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkyloxycarbonylamino means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkyloxycarbonyl examples include methyloxycarbonylamino, ethyloxycarbonylamino, propyloxycarbonylamino.
  • Alkenyloxycarbonylamino means a group in which the above “alkenyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenyloxycarbonyl For example, ethylenyloxycarbonylamino, propenyloxycarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkynyloxycarbonylamino means a group in which the above “alkynyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynyloxycarbonyl For example, ethynyloxycarbonylamino, propynyloxycarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • 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.
  • 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.
  • the “aromatic carbocyclic group” of “aromatic carbocyclic sulfonylamino” and “aromatic carbocyclic oxycarbonylamino” is the same as the above “aromatic carbocyclic group”.
  • “Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom.
  • “Aromatic carbocyclic amino” means a group in which the “aromatic carbocycle” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • phenylamino, naphthylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “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 carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • “Aromatic carbocyclic carbonyloxy” means a group in which the above “aromatic carbocyclic carbonyl” is bonded to an oxygen atom. For example, phenylcarbonyloxy, naphthylcarbonyloxy and the like can be mentioned.
  • “Aromatic carbocyclic sulfonyloxy” means a group in which the above “aromatic carbocyclic sulfonyl” is bonded to an oxygen atom.
  • phenylsulfonyloxy, naphthylsulfonyloxy and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic oxysulfonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a sulfonyl group. For example, phenyloxysulfonyl, naphthyloxysulfonyl and the like can be mentioned.
  • the “aromatic carbocyclic carbamoyl” means a group in which the “aromatic carbocyclic” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. For example, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.
  • the “aromatic carbocyclic sulfamoyl” means a group in which the “aromatic carbocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include phenylsulfamoyl and naphthylsulfamoyl. Further, the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • “Aromatic carbocyclic carbonylamino” means a group in which the above “aromatic carbocyclic carbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • phenylcarbonylamino, naphthylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “Aromatic carbocyclic sulfonylamino” means a group in which the above “aromatic carbocyclic sulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • phenylsulfonylamino, naphthylsulfonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “Aromatic carbocyclic oxycarbonylamino” means a group in which the above “aromatic carbocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • phenyloxycarbonylamino, naphthyloxycarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic amino”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic sulfonyl”, “non-aromatic carbon” “Ring carbonyloxy”, “Non-aromatic carbocyclic sulfonyloxy”, “Non-aromatic carbocyclic oxycarbonyl", “Non-aromatic carbocyclic oxysulfonyl", “Non-aromatic carbocyclic carbamoyl", “Non-aromatic carbocycle”
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocyclic amino means a group in which “non-aromatic carbocycle” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • cyclopropylamino, cyclohexylamino, cyclohexenylamino 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 carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • Non-aromatic carbocyclic carbonyloxy means a group in which the above “non-aromatic carbocyclic carbonyl” is bonded to an oxygen atom.
  • non-aromatic carbocyclic sulfonyloxy means a group in which the “non-aromatic carbocyclic sulfonyl” is bonded to an oxygen atom.
  • examples include cyclopropylsulfonyloxy, cyclohexylsulfonyloxy, cyclohexenylsulfonyloxy and the like.
  • 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 oxysulfonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a sulfonyl group.
  • non-aromatic carbocyclic carbamoyl means a group in which the “non-aromatic carbocyclic” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like.
  • non-aromatic carbocyclic sulfamoyl means a group in which the “non-aromatic carbocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. Examples include cyclopropylsulfamoyl, cyclohexylsulfamoyl, cyclohexenylsulfamoyl and the like. Further, the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • non-aromatic carbocyclic carbonylamino means a group in which the above “non-aromatic carbocyclic carbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • cyclopropylcarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • non-aromatic carbocyclic sulfonylamino means a group in which the above “non-aromatic carbocyclic sulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • examples thereof include cyclopropylsulfonylamino, cyclohexylsulfonylamino, cyclohexenylsulfonylamino and the like.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Non-aromatic carbocyclic oxycarbonylamino means a group in which the above “non-aromatic carbocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include cyclopropyloxycarbonylamino, cyclohexyloxycarbonylamino, cyclohexenyloxycarbonylamino and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • the “aromatic heterocyclic amino” means a group in which the “aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • pyridylamino, oxazolylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “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.
  • “Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group.
  • pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • “Aromatic heterocyclic carbonyloxy” means a group in which the above “aromatic heterocyclic carbonyl” is bonded to an oxygen atom.
  • pyridylcarbonyloxy, oxazolylcarbonyloxy and the like can be mentioned.
  • the “aromatic heterocyclic sulfonyloxy” means a group in which the above “aromatic heterocyclic sulfonyl” is bonded to an oxygen atom.
  • pyridylsulfonyloxy, oxazolylsulfonyloxy and the like can be mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • the “aromatic heterocyclic oxysulfonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a sulfonyl group.
  • pyridyloxysulfonyl, oxazolyloxysulfonyl and the like can be mentioned.
  • “Aromatic heterocycle carbamoyl” means a group in which “aromatic heterocycle” is replaced with one hydrogen atom bonded to a nitrogen atom of a carbamoyl group.
  • “aromatic heterocycle” is replaced with one hydrogen atom bonded to a nitrogen atom of a carbamoyl group.
  • pyridylcarbamoyl, oxazolylcarbamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • the “aromatic heterocyclic sulfamoyl” means a group in which the “aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • pyridyl sulfamoyl, oxazolyl sulfamoyl, etc. are mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • the “aromatic heterocyclic carbonylamino” means a group in which the above “aromatic heterocyclic carbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • the “aromatic heterocyclic sulfonylamino” means a group in which the above “aromatic heterocyclic sulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic oxycarbonylamino means a group in which the above “aromatic heterocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • Non-aromatic heterocyclic oxy “Non-aromatic heterocyclic amino”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic sulfonyl”, “Non-aromatic heterocyclic” Ring carbonyloxy, non-aromatic heterocyclic sulfonyloxy, non-aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxysulfonyl, non-aromatic heterocyclic carbamoyl, non-aromatic heterocyclic
  • the “non-aromatic heterocycle” moiety of “sulfamoyl”, “non-aromatic heterocycle carbonylamino”, “non-aromatic heterocycle sulfonylamino”, and “non-aromatic heterocycle oxycarbonylamino” is also the above “non-aromatic” The same as “hetero
  • 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.
  • the “non-aromatic heterocyclic amino” means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • piperidinylamino, tetrahydrofurylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • 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 carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl 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.
  • Non-aromatic heterocyclic carbonyloxy means a group in which the above “non-aromatic heterocyclic carbonyl” is bonded to an oxygen atom.
  • piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxy and the like can be mentioned.
  • non-aromatic heterocyclic sulfonyloxy means a group in which the above “non-aromatic heterocyclic sulfonyl” is bonded to an oxygen atom.
  • piperidinylsulfonyloxy, tetrahydrofurylsulfonyloxy and the like can be mentioned.
  • 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 oxysulfonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a sulfonyl group.
  • piperidinyloxysulfonyl, tetrahydrofuryloxysulfonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic carbamoyl” means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • piperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like can be mentioned.
  • non-aromatic heterocyclic sulfamoyl means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • non-aromatic heterocyclic sulfamoyl means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • piperidinyl sulfamoyl, tetrahydrofuryl sulfamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • non-aromatic heterocyclic carbonylamino means a group in which the above “non-aromatic heterocyclic carbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • non-aromatic heterocyclic carbonylamino For example, piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • the “non-aromatic heterocyclic sulfonylamino” means a group in which the above “non-aromatic heterocyclic sulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • non-aromatic heterocyclic oxycarbonylamino means a group in which the above “non-aromatic heterocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • piperidinyloxycarbonylamino, tetrahydrofuryloxycarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • 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.
  • Haloalkylamino means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples thereof include monofluoromethylamino, monofluoroethylamino, trifluoromethylamino, trichloromethylamino, trifluoroethylamino, trichloroethylamino and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” or the above “haloalkyl”. Preferable embodiments of “haloalkylamino” include trifluoromethylamino and trichloromethylamino.
  • Haloalkylsulfanyl means a group in which the above “haloalkyl” is bonded to a sulfanyl group.
  • monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl and trichloromethylsulfanyl.
  • Haloalkylcarbonyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
  • monofluoromethylcarbonyl, monofluoroethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, trifluoroethylcarbonyl, trichloroethylcarbonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylcarbonyl” include trifluoromethylcarbonyl and trichloromethylcarbonyl.
  • Haloalkylsulfonyl means a group in which the above “haloalkyl” is bonded to a sulfonyl group.
  • monofluoromethylsulfonyl, monofluoroethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, trifluoroethylsulfonyl, trichloroethylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfonyl” include trifluoromethylsulfonyl and trichloromethylsulfonyl.
  • Haloalkylcarbamoyl means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include monofluoromethylcarbamoyl, monofluoroethylcarbamoyl, trifluoromethylcarbamoyl, trichloromethylcarbamoyl, trifluoroethylcarbamoyl, trichloroethylcarbamoyl and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl” or the above “haloalkyl”. Preferable embodiments of “haloalkylcarbamoyl” include trifluoromethylcarbamoyl and trichloromethylcarbamoyl.
  • Haloalkylsulfamoyl means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include monofluoromethylsulfamoyl, monofluoroethylsulfamoyl, trifluoromethylsulfamoyl, trichloromethylsulfamoyl, trifluoroethylsulfamoyl, trichloroethylsulfamoyl and the like.
  • haloalkylsulfamoyl include trifluoromethylsulfamoyl and trichloromethylsulfamoyl.
  • Haloalkylcarbonylamino means a group in which the above “haloalkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • monofluoromethylcarbonylamino, monofluoroethylcarbonylamino, trifluoromethylcarbonylamino, trichloromethylcarbonylamino, trifluoroethylcarbonylamino, trichloroethylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” or the above “haloalkyl”.
  • Preferable embodiments of “haloalkylcarbonylamino” include trifluoromethylcarbonylamino and trichloromethylcarbonylamino.
  • Haloalkylsulfonylamino means a group in which the above “haloalkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • monofluoromethylsulfonylamino, monofluoroethylsulfonylamino, trifluoromethylsulfonylamino, trichloromethylsulfonylamino, trifluoroethylsulfonylamino, trichloroethylsulfonylamino and the like can be mentioned.
  • haloalkylsulfonylamino include trifluoromethylsulfonylamino and trichloromethylsulfonylamino.
  • Haloalkylcarbonyloxy means a group in which the above “haloalkylcarbonyl” is bonded to an oxygen atom.
  • monofluoromethylcarbonyloxy, monofluoroethylcarbonyloxy, trifluoromethylcarbonyloxy, trichloromethylcarbonyloxy, trifluoroethylcarbonyloxy, trichloroethylcarbonyloxy and the like can be mentioned.
  • Preferable embodiments of “haloalkylcarbonyloxy” include trifluoromethylcarbonyloxy and trichloromethylcarbonyloxy.
  • Haloalkylsulfonyloxy means a group in which the above “haloalkylsulfonyl” is bonded to an oxygen atom.
  • monofluoromethylsulfonyloxy, monofluoroethylsulfonyloxy, trifluoromethylsulfonyloxy, trichloromethylsulfonyloxy, trifluoroethylsulfonyloxy, trichloroethylsulfonyloxy and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfonyloxy” include trifluoromethylsulfonyloxy and trichloromethylsulfonyloxy.
  • Haloalkyloxycarbonyl means a group in which the above “haloalkyloxy” is bonded to a carbonyl group. Examples thereof include monofluoromethyloxycarbonyl, monofluoroethyloxycarbonyl, trifluoromethyloxycarbonyl, trichloromethyloxycarbonyl, trifluoroethyloxycarbonyl, trichloroethyloxycarbonyl and the like. Preferable embodiments of “haloalkyloxycarbonyl” include trifluoromethyloxycarbonyl and trichloromethyloxycarbonyl.
  • Haloalkyloxysulfonyl means a group in which the above “haloalkyloxy” is bonded to a sulfonyl group.
  • monofluoromethyloxysulfonyl, monofluoroethyloxysulfonyl, trifluoromethyloxysulfonyl, trichloromethyloxysulfonyl, trifluoroethyloxysulfonyl, trichloroethyloxysulfonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkyloxysulfonyl” include trifluoromethyloxysulfonyl and trichloromethyloxysulfonyl.
  • substituent group A examples include substituent group A.
  • the carbon atom at any position may be bonded to one or more groups selected from the substituent group A.
  • Substituent group A halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, formyl, imino, hydroxyimino, cyanoimino, alkyl optionally substituted by one or more groups selected from substituent group C2 Oxy, alkylamino optionally substituted with one or more groups selected from substituent group C2, alkylsulfanyl optionally substituted with one or more groups selected from substituent group C2, substituent group C2 1 selected from alkylimino optionally substituted with one or more groups selected from the above, alkyloxyimino optionally substituted with one or more groups selected from the substituent group C2, 1 selected from substituent group C2 Alkylcarbonyl which may be substitute
  • alkylsulfonyl alkylcarbonylamino optionally substituted with one or more groups selected from substituent group C2, alkylsulfonylamino optionally substituted with one or more groups selected from substituent group C2 From alkylcarbamoyl optionally substituted with one or more groups selected from group C2, alkylsulfamoyl optionally substituted with one or more groups selected from substituent group C2, from substituent group C2 Alkylcarbonyloxy optionally substituted with one or more selected groups, alkyloxycarbonyl optionally substituted with one or more groups selected from substituent group C2, 1 selected from substituent group C2 Alkylsulfonyloxy which may be substituted with the above groups, Al which may be substituted with one or more groups selected from Substituent Group C2 Ruoxysulfonyl, an aromatic carbocyclic group which may be substituted with one or more groups selected from substituent group E, and a non-substituted group which is substituted
  • the carbon atom at any position may be bonded to one or more groups selected from the substituent group B.
  • Substituent group B alkyl optionally substituted by one or more groups selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, formyl, imino, hydroxyimino, cyanoimino, substituent group D Oxy, alkylamino optionally substituted with one or more groups selected from substituent group D, alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, substituent group D 1 selected from alkylimino optionally substituted with one or more groups selected from the above, alkyloxyimino optionally substituted with one or more groups selected from the substituent group D, 1 selected from substituent group D Alkylcarbonyl which may be substituted with the above groups, and alkylsulfonyl which may be substituted with one or more groups selected from Substi
  • Aromatic carbocyclic sulfonyloxy optionally substituted with a group
  • Non-aromatic carbocyclic sulfonyloxy optionally substituted with one or more groups selected from Substituent Group E, selected from Substituent Group E
  • An aromatic heterocyclic sulfonyloxy which may be substituted with one or more groups
  • a non-aromatic heterocyclic sulfonyloxy which may be substituted with one or more groups selected from substituent group E.
  • the atom at any position on the ring may be bonded to one or more groups selected from the substituent group C1.
  • Substituent group C1 selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted with one or more groups selected from substituent group D, and substituent group D Alkenyl optionally substituted with one or more groups, alkynyl optionally substituted with one or more groups selected from substituent group D, substituted with one or more groups selected from substituent group D Alkyloxy which may be substituted, alkenyloxy which may be substituted with one or more groups selected from substituent group D, alkynyloxy which may be substituted with one or more groups selected from substituent group D, Alkylamino optionally substituted with one or more groups selected from Substituent Group D, Alkenylamino optionally substituted with one or more groups selected from Substituent Group D , Al
  • Substituent group C2 halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyloxy, haloalkyloxy, alkylamino, haloalkylamino, alkylsulfanyl, haloalkylsulfanyl, and Aromatic carbocyclic group optionally substituted with one or more groups selected from substituent group F, Non-aromatic carbocycle optionally substituted with one or more groups selected from substituent group F An aromatic heterocyclic group optionally substituted with one or more groups selected from the formula group, substituent group F, and non-substituted optionally substituted with one or more groups selected from substituent group F Aromatic heterocyclic group.
  • Substituent group D halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, and cyano.
  • Substituent group E halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, and cyano, and Selected from alkyl optionally substituted with one or more groups selected from substituent group D, alkyloxy optionally substituted with one or more groups selected from substituent group D, selected from substituent group D An alkylamino optionally substituted with one or more groups, an alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, and one or more groups selected from substituent group D Optionally substituted alkylcarbonyl, optionally substituted with one or more groups selected from substituent group D, optionally substituted with one or more groups selected from substituent group D Alkylcarbonylamino, alkylsulfonylamin
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with one or more “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic amino”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic sulfonyl”, “non-aromatic” Aromatic carbocyclic carbonyloxy ",” Non-aromatic carbocyclic sulfonyloxy ",” Non-aromatic carbocyclic oxycarbonyl ",” Non-aromatic carbocyclic oxysulfonyl ",” Non-aromatic carbocyclic carbamoyl ",” Non-aromatic Carbocyclic sulfamoyl, non-aromatic carbocyclic carbonylamino, non-aromatic carbocyclic sulfonylamino, non-aromatic carbocyclic oxycarbonylamino, non-aromatic heterocyclic oxy, non-aromatic
  • Substituted or unsubstituted aromatic carbocyclic group in R 1, "substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic heterocyclic group”, “substituted or unsubstituted”
  • substituent on the ring of “substituted non-aromatic heterocyclic group” and “substituted phenyl” include, for example, halogen, alkyl optionally substituted with one or more groups selected from substituent group D And alkylamino optionally substituted with one or more groups selected from substituent group D.
  • halogen alkyl, haloalkyl, alkylamino and the like can be mentioned.
  • mode a halogen and alkyl are mentioned, for example.
  • halogen is mentioned.
  • substituents of “substituted or unsubstituted alkyl” and “substituted or unsubstituted alkyloxy” in R 2a , R 2b , R 2c and R 2d include halogen, hydroxy, cyano and the like. As one aspect, for example, halogen and the like can be mentioned.
  • substituents of “substituted or unsubstituted alkyl” and “substituted or unsubstituted alkylcarbonyl” in R 7a include halogen, hydroxy, cyano and the like. As one aspect, for example, halogen and the like can be mentioned.
  • Substituted or unsubstituted alkyl “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy” in R Y ,
  • substituent of “substituted or unsubstituted alkynyloxy” is, for example, substituted with one or more groups selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substituent group D Alkyloxy which may be substituted, alkylamino which may be substituted with one or more groups selected from substituent group D, alkylsulfanyl which may be substituted with one or more groups selected from substituent group D, Alkylcarbonyl optionally substituted with one or more groups selected from Substitu
  • halogen hydroxy, cyano and the like can be mentioned.
  • halogen is mentioned.
  • "Substituted or unsubstituted aromatic carbocyclic group" in R Y, "substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic heterocyclic group”, and "substituted or Examples of the substituent on the ring of the “unsubstituted non-aromatic heterocyclic group” include one or more groups selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano and substituent group D.
  • alkyl optionally substituted with one or more groups selected from substituent group D, optionally substituted with one or more groups selected from substituent group D
  • substituent group D examples thereof include alkylamino, alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, and the like.
  • halogen alkyl optionally substituted with one or more groups selected from substituent group D, alkyloxy optionally substituted with one or more groups selected from substituent group D Etc.
  • substituent of “amino”, “substituted or unsubstituted alkenylamino”, and “substituted or unsubstituted alkynylamino” include halogen, hydroxy, cyano and the like.
  • a non-aromatic carbocyclic group which may be substituted with one or more groups selected from a cyclic group and substituent group F, and one or more groups selected from substituent group F may be substituted
  • An aromatic heterocyclic group, a non-aromatic heterocyclic group which may be substituted with one or more groups selected from the substituent group F, and the like can be mentioned.
  • halogenoxy, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, and the like can be mentioned.
  • halogen, hydroxy, cyano, alkyloxy, haloalkyloxy and the like can be mentioned.
  • halogen, hydroxy and the like can be mentioned.
  • alkyl optionally substituted with one or more groups selected from substituent group D for example, selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted with one or more groups selected from substituent group D, and substituent group D
  • An alkyloxy optionally substituted with one or more groups, an alkylamino optionally substituted with one or more groups selected from substituent group D, and one or more groups selected from substituent group D Alkylsulfanyl etc. which may be substituted are mentioned.
  • substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, and “substituted or unsubstituted alkynyl” in R 9a and R 9b include, for example, halogen, hydroxy, carboxy, amino, carbamoyl , Sulfamoyl, sulfo, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, alkylamino optionally substituted with one or more groups selected from substituent group D , An alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, an aromatic carbocyclic group optionally substituted with one or more groups selected from substituent group F, substituted A non-aromatic carbocyclic group optionally substituted with one or more groups selected from group F, substituted with one or more groups selected from substituent group F Which may be aromatic heterocyclic groups, such as 1 or more
  • alkyloxy optionally substituted with one or more groups selected from substituent group D
  • substituent group D Alkylamino optionally substituted with one or more groups selected from the above, alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, one or more groups selected from substituent group F 1 selected from a non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent group F and a substituent group F optionally substituted with an aromatic carbocyclic group optionally substituted with Examples thereof include an aromatic heterocyclic group which may be substituted with the above group, a non-aromatic heterocyclic group which may be substituted with one or more groups selected from Substituent Group F, and the like.
  • halogen, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from Substituent Group D, substituted with one or more groups selected from Substituent Group F
  • a non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent group F, and one or more groups selected from the substituent group F.
  • halogen, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, substituted with one or more groups selected from substituent group D
  • substituent group D Alkylsulfanyl which may be substituted, alkylcarbonyl which may be substituted with one or more groups selected from substituent group D, alkyloxycarbonyl which may be substituted with one or more groups selected from substituent group D
  • alkylcarbonyloxy which may be substituted with one or more groups selected from substituent group D, alkylsulfonyl which may be substituted with one or more groups selected from substituent group D, and the like.
  • halogenoxy, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, and the like can be mentioned.
  • halogen, hydroxy, cyano, alkyloxy, haloalkyloxy and the like can be mentioned.
  • halogen, hydroxy, alkyloxy and the like can be mentioned.
  • One embodiment includes, for example, halogen, hydroxy, cyano, oxo, alkyl and the like.
  • R 9a and R 10a bonded to adjacent ring member atoms, or R 9b and R 10b bonded to adjacent ring member atoms, together, are substituted or unsubstituted aromatic carbocycles, substituted or unsubstituted A non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring ", and" R 9a and R 10aa bonded to adjacent atoms are To form a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring " situational, “Substituted or unsubstituted aromatic carbocycle”, “Substituted or unsubstit
  • alkyl optionally substituted with one or more groups selected from substituent group D for example, selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted with one or more groups selected from substituent group D, and substituent group D
  • An alkyloxy optionally substituted with one or more groups, an alkylamino optionally substituted with one or more groups selected from substituent group D, and one or more groups selected from substituent group D Alkylsulfanyl etc. which may be substituted are mentioned.
  • R 10a bonded to adjacent ring member atoms or two R 10b bonded to adjacent ring member atoms together form a substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-substituted ring
  • R 10ab and R 10ac bonded to adjacent atoms are taken together to form a substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, substituted or unsubstituted aromatic heterocycle, Or “forms a substituted or unsubstituted non-aromatic heterocycle”, and “R 10ac and R 10ad bonded to adjacent atoms are taken together to form a substituted or unsubstituted aromatic carbocycle,
  • alkyl optionally substituted with one or more groups selected from substituent group D, and substituent group D
  • alkyloxy optionally substituted with one or more groups, an alkylamino optionally substituted with one or more groups selected from substituent group D, and one or more groups selected from substituent group D Alkylsulfanyl etc. which may be substituted are mentioned.
  • alkyl and the like can be mentioned.
  • halogen, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, substituted with one or more groups selected from substituent group D
  • substituent group D Alkylalkyl which may be substituted, alkylsulfanyl which may be substituted with one or more groups selected from substituent group D, and the like.
  • halogen, hydroxy and the like can be mentioned.
  • halogen and the like can be mentioned.
  • alkyloxy optionally substituted with one or more groups selected from substituent group D
  • substituent group D Alkylamino optionally substituted with one or more groups selected from the above, alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, one or more groups selected from substituent group F 1 selected from a non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent group F and a substituent group F optionally substituted with an aromatic carbocyclic group optionally substituted with Examples thereof include an aromatic heterocyclic group which may be substituted with the above group, a non-aromatic heterocyclic group which may be substituted with one or more groups selected from Substituent Group F, and the like.
  • halogen, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from Substituent Group D, substituted with one or more groups selected from Substituent Group F
  • a non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent group F, and one or more groups selected from the substituent group F.
  • halogenoxy, hydroxy, cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, and the like can be mentioned.
  • halogen, hydroxy, cyano, alkyloxy, haloalkyloxy and the like can be mentioned.
  • halogen, hydroxy, alkyloxy and the like can be mentioned.
  • hydroxy and the like can be mentioned.
  • alkyl optionally substituted with one or more groups selected from substituent group D, and substituent group D
  • alkyloxy optionally substituted with one or more groups, an alkylamino optionally substituted with one or more groups selected from substituent group D, and one or more groups selected from substituent group D Alkylsulfanyl etc. which may be substituted are mentioned.
  • alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like can be mentioned.
  • (A) The following compound (a-1) or (a-2) or a pharmaceutically acceptable salt thereof:
  • (A-1) A compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom, halogen, cyano, or substituted or unsubstituted alkyl.
  • (A-2) A compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 is cyano.
  • (B) The compound according to any one of the following (b-1) to (b-3) or a pharmaceutically acceptable salt thereof.
  • (B-1) The compound represented by the formula (II), the formula (III) or the above (a) or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl. .
  • (B-2) A compound represented by formula (II), formula (III) or the above (a) or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom or halogen.
  • (B-3) A compound represented by formula (II), formula (III) or the above (a) or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom.
  • (C) The compound according to any one of the following (c-1) to (c-3) or a pharmaceutically acceptable salt thereof.
  • (C-1) A compound represented by formula (I), formula (II), formula (III), the above (a) or (b) or a pharmaceutically acceptable salt thereof, wherein Y 1 is O.
  • (C-2) Formula (I), Formula (II), Formula (III), wherein R Y is a hydrogen atom, hydroxy, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy The compound shown in (a) or (b) or a pharmaceutically acceptable salt thereof.
  • (C-3) The compound represented by formula (I), formula (II), formula (III), (a) or (b) above, or a pharmaceutically acceptable salt thereof, wherein R Y is a hydrogen atom.
  • (D) The following compound (d-1) or (d-2) or a pharmaceutically acceptable salt thereof: (D-1) In the formula (I), the formula (II), the formula (III), and any one of the above (a) to (c), wherein R 7a is a hydrogen atom or substituted or unsubstituted alkyl. Or a pharmaceutically acceptable salt thereof. (D-2) The compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (c), wherein R 7a is a hydrogen atom, or a pharmaceutically acceptable salt thereof Salt.
  • R 2a and R 2b are each independently a hydrogen atom, halogen, or substituted or unsubstituted alkyl, or R 2a and R 2b bonded to the same carbon atom are taken together A compound represented by formula (I), formula (II), formula (III), and any of the above (a) to (d), or a pharmaceutically acceptable salt thereof, which forms oxo.
  • R 2a and R 2b are each independently a hydrogen atom or halogen, of formula (I), formula (II), formula (III), and (a) to (d) above The compound shown in any one or its pharmaceutically acceptable salt.
  • E-3) A compound represented by the formula (I), the formula (II), the formula (III), or any one of the above (a) to (d), wherein R 2a and R 2b are hydrogen atoms, or a compound thereof Pharmaceutically acceptable salt.
  • (F) The following compound (f-1) or (f-2) or a pharmaceutically acceptable salt thereof:
  • (F-1) A compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (e), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof Salt.
  • (F-2) A compound represented by the formula (I), the formula (II), the formula (III) and any one of the above (a) to (e), wherein n is 1, or a pharmaceutically acceptable product thereof salt.
  • (G) The compound according to any one of the following (g-1) to (g-3) or a pharmaceutically acceptable salt thereof.
  • (G-1) Formula (I), Formula (II), Formula (III), and the above (R) wherein R 2c and R 2d are each independently a hydrogen atom, halogen, or substituted or unsubstituted alkyl.
  • R 2c and R 2d are each independently a hydrogen atom, halogen, or substituted or unsubstituted alkyl.
  • R 2c and R 2d are each independently a hydrogen atom or halogen, of formula (I), formula (II), formula (III), and (a) to (f) above
  • (G-3) A compound represented by the formula (I), the formula (II), the formula (III), or any one of the above (a) to (f), wherein R 2c and R 2d are hydrogen atoms, or a compound thereof Pharmaceutically acceptable salt.
  • (H) The compound described in the following (h-1) or (h-2) or a pharmaceutically acceptable salt thereof.
  • H-1 A compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (g), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof Salt.
  • H-2) A compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (g), wherein m is 0, or a pharmaceutically acceptable salt thereof salt.
  • R 5 is a hydrogen atom, halogen, 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 alkylamino, substituted or unsubstituted alkenylamino, substituted or unsubstituted alkynylamino, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl Substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylsulfanyl, substituted or non-substituted Substituted alkylcarbamoyl, substituted or unsubstituted alkylcarbonylamino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Or a compound represented by formula (I), formula (II), formula (III), and any of the above (a) to (h), which is a substituted or unsubstituted non-aromatic heterocyclic group, or Its pharmaceutically acceptable salt.
  • (I-5) Formula (I), Formula (II), Formula (III), and (a) to (h) above, wherein R 5 is a hydrogen atom, halogen, cyano, or substituted or unsubstituted alkyl. Or a pharmaceutically acceptable salt thereof.
  • R 5 is a hydrogen atom; halogen; cyano; unsubstituted alkyl; alkyl substituted with one or more groups selected from halogen, hydroxy, cyano, alkyloxy, and haloalkyloxy
  • R 5 is a hydrogen atom; halogen; cyano; unsubstituted alkyl; alkyl substituted with one or more groups selected from halogen, hydroxy, cyano, alkyloxy, and haloalkyloxy
  • (J) The compound according to any one of the following (j-1) to (j-7) or a pharmaceutically acceptable salt thereof.
  • (J-1) The compound represented by formula (I), formula (II), formula (III), and any of the above (a) to (i), wherein R 1 is substituted phenyl, or a compound thereof Pharmaceutically acceptable salt.
  • (J-2) Formula (I), wherein R 1 is phenyl substituted with one or more halogens and further optionally substituted with one or more groups selected from halogen, alkyl, and haloalkyl A compound represented by (II), formula (III), and any one of the above (a) to (i) or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl substituted with one or more halogens, represented by formula (I), formula (II), formula (III), and any of (a)-(i) above Or a pharmaceutically acceptable salt thereof.
  • J-4) any one of formula (I), formula (II), formula (III), and (a) to (i) above, wherein R 1 is phenyl substituted with 2 to 3 halogens Or a pharmaceutically acceptable salt thereof.
  • R 1 is (Wherein R 1a , R 1b and R 1c are each independently halogen), the groups represented by formula (I), formula (II), formula (III), and the above (a) A compound represented by any one of (i) or a pharmaceutically acceptable salt thereof.
  • (K) The compound according to any one of the following (k-1) to (k-5) or a pharmaceutically acceptable salt thereof.
  • (K-1) R 3 is A compound represented by formula (I), formula (II), formula (III), and any of the above (a) to (j), or a pharmaceutically acceptable salt thereof.
  • (K-2) Formula (I), Formula (II), Formula (III), (a) to (j) above, and (k ⁇ ), wherein Ring C is cyclopentane or a 5-membered aromatic heterocycle The compound shown in any one of 1) or its pharmaceutically acceptable salt.
  • (L) The compound according to any one of the following (l-1) to (1-10) or a pharmaceutically acceptable salt thereof.
  • (L-1) R 3 is Wherein R 9a , R 10a and p1 have the same meaning as in the above (1); ring B ′ has the same meaning as in the above (2), A compound represented by formula (II), formula (III), and any of the above (a) to (j), or a pharmaceutically acceptable salt thereof.
  • R 10a and R 10b are each independently halogen, hydroxy, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitute
  • R 10a and R 10b are each independently halogen, hydroxy, carbamoyl, sulfamoyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfanyl, Substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted
  • R 10a and R 10b are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyl Sulfonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted nonaromatic heterocyclic group, substituted or unsubstituted Aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy, formula (I), formula (II), formula (III), (a) to (k) and (l-1) above Or a pharmaceutically acceptable salt thereof.
  • R 10a and R 10b each independently represent halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfur Moyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic heterocyclic oxy
  • R 10a and R 10b are each independently substituted with one or more groups selected from halogen; cyano; unsubstituted alkyl; halogen, hydroxy, cyano, alkyloxy, and haloalkyloxy Alkyl; unsubstituted alkyloxy; or alkyloxy substituted with one or more groups selected from halogen, hydroxy, cyano, alkyloxy, and haloalkyloxy, of formula (I), formula (II), formula ( III), a compound represented by any one of (a) to (k) and (l-1) above, or a pharmaceutically acceptable salt thereof.
  • R 10a and R 10b are each independently halogen; cyano; unsubstituted alkyl; alkyl substituted with one or more groups selected from halogen and hydroxy; unsubstituted alkyloxy; or Of formula (I), formula (II), formula (III), (a) to (k) and (l-1) above, which is alkyloxy substituted with one or more groups selected from halogen and hydroxy
  • R 10a and R 10b are each independently halogen; alkyl; haloalkyl; alkyloxy; or haloalkyloxy, the compounds of formula (I), formula (II), formula (III), ) To (k) and (l-1), or a pharmaceutically acceptable salt thereof.
  • (1-10) Formula (I), Formula (II), Formula (III), (a) to (k) above, wherein R 10a and R 10b are each independently halogen; alkyl; or alkyloxy And a compound represented by any one of (l-1), or a pharmaceutically acceptable salt thereof.
  • R 10a and R 10b each independently represent halogen; alkyl; alkyloxy; non-aromatic heterocyclic group; non-aromatic heterocyclic group substituted with alkyl; alkyloxyalkyl; haloalkyl Hydroxyalkyl; alkylsulfonyl; alkylsulfinyl or alkylsulfoxyimino; any one of formulas (I), (II), (III), (a)-(k) and (l-1) above Or a pharmaceutically acceptable salt thereof.
  • (M) The compound according to any one of the following (m-1) to (m-4) or a pharmaceutically acceptable salt thereof.
  • (M-1) A compound represented by formula (I), formula (II), formula (III), and any one of the above (a) to (l), wherein p1 is 1 or 2, or a pharmaceutically acceptable salt thereof Salt.
  • (M-2) The compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (l) or a pharmaceutically acceptable salt thereof, wherein p1 is 2. .
  • (M-3) The compound represented by the formula (I), the formula (II), the formula (III), and any one of the above (a) to (l), or a pharmaceutically acceptable salt thereof, wherein p1 is 1.
  • (M-4) any one of formula (I), formula (II), formula (III), and (a) to (l) and (m-1) to (m-3) above, wherein p2 is 1 Or a pharmaceutically acceptable salt thereof
  • R 3 is (Wherein R 9a has the same meaning as (1) above; ring B ′ and R 10ac have the same meaning as (2) above; R 10ad is halogen, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbony
  • R 3 is Or a pharmaceutically acceptable salt thereof, which is a group represented by the formula (n-1): (N-3) R 10ad is halogen, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenyl Carbonyl, substituted or unsubstituted alkynylcarbonyl, substitute
  • R 10ad is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Or a compound or a pharmaceutically acceptable salt thereof according to the above (n-1) or (n-2), which is substituted or unsubstituted alkynyloxy.
  • R 10ad is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or The compound of the above (n-1) or (n-2), which is substituted or unsubstituted alkynyloxy, or a pharmaceutically acceptable salt thereof.
  • N-6 The compound described in (n-1) or (n-2) above, wherein R 10ad is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharmaceutical thereof Top acceptable salt.
  • N--7 The compound described in (n-1) or (n-2) above, wherein R 10ad is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof Salt.
  • R 10ad is halogen; cyano; unsubstituted alkyl; alkyl substituted with one or more groups selected from halogen and hydroxy; unsubstituted alkyloxy; or 1 selected from halogen and hydroxy
  • R 10ad is halogen; unsubstituted alkyl; alkyl substituted with one or more groups selected from halogen and hydroxy; unsubstituted alkyloxy; or one or more selected from halogen and hydroxy
  • (N-10) The compound of the above (n-1) or (n-2), or a pharmaceutically acceptable salt thereof, wherein R 10ad is halogen; alkyl; haloalkyl; alkyloxy; or haloalkyloxy.
  • R 3 is (Wherein, R 9a is as defined the above (1), R 10aa, R 10ab , and R 10ac, the above (2) and is as defined) is a group represented by the formula (I), A compound represented by formula (III) and any one of the above (a) to (j), or a pharmaceutically acceptable salt thereof.
  • R 3 is (Wherein, R 9a is as defined the above (1), R 10aa, R 10ab , and R 10ac, the above (2) and is as defined) is a group represented by the formula (I), The compound according to formula (II), formula (III), and any of the above (a) to (j), or a pharmaceutically acceptable salt thereof.
  • R 10aa is halogen, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenyl Carbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted
  • R 10aa is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or A compound of the formula (II), the above (o-1) or (o-2), which is substituted or unsubstituted alkynyloxy, or a pharmaceutically acceptable salt thereof.
  • R 10aa and R 10ab are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, o-1) or the compound described in (o-2), or a pharmaceutically acceptable salt thereof.
  • R 10aa is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, Or a pharmaceutically acceptable salt thereof.
  • R 10ab is halogen, carbamoyl, sulfamoyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted Alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl Sulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxy
  • R 10ab is halogen; alkyl; haloalkyl, the compound of formula (II) and any of the above (o-1) to (o-10), or a pharmaceutically acceptable salt thereof salt.
  • R 10ab is halogen.
  • R 10ac is halogen, hydroxy, carboxy, carbamoyl, sulfamoyl, 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 alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or Unsubstituted alkenylcarbonyl, substituted or unsubstituted, substituted or unsubstituted
  • R 10ac is halogen, hydroxy, carboxy, carbamoyl, sulfamoyl, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenyl Carbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfon
  • R 10ac is halogen, hydroxy, carbamoyl, sulfamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkylsulfonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubsti
  • R 10ac is halogen, carbamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic oxy, or a substituted or unsubstituted non-aromatic heterocyclic oxy, (P-5) R 10ac is halogen, carbamoyl, cyano, substituted alkyl, substituted alkyloxy, substituted or unsubstituted alkylcarbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic group, The compound according to formula (II) and any one of the above (n) to (o), or a pharmaceutically acceptable salt thereof.
  • R 10ac is halogen; carbamoyl; cyano; alkyl substituted with one or more hydroxy or alkyloxy and further optionally substituted with halogen; substituted with one or more hydroxy or alkyloxy, and further halogen A substituted or unsubstituted alkylcarbamoyl; a non-aromatic carbocyclic group substituted with one or more hydroxy or alkyloxy and further substituted with halogen; substituted or unsubstituted A substituted or unsubstituted non-aromatic heterocyclic group; a non-aromatic carbocyclic oxy optionally substituted with one or more hydroxy or alkyloxy and further substituted with halogen; Unsubstituted aromatic heterocyclic oxy; or substituted or unsubstituted non-aromatic compounds A ring-oxy, Formula (II), and the compound or a pharmaceutically acceptable salt thereof, as claimed in any one of the above (n) ⁇ (
  • R 10ac is halogen; carbamoyl; cyano; alkyl substituted with one or more hydroxy or alkyloxy and further optionally substituted with halogen; substituted with one or more hydroxy or alkyloxy, and further halogen Substituted or unsubstituted alkylcarbamoyl; substituted or unsubstituted aromatic heterocyclic group; substituted or unsubstituted nonaromatic heterocyclic group; substituted or unsubstituted aromatic A compound represented by the formula (II) and any one of the above (n) to (o), or a pharmaceutically acceptable salt thereof, which is a heterocyclic oxy; or a substituted or unsubstituted non-aromatic heterocyclic oxy.
  • R 10ac is halogen; carbamoyl; cyano; alkyl substituted with one or more hydroxy or alkyloxy and further optionally substituted with halogen; or substituted with one or more hydroxy or alkyloxy;
  • R 10ac is halogen; carbamoyl; cyano; alkyl substituted with one or more groups selected from hydroxy; alkyloxy substituted with one or more groups selected from hydroxy; or alkylcarbamoyl; or A compound according to formula (II) and any one of the above (n) to (o), which is a non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
  • R 9a and R 9b are substituted or unsubstituted alkyl, represented by formula (I), formula (II), formula (III), and any of the above (a) to (p) Or a pharmaceutically acceptable salt thereof.
  • Q-2) Shown in formula (I), formula (II), formula (III), and any of the above (a) to (p), wherein R 9a and R 9b are halogen, alkyl, or haloalkyl Or a pharmaceutically acceptable salt thereof.
  • R 1a includes halogen.
  • A-1 R 1a includes a fluorine atom.
  • examples of R 1b include a hydrogen atom or a halogen.
  • Examples of ⁇ A— include ⁇ C (—fluorine atom) —.
  • R 1c includes halogen.
  • C-1 R 1c includes a fluorine atom.
  • C-2) R 5 includes a hydrogen atom or unsubstituted C1-C3 alkyl.
  • D-1 R 5 includes a hydrogen atom or unsubstituted methyl.
  • D-2 R 5 includes a hydrogen atom.
  • D-3 R 5 includes unsubstituted methyl.
  • D-4 includes unsubstituted C1-C3 alkyl or halogen.
  • R 9a includes unsubstituted methyl.
  • R 9a includes halogen.
  • R 10ab include a hydrogen atom, halogen, or substituted or unsubstituted alkyl (the substituent is hydroxy, halogen, or cyano).
  • F-1 R 10ab includes a hydrogen atom, halogen, or unsubstituted methyl.
  • F-2 includes a hydrogen atom, halogen, or unsubstituted methyl.
  • F-3 R 10ab includes halogen.
  • R 10ac includes substituted or unsubstituted alkyl (the substituent is hydroxy, halogen, cyano, alkyloxy, alkyloxycarbonyl or alkylcarbonyl).
  • R 10ac includes substituted or unsubstituted alkyloxy (substituents are halogen, hydroxy, cyano, alkylsulfonyl, alkylsulfanyl).
  • Examples of R 10ac include substituted or unsubstituted carbamoyl (the substituent is alkyl).
  • R 10ac includes substituted or unsubstituted sulfonyl (the substituent is alkyl or haloalkyl).
  • R 10ac includes substituted or unsubstituted sulfinyl (the substituent is alkyl or haloalkyl).
  • R 10ac includes substituted or unsubstituted sulfanyl (the substituent is alkyl or haloalkyl).
  • R 10ac includes a substituted or unsubstituted non-aromatic carbocyclic group (the substituent is hydroxy).
  • R 10ac includes a substituted or unsubstituted non-aromatic heterocyclic group (the substituent is hydroxy, oxo or alkyl).
  • R 10ac includes a substituted or unsubstituted aromatic carbocyclic group (the substituent is alkyl, halogen, haloalkyl or cyano).
  • R 10ac includes a substituted or unsubstituted aromatic heterocyclic group (the substituent is alkyl, halogen, haloalkyl or cyano).
  • R 10ac includes substituted or unsubstituted benzthiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted Examples include substituted oxadiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, or substituted or unsubstituted pyridazinyl.
  • R 10ac includes substituted or unsubstituted benzthiazolyl (the substituent is alkyl, halogen or cyano), substituted or unsubstituted oxazolyl (the substituent is alkyl, halogen or cyano), substituted or unsubstituted imidazolyl (Substituents are alkyl, halogen or cyano), substituted or unsubstituted tetrazolyl (substituent is alkyl, halogen or cyano), substituted or unsubstituted triazolyl (substituent is alkyl, halogen or cyano), Substituted or unsubstituted pyridyl (substituent is alkyl, halogen or cyano), substituted or unsubstituted oxadiazolyl (substituent is alkyl, halogen or cyano), substituted
  • R 10ac includes substituted or unsubstituted benzthiazolyl (substituent is methyl or halogen), substituted or unsubstituted oxazolyl (substituent is methyl or halogen), substituted or unsubstituted imidazolyl (substituent is , Methyl or halogen), substituted or unsubstituted tetrazolyl (substituent is methyl or halogen), substituted or unsubstituted triazolyl (substituent is methyl or halogen), substituted or unsubstituted pyridyl (as substituent) Is methyl or halogen), substituted or unsubstituted oxadiazolyl (methyl or halogen as a substituent), substituted or unsubstituted isoxazolyl (methyl or halogen as a substituent), substituted or unsubstituted isoxazolyl (methyl
  • R 10ac includes substituted or unsubstituted oxazolyl (substituent is methyl or halogen), substituted or unsubstituted imidazolyl (substituent is methyl or halogen), substituted or unsubstituted tetrazolyl (substituent is , Methyl or halogen), substituted or unsubstituted triazolyl (substituent is methyl or halogen), substituted or unsubstituted oxadiazolyl (substituent is methyl or halogen), substituted or unsubstituted isoxazolyl (as substituent) Is methyl or halogen) or substituted or unsubstituted pyrazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted oxazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted imidazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted tetrazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted triazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted oxadiazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted isoxazolyl (the substituent is methyl or halogen).
  • R 10ac includes substituted or unsubstituted pyrazolyl (the substituent is methyl or halogen).
  • R 10ad includes a hydrogen atom.
  • A′- includes ⁇ C (—F or —Cl) — (hereinafter referred to as J-3).
  • the compounds of formula (I), formula (I ′), formula (II) or formula (III) are not limited to specific isomers, but all possible isomers (eg keto-enol isomerism) Isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
  • the compounds in which R 7a is a hydrogen atom in formula (I), formula (II) and formula (III) include the following tautomers.
  • the compound represented by the formula (I ′) includes the following tautomers.
  • p1 hydrogen atoms bonded to the ring-constituting atom of ring B can be replaced by R 10a or R 10c .
  • p2 hydrogen atoms bonded to the ring constituent atoms of Ring C can be replaced by R 10b or R 10d.
  • p3 hydrogen atoms bonded to the ring constituent atoms of Ring D may be replaced by R 10e.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I), formula (I ′), formula (II) or formula (III) are hydrogen, carbon and / or other atoms, respectively.
  • isotope examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I), the formula (I ′), the formula (II) or the formula (III) 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), the formula (I ′), the formula (II) or the formula (III). .
  • 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.
  • Radiolabeled compounds of the compounds represented by formula (I), formula (I ′), formula (II) or formula (III) can be prepared by methods well known in the art.
  • a tritium-labeled compound represented by the formula (I), the formula (I ′), the formula (II) or the formula (III) can be converted into the formula (I), the formula (I) by catalytic dehalogenation using tritium.
  • ') can be prepared by introducing tritium into a specific compound represented by formula (II) or formula (III).
  • This method comprises a compound of formula (I), formula (I ′), formula (II) or formula (III) in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by formula (I), formula (I ′), formula (II) or formula (III) include, for example, formula (I), formula (I ′), formula (II) ) Or a compound represented by formula (III) and an alkali metal (eg, lithium, sodium, potassium, etc.), an alkaline earth metal (eg, calcium, barium, etc.), magnesium, a transition metal (eg, zinc, iron, etc.) , Ammonia, organic bases (eg trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, 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,
  • the compound represented by the formula (I), formula (I ′), formula (II) or formula (III) of the present invention or a pharmaceutically acceptable salt thereof is a solvate (for example, hydrate etc.) and / or Alternatively, crystal polymorphs may be formed, and the present invention also includes such various solvates and crystal polymorphs.
  • the “solvate” is coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I), the formula (I ′), the formula (II) or the formula (III). You may do it.
  • a crystal polymorph may be formed by recrystallizing a compound represented by formula (I), formula (I ′), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof.
  • 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 enzymatically oxidized, reduced, hydrolyzed, etc.
  • a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate compound
  • acyloxy derivatives and sulfonyloxy derivatives produced by reacting acyl halides, suitable acid anhydrides, suitable sulfonyl chlorides, suitable sulfonyl anhydrides and mixed anhydrides, or by reacting with a condensing agent.
  • Prodrugs are exemplified.
  • the compound according to the present invention has a P2X 7 receptor antagonistic action, it is useful as a therapeutic and / or prophylactic agent for diseases involving the P2X 7 receptor.
  • Diseases P2X 7 receptor is involved, pain, central diseases, such as immune and inflammatory diseases and the like, preferably pain (Non-Patent Documents 7-8 and Patent Document 1, etc.).
  • the effect of opioid drugs on analgesic resistance can be expected.
  • the pain preferably herpes zoster pain, postherpetic neuralgia, trigeminal neuralgia, thalamic pain, cancer pain, postoperative pain, sciatica, afferent blockage pain, etc .; Strangulated neuropathy, carpal tunnel syndrome, diabetes, Guillain-Barre syndrome, myofascial pain syndrome, fibromyalgia syndrome, complex local pain syndrome, causalgia, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, intervertebral disc herniation , Arthritis, rheumatoid arthritis, osteoarthritis, cervical spondylosis, spinal stenosis, brachial plexus withdrawal syndrome, shoulder syndrome, cystitis (including acute and interstitial), ulcerative colitis, Crohn's disease Pain associated with diseases such as irritable bowel syndrome, gout, depression; Pain associated with drug therapy and pain associated with radiation
  • Central diseases include Alzheimer's dementia (Alzheimer's disease, Alzheimer's senile dementia, etc.), cerebral amyloid angiopathy, Parkinson's disease, Creutzfeldt-Jakob disease, Huntington's chorea, depression, schizophrenia, attention deficit Examples include dyskinetic disorder, sleep disorder, autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Alzheimer's dementia Alzheimer's senile dementia, etc.
  • cerebral amyloid angiopathy Alzheimer's dementia
  • Parkinson's disease Creutzfeldt-Jakob disease
  • Huntington's chorea depression
  • schizophrenia attention deficit
  • Examples include dyskinetic disorder, sleep disorder, autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Alzheimer type dementia Alzheimer type senile dementia etc.
  • cerebral amyloid angiopathy Parkinson's disease
  • Parkinson's disease depression
  • schizophrenia attention deficit hyperactivity disorder
  • sleep disorder Examples include autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Immune / inflammatory diseases include rheumatoid arthritis, osteoarthritis, osteoarthritis, asthma, bronchitis, chronic obstructive pulmonary disease, emphysema, septic shock, hepatitis (including non-alcoholic steatohepatitis), liver fibrosis, Cirrhosis, cholecystitis, glomerulonephritis, nephrotic syndrome, pancreatitis (including acute and chronic), cystitis (including acute and interstitial), urethritis (including acute and chronic), prostatitis, ulcerative colitis , Crohn's disease, irritable bowel syndrome, psoriasis, atopic dermatitis, contact dermatitis, eczema skin disease, delayed hypersensitivity reaction, conjunctivitis, uveitis, malignant cells (prostate cancer, breast cancer, lung cancer, uterine cancer, Pancreatic cancer, colon cancer, etc.) proliferation and met
  • cardiovascular diseases such as atherosclerosis, ischemic heart disease and diabetes
  • bone diseases such as osteoporosis, bone Paget's disease, osteonecrosis, and temporomandibular disorders.
  • Active bladder stress urinary incontinence, prostatic hypertrophy and the like.
  • an immune / inflammatory disease preferably rheumatoid arthritis, osteoarthritis, osteoarthritis, asthma, bronchitis, chronic obstructive pulmonary disease, cystitis (including acute and interstitial), ulcerative colitis, clone Diseases and the like.
  • the compound represented by the formula (I), the formula (I ′), the formula (II) or the formula (III) according to the present invention can be produced, for example, by a general synthesis method shown below. All of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
  • DIBAL diisobutylaluminum hydride
  • DIEA N, N-diisopropylethylamine
  • DMA N, N-dimethylacetamide
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EDC ⁇ HCl 1-ethyl-3- (3-dimethylaminopropyl )
  • NMP N-methylpyrrolidone
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • HOAt 1-hydroxy-7-aza Benzotriazole
  • HOBt 1-hydroxybenzotriazole
  • TMS trimethylsilyl
  • Examples of the base include metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.) and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used relative to compound (A-1).
  • Examples of the reaction solvent include ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, water, and mixed solvents thereof.
  • the reaction temperature is 0 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 16 hours.
  • the obtained desired compound (A-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (A-4) can be obtained by reacting compound (A-2) and compound (A-3) in the presence of a base in an appropriate solvent. In this reaction, compound (A-3) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-2).
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. .
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-2).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, water and the like, and can be used alone or in combination.
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (A-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (I ⁇ ) can be obtained by reacting compound (A-4) and compound (A-5), if necessary, in the presence of a palladium catalyst and a base or acid, in the absence of a solvent or in a suitable solvent. In this reaction, compound (A-5) can be used at 1.0 molar equivalent or more, preferably 1.0-5.0 molar equivalents, relative to compound (A-4).
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. .
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • Examples of the acid include acetic acid and propionic acid.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • Palladium catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, PdCl 2 (dppf) CH 2 Cl 2 and the like.
  • the base can be used at 0.001 to 0.5 molar equivalent relative to compound (A-4).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, water, etc., used alone or in combination. be able to.
  • alcohols eg, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane,
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Method B By synthesizing Method B using different starting materials, the compounds represented by Formula (II) and Formula (III) can be similarly synthesized.
  • Method B (In the formula, PG 1 is a suitable protecting group for a hydroxyl group; G 1 , G 2 and G 3 have the same meanings as the method A; the other symbols have the same meanings as in the above (1).)
  • Process 1 Compound (B-2) can be obtained by reacting compound (A-1) with compound (B-1) in a suitable solvent in the presence of a base. In this reaction, compound (B-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-1).
  • Examples of the base include metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxy). And potassium tert-butoxide), metal alkyl (eg, butyllithium, etc.) and the like.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal carbonates eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • metal alkoxides eg, sodium methoxide, sodium ethoxy
  • potassium tert-butoxide metal alkyl (eg, butyllithium, etc.) and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 1.5 molar equivalent can be used with respect to compound (A-1).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, and mixed solvents thereof.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is 0.1 to 80 hours, preferably 1 to 16 hours.
  • the obtained desired compound (B-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 The compound (B-3) can be obtained by reacting the compound (B-2) and the compound (A-5) according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (B-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (B-4) can be obtained by deprotecting compound (B-3) in an appropriate solvent in the presence of an acid, a Lewis acid or a base.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, hydrobromic acid-acetic acid, hydrobromic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like.
  • Examples of the base include tetrabutylammonium fluoride and hydrogen fluoride-pyridine.
  • the compound (B-3) can be used at 0.01 molar equivalent or more, preferably 0.5 to 10.0 molar equivalent.
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, DMA, pyridine, water, etc. may be mentioned alone or in combination. Can be used.
  • alcohols eg, methanol, ethanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane,
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (B-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ ) can be obtained by reacting compound (B-4) and compound (A-3) according to the synthesis method described in Method A, Step 2.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Method C By synthesizing Method C using different starting materials, the compounds represented by Formula (II) and Formula (III) can be similarly synthesized.
  • R 5A is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; Is the same meaning.
  • Process 1 The compound (IC-2) can be obtained by hydrolysis using the compound (IC-1) obtained by the method A in the presence of an acid or a base. Examples of the acid include hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, tetrabutylammonium Fluoride etc. are mentioned. 1 molar equivalent or more, preferably 5 molar equivalents can be used with respect to compound (IC-1).
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile, DMA, water and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (IC-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (IC-3) can be obtained by condensing compound (IC-2) and ammonium chloride in a suitable solvent.
  • the condensing agent include 1-hydroxybenzotriazole, HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium, etc.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (IC-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (IC-4) can be obtained by reacting compound (IC-3) with a dehydrating agent in a suitable solvent or without solvent in the presence of a base.
  • the dehydrating agent include thionyl chloride, trifluoroacetic anhydride, diphosphorus pentoxide and the like, and 1 mole equivalent or more, preferably 1.0 to 5.0 mole equivalent based on the compound (IC-3). can do.
  • reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, NMP, acetonitrile, DMA and the like, which can be used alone or in combination.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.
  • Halogenated hydrocarbons e
  • the reaction temperature is ⁇ 10 to 150 ° C., preferably 0 to 100 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (IC-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Compound (ID-1) can be obtained by reacting compound (IC-1) obtained by Method A with a reducing agent in a suitable solvent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, DIBAL and the like, and 1.0 molar equivalent or more with respect to compound (IC-1), preferably 1.0 Up to 10.0 molar equivalents can be used.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, Dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, NMP, acetonitrile, water and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is -78 to 150 ° C, preferably 0 to 100 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.
  • the obtained desired compound (ID-1) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Compound (IE-1) can be obtained by reacting compound (ID-1) obtained by Method D with a fluorinating agent in a suitable solvent.
  • the fluorinating agent include N, N-diethylaminosulfur trifluoride, N, N-bis (2-methoxyethyl) aminosulfur trifluoride, and the like. Molar equivalents or more, preferably 1.0 to 10.0 molar equivalents can be used.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) ) And the like, and can be used alone or in combination.
  • the reaction temperature is ⁇ 0 to 80 ° C., preferably 0 to 60 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 1 to 12 hours.
  • CF2H The obtained desired compound (IE-1) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 1 Compound (F-3) can be obtained by reacting compound (F-1) with compound (F-2) in a suitable solvent in the presence of an acid. In this reaction, compound (F-2) can be used at 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (F-1).
  • the acid include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.
  • 0.05 molar equivalent or more, preferably 0.1 to 2.0 molar equivalent can be used with respect to compound (F-1).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 20 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 12 hours.
  • the obtained desired compound (F-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (F-4) can be obtained by reacting compound (F-3) with trimethylsilyl isothiocyanate in an appropriate solvent or without solvent.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 12 hours.
  • the obtained desired compound (F-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (F-5) can be obtained by reacting compound (F-4) with methyl iodide in the presence of a base in an appropriate solvent.
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. .
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used relative to compound (F-4).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 8 hours.
  • the obtained desired compound (F-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (II ⁇ ) can be obtained by reacting compound (F-5) and compound (A-5) according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (II ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • G 3 is as defined in the method A; R G is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group And other symbols have the same meanings as in (1) above.
  • Process 1 Compound (G-2) can be obtained by reacting compound (G-1) with S-methylisothiosemicarbazide iodate in the presence of an acid without solvent or in a suitable solvent. Examples of the acid include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • alcohols eg, methanol, ethanol, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane, etc.
  • Ethers eg,
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 16 hours.
  • the obtained desired compound (G-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 The compound (G-3) can be obtained by reacting the compound (G-2) and the compound (A-5) according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (G-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (I ⁇ ) can be obtained by reacting compound (G-3) and compound (A-3) according to the synthesis method described in Method A, Step 2.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • G 1 is a leaving group such as halogen, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl;
  • X is bromine or iodine;
  • R A and R B are each independently a hydrogen atom, substituted or unsubstituted alkyl, or taken together to form a substituted or unsubstituted non-aromatic heterocycle;
  • ring E is a 6-membered aromatic carbon A ring or a 6-membered aromatic heterocycle;
  • ring F is a 5-membered aromatic heterocycle;
  • R xx is fluorine, chlorine, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl (It is oxy, and other symbols have the same meaning as in the above (1).)
  • Process 1 Compound (H-2)
  • compound (H-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-4).
  • the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc.
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal carbonates eg, Sodium carbonate, potassium
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • the acid include acetic acid and propionic acid.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile and the like can be mentioned, and these can be used alone or in combination.
  • alcohols eg, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexan
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 3 to 18 hours.
  • the obtained desired compound (H-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (H-4) can be obtained by reacting compound (H-2) with boronic acid or boronic ester (H-3) in a suitable solvent in the presence of a metal catalyst and a base. In this reaction, boronic acid or boronic acid ester (H-3) is used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (H-2).
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, PdCl 2 (dppf) CH 2 Cl 2 and the like.
  • the base can be used at 0.001 to 1.0 molar equivalent relative to compound (H-2).
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, phosphoric acid
  • Examples include potassium and potassium hydrogen phosphate.
  • the base can be used at 1.0 to 10.0 molar equivalents relative to compound (H-2).
  • Examples of the reaction solvent include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane).
  • the reaction temperature is 20 to 250 ° C., optionally under microwave irradiation, preferably 0 to 200 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.1 to 12 hours.
  • the obtained desired compound (H-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • G 1 is a leaving group such as halogen, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl; R A is substituted or unsubstituted alkyl R yy is substituted or unsubstituted alkyl; other symbols are as defined in the above (1).
  • Process 1 Compound (J-2) can be obtained by reacting compound (A-4) obtained by Method A with compound (J-1) in the presence of a base or acid in the absence of a solvent or in a suitable solvent. it can.
  • compound (J-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-4).
  • the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. .
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal carbonates eg, Sodium carbonate
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • the acid include acetic acid and propionic acid.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-4).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile and the like can be mentioned, and these can be used alone or in combination.
  • alcohols eg, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexan
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 3 to 18 hours.
  • the obtained desired compound (J-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 The compound (J-3) can be obtained by hydrolyzing (J-2) in the presence of an acid or a base. Examples of the acid include hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, tetrabutylammonium Fluoride etc. are mentioned. 1 molar equivalent or more, preferably 5 molar equivalents can be used with respect to compound (J-2).
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile, DMA, water and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (J-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (J-4) can be obtained by condensing compound (J-3) and tert-butyl carbamate in an appropriate solvent.
  • the condensing agent include 1-hydroxybenzotriazole, HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium, etc.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (J-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (J-5) can be obtained by deprotecting compound (J-4) with an acid in a suitable solvent. Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid and the like. 1 molar equivalent or more, preferably 1 to 5 molar equivalents can be used with respect to compound (J-4).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 20 to 100 ° C., preferably 20 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 8 hours.
  • the obtained desired compound (J-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 5 Compound (J-7) can be obtained by reacting compound (J-5) and compound (J-6) in the presence of an acid without solvent or in a suitable solvent.
  • Compound (J-6) can be used at 1.0 mol equivalent or more, preferably 3.0 to 5.0 mol equivalent, relative to compound (J-5).
  • Examples of the acid include hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • the compound (J-5) can be used in an amount of 0.1 molar equivalent or more, preferably 0.2 to molar equivalent.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 20 to 150 ° C., preferably 40 to 100 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 12 hours.
  • the obtained desired compound (J-7) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • [K method] In the formula, R ZZ is substituted or unsubstituted alkyl; other symbols are as defined in the above (1).
  • Process 1 Compound (K-1) can be obtained by condensing compound (J-3) obtained by Method J and ammonium chloride in an appropriate solvent. In this reaction, ammonium chloride can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to compound (J-3).
  • condensing agent examples include WSCD HCl, Condensing agents such as 1-hydroxybenzotriazole, HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium, and triethylamine, diisopropylethylamine And the like. 1 molar equivalent or more, preferably 1 to 5 molar equivalents can be used relative to compound (J-3).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is ⁇ 10 to 200 ° C., preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (K-1) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (K-2) can be obtained by reacting compound (K-1) with a dehydrating agent in a suitable solvent or without solvent in the presence of a base according to the synthesis method described in Method C, Step 3. .
  • the obtained desired compound (K-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (K-3) can be obtained by reacting compound (K-2) with hydroxyamine hydrochloride in the presence of a base in an appropriate solvent.
  • hydroxyamine hydrochloride can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent based on compound (K-2).
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, phosphoric acid
  • Examples include potassium and potassium hydrogen phosphate. 1.0 to 10.0 molar equivalents can be used with respect to compound (K-2).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 40 to 150 ° C, preferably 40 to 100 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 8 hours.
  • the obtained desired compound (K-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (K-5) can be obtained by reacting compound (K-3) and compound (K-4) in the presence of an acid without solvent or in a suitable solvent. In this reaction, compound (K-4) can be used at 1.0 molar equivalent or more, preferably 3.0 to 5.0 molar equivalents, relative to compound (K-3).
  • the acid include hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • the compound (K-3) can be used at 0.1 molar equivalent or more, preferably 0.2 to molar equivalent.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 20 to 150 ° C., preferably 40 to 100 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 12 hours.
  • the obtained desired compound (K-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • G 1 is a leaving group such as halogen, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl;
  • X is bromine or iodine; The symbol of is the same as (1) above.
  • Process 1 Compound (L-2) can be obtained by reacting compound (A-4) obtained by Method A with butter compound (L-1) in butyric acid.
  • compound (L-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-4).
  • the reaction temperature is 40 to 200 ° C., optionally under microwave irradiation, preferably 40 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 3 to 18 hours.
  • the obtained desired compound (L-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (L-3) can be obtained by reacting (L-2) in trifluoroacetic acid.
  • the reaction temperature is 20 to 100 ° C., preferably 40 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 8 hours.
  • the obtained desired compound (L-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (L-5) can be obtained by reacting compound (L-3) with compound (L-4) in a suitable solvent in the presence of a metal catalyst and a base. In this reaction, compound (L-4) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (L-3).
  • Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, PdCl 2 (dppf) CH 2 Cl 2 and the like.
  • the compound can be used at 0.001 to 0.5 molar equivalent relative to compound (L-3).
  • a phosphorus ligand capable of coordinating with a palladium atom which is a central element of the palladium catalyst can be used together with the catalyst.
  • Examples of the phosphorus ligand include triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine, tris (2,6-dimethoxyphenyl) phosphine, tris [2- (Diphenylphosphino) ethyl] phosphine, bis (2-methoxyphenyl) phenylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2- (diphenylphosphino) -2 '-(N, N-dimethylamino) biphenyl, tri-tert-butylphosphine, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane, 1,2-bis (dimethylphosphino) e
  • the amount of the phosphorus ligand used can be 0.5 to 2.5 molar equivalents, preferably 1.0 to 1.5 molar equivalents, relative to the palladium compound.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, phosphoric acid Examples include potassium and potassium hydrogen phosphate.
  • the base can be used at 1.0 to 10.0 molar equivalents relative to compound (L-3).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, DMA, NMP, DMSO, water and a mixed solvent thereof.
  • the reaction temperature is 20 to 250 ° C., optionally under microwave irradiation, preferably 0 to 200 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
  • the obtained desired compound (L-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Acetonitrile and the like, and can be used alone or in combination.
  • the reaction temperature is ⁇ 10 to 110 ° C., preferably 0 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ′) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • the compounds represented by the formulas (II) and (III) can be synthesized in the same manner.
  • [ ⁇ method] In the formula, Y 1A is C ⁇ N (R Y ), and the other symbols have the same meanings as in (1).
  • Compound (I ⁇ ′′) can be obtained by reacting compound (I ⁇ ′) with compound ( ⁇ -1) in the presence of an acid or base in an appropriate solvent.
  • compound ( ⁇ -1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to compound (I ⁇ ′).
  • the acid include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.
  • 0.05 mol equivalent or more, preferably 0.1 to 2.0 mol equivalent, can be used with respect to compound (I ⁇ ′).
  • the base include pyridine, triethylamine, DIEA and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 20.0 molar equivalent can be used with respect to compound (I ⁇ ′).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 0 to 150 ° C., preferably 0 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ′′) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • optically active form of the compound represented by the formula (I), formula (I ′), formula (II) or formula (III) is optically active by carrying out asymmetric synthesis at an appropriate stage using optically active starting materials.
  • An intermediate can be obtained, or it can be produced by optical resolution of an intermediate or final product that is a racemate at an appropriate stage.
  • Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
  • Preferred compounds of the present invention not only P2X 7 receptor antagonism, has a utility as a pharmaceutical, it has the following one, or all of the outstanding features.
  • 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.
  • h) high P2X 7 receptor selectivity for example, a selectivity, etc.
  • to other receptors P2X family has the following one, or all of the outstanding features.
  • parenteral administration When administering the pharmaceutical composition of the present invention, it 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.
  • Oral administration is in accordance with conventional methods, such as solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, syrups, It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
  • the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • Parenteral administration includes injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, ointments Any of the commonly used dosage forms such as plasters, jelly preparations, cream preparations, patches, poultices, external powders, suppositories, etc. can be suitably administered.
  • the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type and the like.
  • 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 dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of illness, administration route, etc. However, when administered orally, usually 0.05 to 300 mg / man / day, preferably in the range of 0.1-100 mg / man / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / man / day, preferably 0.01 to 1 mg / man / day. This may be administered once to several times a day.
  • reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed with 0.1 mol / L hydrochloric acid aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the crude product of compound 3 (698.6 mg) was obtained as a pale yellow foam Obtained as a substance.
  • reaction solution was poured into ice water and extracted with ethyl acetate.
  • organic layer was washed with 5% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain Compound I-0024 (79 mg, yield 17%).
  • Process 2 A solution of the crude product of Compound 20 (2.32 g) and Compound 21 (1.70 g, 9.99 mmol) in acetic acid (17 mL) was stirred at 90 ° C. for 1 hour. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a crude product of compound 22 (435 mg).
  • Process 3 Compound 22 (100 mg, 0.51 mmol) and 4,5-dimethoxy-2-methylaniline (104 mg, 0.62 mmol) were dissolved in acetic acid (1.0 mL) and stirred at 80 ° C. for 5 hours.
  • N-dimethylformamide of compound I-0285 (0.200 g, 0.495 mmol), tert-butyl carbamate (0.078 g, 0.594 mmol) and N-hydroxybenzotriazole (0.067 g, 0.495 mmol)
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.123 g, 0.643 mmol) and stirred overnight at room temperature.
  • Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Trifluoroacetic acid (2.6 mL, 33.7 mmol) was added to a solution of compound I-0286 (0.264 g, 0.495 mmol) in dichloromethane (5.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 2 mol / L aqueous sodium carbonate solution (10 mL), and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration to give compound I-0287 (0.135 g, yield 65%) as a light ocher solid.
  • the following compounds were synthesized according to the general synthesis method and the method described in the examples.
  • the chemical structural formula and physical properties are shown below.
  • the compound described as a in the optical activity column is a mixture of R-form and S-form.
  • the compound described as “b” in the optical activity column is unknown in steric information, but is either R-form or S-form.
  • the compound described as “c” in the optical activity column indicates that the stereo is determined as shown in the chemical structure.
  • the IC50 is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.
  • the inhibition rate was calculated from the following equation based on the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity from immediately before the addition of the compound of the present invention to 20 minutes later.
  • Inhibition rate (1 ⁇ (change amount by compound of the present invention ⁇ change amount by positive control) / (change amount by negative control ⁇ change amount by positive control)) ⁇ 100
  • the inhibitory activity of the compound of the present invention was evaluated by calculating the concentration (IC 50 ) at which inhibition was 50% by the logistic approximation method.
  • the evaluation results of the human P2X 7 receptor inhibitory activity of the present compounds other than the above are shown in the table below.
  • the IC 50 value is defined as “A” when less than 10 nmol / L is “B” when 10 nmol / L or more but less than 100 nmol / L, and “C” when 100 nmol / L or more but less than 500 nmol / L.
  • Test Example 2 introducing and expressing rat P2X 7 Evaluation rat P2X 7 receptor gene of the receptor inhibitory activity (including single nucleotide polymorphisms of GenBank accession sequence NM_019256.1 However C586T and C652A) in 1321N1 cells.
  • the 1321N1 cells were stably expressing the rat P2X 7 receptor TC process 384 anachronism transparent flat bottom plate; seeded to be 10,000 per well in (Falcon Corning), medium (10% fetal calf serum, 2mM Incubate in DMEM (D6546; manufactured by SIGMA) containing GlutaMax-1 and 1% penicillin / streptomycin mixed solution at 37 ° C. under 5% carbon dioxide for 1 day.
  • DMEM D6546; manufactured by SIGMA
  • DMSO solutions of the compounds of the present invention diluted to different concentrations using a buffer for dilution are dispensed at 15 ⁇ L per well with a built-in automatic dispenser and measurement of fluorescence intensity is continued for 20 minutes.
  • the value of the maximum fluorescence intensity when the DMSO solution as the solvent of the compound of the present invention is added is 0% inhibition (negative control), and the value of the maximum fluorescence intensity when the known inhibitor is added is 100% inhibition (positive control).
  • the inhibition rate is calculated from the following equation based on the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity immediately before the addition of the compound of the present invention and after 20 minutes.
  • Inhibition rate (1 ⁇ (change amount by compound of the present invention ⁇ change amount by positive control) / (change amount by negative control ⁇ change amount by positive control)) ⁇ 100
  • the inhibitory activity of the compound of the present invention is evaluated by calculating the concentration (IC 50 ) at which inhibition is 50% by the logistic approximation method.
  • Test 3-1 Evaluation of drug efficacy by Seltzer model ⁇ Preparation of rat Partial Scientific Nerve Ligation model (sciatic nerve partial ligation model)> Rats were anesthetized with isoflurane and the left leg hair was shaved. The skin at the upper thigh was incised, and the muscle was broken to expose the sciatic nerve. About half of the sciatic nerve was strongly ligated with nylon thread, and the muscle and skin were sutured. This was the operation side. The right foot was treated in the same manner as sciatic nerve ligation, and the sham operation was performed. ⁇ Evaluation (1)> Two weeks after the operation, the effect on mechanical allodynia was evaluated by von Frey filament.
  • Pain thresholds were evaluated for the left and right hind paws and used as pre-treatment thresholds. Animals having a pain threshold of 0.6 to 2 g after surgery and a pain threshold of 8 to 15 g on the sham operation side were adopted for evaluation of drug efficacy. For animal training, the same operation was performed before the pain threshold measurement before the treatment. The compound of the present invention was administered to the adopted animals.
  • the compound of the present invention was pulverized using a mortar and pestle, and a suspension or solution was adjusted with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Animals were orally administered using an oral sonde. 1 to 5 hours after administration, the pain threshold value of the left and right hind legs was evaluated and used as the pain threshold value after the treatment. The% reversal value was calculated by the following method and compared as the analgesic effect of the compounds.
  • % Reversal value (logarithm of pain threshold value after surgical side treatment ⁇ logarithm of pain threshold value before surgical side treatment) / (logarithm of pain threshold value before surgical side treatment ⁇ logarithm of pain threshold value before surgical side treatment) ⁇ 100 (result) ⁇ Evaluation (2)>
  • Analgesiometer (Randall Selitto) evaluates the effect on mechanical hyperalgesia. Two weeks after the operation, the rat hind limb is compressed by an analgesiometer so that the stimulation pressure increases by 16 g per second, and the pressure when the rat exhibits escape behavior is set as a pain threshold. Pain thresholds are evaluated for the left and right hind limbs and set as pre-treatment pain thresholds.
  • Animals with a surgical threshold of 60-90 g and a sham surgical threshold of 100-175 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, and a suspension or solution is prepared using 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg, and an oral sonde is used.
  • Orally administered to animals. 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 3-2 Evaluation of drug efficacy using the cauda equina nerve compression model ⁇ Production of model animals>
  • 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.
  • Animals with a pain threshold of 8-15 g in the sham-operated group are adopted for drug efficacy evaluation. For animal training, the same operation is performed before measuring the pain threshold before treatment.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is pulverized using a mortar and pestle, and the suspension or solution is adjusted with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Animals are administered orally using an oral sonde. 1 to 5 hours after administration, the pain threshold value of the left and right hind legs is evaluated, and the pain threshold value after treatment is used.
  • The% reversal value is calculated by the following method and compared as the analgesic effect of the compound.
  • Test 3-3 Efficacy Evaluation by EAE Model ⁇ Production of Rat Experimental Autoimmune Encephalomyelitis Model (Experimental Autoimmune Encephalomyelitis Model)> Rats (Lewis rat females) are anesthetized with isoflurane and the back of the ridge is shaved. Immunization is carried out by preparing a 1 g / L emulsion prepared by mixing 1: 1 CFA (complete Freund's Adjuvant) and MBP (Myelin Basic Protein) saline solution, and administering 100 uL subcutaneously on the back of the rat tail. This is a treatment group.
  • 1 CFA complete Freund's Adjuvant
  • MBP Myelin Basic Protein
  • the pain threshold is evaluated for both hind paws, and the threshold value for both legs in the treatment group is 4 g or less, and the more painful value of 0.6 to 2 g is set as the threshold before drug administration.
  • Animals with a pain threshold of 6-15 g in the sham-treated group are adopted for drug efficacy evaluation.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is pulverized using a mortar and pestle, and the suspension or solution is adjusted with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Animals are administered orally using an oral sonde.
  • % Reversal value (logarithm of pain threshold value after treatment group drug administration ⁇ logarithm of pain threshold value before treatment group drug administration) / (logarithm of pain threshold value before sham treatment drug administration ⁇ pain threshold value before treatment group drug administration) Logarithm) x 100
  • the inhibitory activity against the P2X7 receptor can also be evaluated by using the evaluation method described in British Journal of Pharmacology (2013) 170 624-640.
  • Test Example 4 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin, which is a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4), The degree to which the amount of each metabolite produced is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • a fluorescent multilabel counter or LC / MS / MS
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxylated The body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
  • a control (100%) was obtained by adding DMSO, which is a solvent in which the compound was dissolved instead of the compound of the present invention, to the reaction solution, and the residual activity (%) was calculated.
  • IC 50 is calculated by inverse estimation.
  • Test Example 5-1 CYP3A4 Fluorescence MBI Test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compound of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • 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.
  • Test Example 5-2 CYP3A4 (MDZ) MBI Test Regarding the CYP3A4 inhibition of the compound of the present invention, this is a test for evaluating the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action resulting from the metabolic reaction of the compound of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • MBI mechanism based inhibition
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL at the time of reaction (at 10-fold dilution); 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 was dissolved, instead of the compound of the present invention to the reaction solution, and calculating the residual activity (%) when each concentration of the compound of the present invention was added, Using the concentration and the inhibition rate, IC is calculated by inverse estimation using a logistic model.
  • Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value, and 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”.
  • Administration method Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle. (6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS. (7) Statistical analysis: The plasma concentration-time curve area (AUC) was calculated by the non-linear least-squares method for plasma compound concentration transition, and the dose ratio and AUC ratio of the oral administration group and intravenous administration group From the above, the bioavailability (BA) of the compound of the present invention is calculated.
  • AUC plasma concentration-time curve area
  • Test Example 7 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For strain TA98, 7.70 to 8.00 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • 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, citrate Bacteria were suspended in sodium dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L, and 120 mL Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, Glucose: MicroF buffer containing 8 mg / mL). For TA100 strain, add 3.10 to 3.42 mL of bacterial solution to 120 to 130 mL of Exposure medium 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).
  • Test Example 8 hERG Test
  • hERG hERG Test
  • 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.
  • the extracellular solution in which the compound of the invention is dissolved at the target concentration is applied to the cells for 7 minutes or longer at room temperature.
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential by using analysis software (QPatch Assay software; Sophion Bioscience A / S). Further, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the medium is calculated as an inhibition rate, and the influence of the compound of the present invention on I Kr is evaluated.
  • SPE solid phase extraction
  • the composition of JP-1 solution is as follows. Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
  • the composition of JP-2 solution is as follows. 1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
  • Test Example 10 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • Test Example 11 Powder Solubility Test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water), 20 mmol / L sodium taurocholate (TCA) / JP-2 200 ⁇ L of the solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) is added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added.
  • 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 (1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of an
  • the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 12 Brain transfer test The compound of the present invention was intravenously administered to rats at a dose of 1 ⁇ mol / mL / kg or 0.5 mg / mL / kg, and 30 minutes later, the blood was exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. Let 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 13 P-gp Substrate Test
  • the compound of the present invention is added to one side of a transwell (registered trademark, CORNING), in which human MDR1-expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time.
  • the membrane permeability coefficient was calculated from the axial side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A), and the EFFlux ratio (ER; Calculate the ratio of B ⁇ A and A ⁇ B membrane permeability coefficient).
  • 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.
  • Test Example 14 mdr1a ( ⁇ / ⁇ ) B6 mouse P-gp substrate test animals used mdr1a ( ⁇ / ⁇ ) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse) Method 1. Mice have free access to chow and sterile tap water. 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). Blood and brain samples are immediately chilled on ice. 3.
  • EDTA anticoagulants
  • 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.
  • Test Example 15 Evaluation of human pregnane X receptor (PXR) activation Evaluation was performed using a Human PXR activation (manufactured by Puracyp) kit. DPX2 cells expressing human PXR were seeded at 40000 per well in a 96-well plate and cultured at 37 ° C. under 5% carbon dioxide for 24 hours (medium: 10% fetal calf serum, antibiotics, sodium pyruvate, DPX2 cell culture medium containing D-glucose and phenol red).
  • a DMSO solution of the compound of the present invention is added to a medium (10% It was diluted with fetal bovine serum, D-glucose, antibiotics, dosing medium for DPX2 cells containing sodium pyruvate and L-glutamine.
  • the medium was removed from the 96-well plate cultured for 24 hours, treated with 100 ⁇ L each of the prepared compound solution of the present invention and rifampicin solution, and cultured for 48 hours. After culturing for 48 hours, the medium was removed from the 96-well plate, and 100 ⁇ L each of a reaction solution obtained by adding 5.25 ⁇ L CellTiter-Fluor to 10.5 mL TubeE was filled.
  • the plate was placed on a plate reader (Perkin Elmer), and the fluorescence intensity was measured at intervals of 0.1 seconds per hole. The plate was taken out, and 100 ⁇ L of a solution obtained by adding ONE-Glo Assay Substrate to ONE-Glo Assay Buffer was added to each well. Two minutes after adding the solution, the plate was placed on a plate reader, and the luminescence intensity was measured at intervals of 2 seconds per hole.
  • the PXR activity of the product of the present invention was a value obtained by dividing the emission intensity by the fluorescence intensity. (result)
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are 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 The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make 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 compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • Compounds according to the present invention has an inhibitory effect on P2X 7 receptors, believed to be useful as therapeutic and / or prophylactic agent for a disease or condition P2X 7 receptors are involved.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé présentant une activité inhibitrice du récepteur P2X7 ; et une composition pharmaceutique présentant une activité inhibitrice du récepteur P2X7. L'invention concerne un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable ou un analogue de celui-ci (dans la formule, Y1 représente O ou un groupe similaire ; R1 représente un groupe carbocyclique aromatique substitué ou non substitué ou un groupe similaire ; R2a, R2b, R2c et R2d représentent chacun indépendamment des atomes d'hydrogène ou des groupes similaires ; R7a représente un atome d'hydrogène ou un groupe similaire, R3 est représenté par la formule (II), dans laquelle le cycle B est un carbocycle aromatique à 6 chaînons ou un groupe similaire ; R9a et R10a représentent chacun indépendamment des atomes d'halogène ou des groupes similaires ; R5 représente un atome d'hydrogène ou un groupe similaire ; n est un nombre entier de 1 à 5 ; m est un nombre entier de 0 à 4, et p1 est un nombre entier de 0 à 3).
PCT/JP2017/037919 2016-10-21 2017-10-20 Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant WO2018074565A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2016206711 2016-10-21
JP2016-206711 2016-10-21
JP2017-133193 2017-07-07
JP2017133193 2017-07-07

Publications (1)

Publication Number Publication Date
WO2018074565A1 true WO2018074565A1 (fr) 2018-04-26

Family

ID=62018731

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/037919 WO2018074565A1 (fr) 2016-10-21 2017-10-20 Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant

Country Status (2)

Country Link
TW (1) TW201821411A (fr)
WO (1) WO2018074565A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
WO2021002407A1 (fr) * 2019-07-02 2021-01-07 Ａｇｃ株式会社 Composé contenant un groupe fluoroalkyle et procédé de production associé
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009513497A (ja) * 2003-07-02 2009-04-02 バイエル・ヘルスケア・アクチェンゲゼルシャフト 慢性炎症疾患の処置用のアミド置換１，２，４−トリアジン−５（２ｈ）−オン化合物
WO2012020742A1 (fr) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Nouveaux dérivés hétérocycliques, et composition pharmaceutique comprenant ceux-ci
WO2015099107A1 (fr) * 2013-12-26 2015-07-02 塩野義製薬株式会社 Dérivé cyclique à six chaînons contenant de l'azote et composition pharmaceutique le contenant
WO2016171249A1 (fr) * 2015-04-24 2016-10-27 塩野義製薬株式会社 Dérivé hétérocyclique à 6 chainons et composition pharmaceutique comprenant celui-ci
WO2017204316A1 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009513497A (ja) * 2003-07-02 2009-04-02 バイエル・ヘルスケア・アクチェンゲゼルシャフト 慢性炎症疾患の処置用のアミド置換１，２，４−トリアジン−５（２ｈ）−オン化合物
WO2012020742A1 (fr) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Nouveaux dérivés hétérocycliques, et composition pharmaceutique comprenant ceux-ci
WO2015099107A1 (fr) * 2013-12-26 2015-07-02 塩野義製薬株式会社 Dérivé cyclique à six chaînons contenant de l'azote et composition pharmaceutique le contenant
WO2016171249A1 (fr) * 2015-04-24 2016-10-27 塩野義製薬株式会社 Dérivé hétérocyclique à 6 chainons et composition pharmaceutique comprenant celui-ci
WO2017204316A1 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M.M. HERAVI ET AL., INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 4, 1994, pages 141 - 144, ISSN: 0971-1627 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2021002407A1 (fr) * 2019-07-02 2021-01-07 Ａｇｃ株式会社 Composé contenant un groupe fluoroalkyle et procédé de production associé

Also Published As

Publication number Publication date
TW201821411A (zh) 2018-06-16

Similar Documents

Publication Publication Date Title
JP6358639B2 (ja) ６員複素環誘導体およびそれらを含有する医薬組成物
JP6618120B2 (ja) ＴｒｋＡ阻害活性を有する複素環および炭素環誘導体
JP6812059B2 (ja) ＴｒｋＡ阻害活性を有する複素環誘導体
JP6422164B2 (ja) 含窒素６員環誘導体およびそれらを含有する医薬組成物
JP6281952B2 (ja) Ｈｉｖ複製阻害剤
JPWO2012147762A1 (ja) ピリジン誘導体およびそれを含有するｂａｃｅ１阻害剤
JP2019001806A (ja) 新規アルキレン誘導体
WO2017209265A1 (fr) Dérivé hétérocyclique bicyclique et composition pharmaceutique comprenant le dérivé hétérocyclique bicyclique
JPWO2017135399A1 (ja) ＴｒｋＡ阻害活性を有する含窒素複素環および炭素環誘導体
WO2016159082A1 (fr) Dérivé à cycle condensé à 9 chaînons
JPWO2013146754A1 (ja) Ｔｒｐｖ４阻害活性を有する芳香族複素５員環誘導体
WO2018079759A1 (fr) Hétérocycle fusionné ayant une activité inhibitrice de trka et dérivé carbocycle fusionné
JP7038460B2 (ja) 二環性含窒素複素環誘導体およびそれらを含有する医薬組成物
JP7311944B2 (ja) 二環性含窒素複素環誘導体を含有する医薬組成物
WO2015147247A1 (fr) Dérivé tricyclique présentant une activité inhibitrice de la réplication du vih
WO2018074565A1 (fr) Dérivé hétérocyclique à 6 chaînons contenant de l'azote et composition pharmaceutique le contenant
WO2017204316A1 (fr) Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante
WO2015199206A1 (fr) Dérivé de cycle à six chaînons ayant une activité inhibitrice de trpv4
JP2019182806A (ja) 二環性複素環誘導体およびそれらを含有する医薬組成物
WO2017209267A1 (fr) Dérivé de purine
JP2014080395A (ja) アミノラクタム誘導体およびそれらを含有する医薬組成物
JP6692113B2 (ja) ６員複素環誘導体を含有する医薬組成物
JP2019189573A (ja) 縮合複素環および縮合炭素環誘導体を含有する、疼痛の治療および／または予防用医薬組成物
JP2014080394A (ja) イミダゾイミダゾロン誘導体およびそれらを含有する医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17861598

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17861598

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP