WO2015152254A1 - Dérivé hétéroaryle à cycle de cinq chaînons - Google Patents

Dérivé hétéroaryle à cycle de cinq chaînons Download PDF

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WO2015152254A1
WO2015152254A1 PCT/JP2015/060155 JP2015060155W WO2015152254A1 WO 2015152254 A1 WO2015152254 A1 WO 2015152254A1 JP 2015060155 W JP2015060155 W JP 2015060155W WO 2015152254 A1 WO2015152254 A1 WO 2015152254A1
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compound
alkyl
pharmaceutically acceptable
acceptable salt
optionally substituted
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光貴 岩田
恭次 石田
尚明 島田
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel 5-membered heteroaryl derivative that is a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases related to smooth muscle contraction endocrine diseases
  • diseases related to neurodegeneration It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • ⁇ 7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection.
  • neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM).
  • PAM positive allosteric modulator
  • ⁇ 7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs.
  • the involvement of ⁇ 7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, it is assumed that the development of novel modulators of the receptor will lead to novel treatments for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • Patent Document 1 Patent Document 2, Patent Document 3, Patent Document 4
  • Patent Document 5 Patent Document 6
  • the problem to be solved by the present invention is a novel having a positive modulator action of a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) and useful as a novel therapeutic agent for nervous system diseases, mental diseases and inflammatory diseases. It is to provide a compound.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a novel compound represented by the following formula (I) has a positive modulator action of a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR).
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • XYZ is N—COR 4A
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines
  • R 3A and R 3B are both C 1-6 When alkyl, together with the nitrogen atom to which they are attached, is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkyl and C 1-6 alkoxy. It may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. Or a pharmaceutically acceptable salt thereof.
  • R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl.
  • C 1-6 alkyl optionally substituted with 1-5 substituents; 1-5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl in an optionally substituted C 3-10 cycloalkyl; saturated heterocyclic 4-10 membered; a or a hydrogen atom, wherein, (1) R 4A and R 4B are not hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms; (3) when B is B-3, W is an oxygen atom, and XYZ is N-COR 4A , R 4A is not methyl (4) A is unsubstituted phenyl and B is B- In it, W is an oxygen atom, when X-Y-Z is N-COR 4A
  • R 3A , R 3B and R 4A are the same or different and are each 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom , Item 3.
  • R 4B is good fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl, Item 4.
  • A is phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy).
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • A is phenyl (the phenyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.) Item 5.
  • A is pyridyl (the pyridyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.) Item 5.
  • R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl; or C 3-10 cycloalkyl.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom, chlorine or cyano.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is chlorine.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • W is an oxygen atom.
  • Item 12 The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • W is a sulfur atom.
  • Item 12 The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R 2C , R When any two of 2D and R 5 are C 1-6 alkyl, the two alkyls may be combined together to form another ring with the ring to which the alkyl is attached, Item 14.
  • R 2A , R 2B , R 2C , R 2D and R 5 are all hydrogen atoms.
  • Item 14 The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
  • R 6 is optionally fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl; or a hydrogen atom, Item 16.
  • R 6 is a hydrogen atom.
  • Item 16 The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
  • R 3B is a hydrogen atom
  • R 3A and R 4A are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl optionally substituted with 5 substituents; or a 4-10 membered saturated heterocycle, Item 18.
  • XYZ is N—CO—NR 3A R 3B or N—COR 4A .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is N—CO—NR 3A R 3B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is N-COR 4A .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 5 —CO—NR 3A R 3B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 5 —NR 6 —COR 4B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • B is B-1.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • B is B-2.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • [Section 26] B is B-3.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • B is B-4.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • [Item 28] B is B-5.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof.
  • CIAS cognitive impairment associated with schizophrenia
  • cognitive impairment mild cognitive impairment
  • memory impairment in schizophrenia Alzheimer's disease, Down's syndrome
  • attention deficit / hyperactivity disorder or cerebrovascular angiopathy or Item 31 A pharmaceutical composition according to Item 30, for treating and / or preventing learning disorders.
  • a pharmaceutical comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotics .
  • [Item 35] Acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of Items 1 to 29 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine.
  • diseases caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease.
  • neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy.
  • the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • CIAS cognitive dysfunction associated with schizophrenia
  • schizophrenia Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention.
  • the compound of the present invention may exist in the form of a hydrate and / or a solvate, a hydrate of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and / or Alternatively, solvates are also encompassed by the compounds of the present invention.
  • the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
  • a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) into 2 H (D) is also included in the compound represented by the general formula (I). Is done.
  • Crystalline polymorphisms may exist in the compound represented by the general formula (I) obtained as crystals and pharmaceutically acceptable salts thereof, and the compounds of the present invention may be in any crystalline form. included.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-4 alkyl or “C 1-6 alkyl” has 1 to 4 carbon atoms or Means 1-6 alkyl.
  • C 1-6 alkyl “C 1-4 alkyl” is preferable. Specific examples thereof include “C 1-4 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned.
  • Cycloalkyl means a group consisting of monocyclic or polycyclic saturated hydrocarbons.
  • C 3-10 cycloalkyl means a cyclic alkyl having 3 to 10 carbon atoms.
  • crosslinking is mentioned. Specific examples thereof include “C 3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is bonded to an oxygen atom, and is bonded to another moiety via the oxygen atom.
  • C 1-6 alkoxy means alkoxy having 1 to 6 carbon atoms. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
  • the “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • Preferred 4- to 10-membered saturated heterocycles include tetrahydrofuran, tetrahydropyran, and oxetane. More preferred is tetrahydropyran.
  • the “4- to 10-membered nitrogen-containing saturated heterocycle” means 0 to 2 atoms independently selected from the group consisting of 1 to 2 nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms.
  • a saturated heterocyclic ring composed of 4 to 10 atoms is included.
  • azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned.
  • Preferred examples of the 4 to 10-membered nitrogen-containing saturated heterocyclic ring include saturated heterocyclic rings composed of 4 to 10 atoms containing one nitrogen atom in addition to the carbon atom.
  • azetidine, pyrrolidine, piperidine and the like can be mentioned.
  • A, B, W, XYZ, R 1 , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 4A , R 4B , R 5 and R 6 are preferably as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.
  • X—Y—Z is preferably N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B . More preferably, N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B may be mentioned. More preferred is N—CO—NR 3A R 3B or N—COR 4A .
  • A is preferably phenyl or pyridyl (the phenyl and pyridyl are each substituted with halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy. More preferably, phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy.
  • it is 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy.
  • substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy.
  • Examples include optionally substituted phenyl.
  • phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy.
  • B is preferably B-1, B-2, B-3, B-4 or B-5. More preferred is B-1, B-4 or B-5. More preferred is B-1 or B-4.
  • W is preferably an oxygen atom or a sulfur atom. More preferably, an oxygen atom is mentioned.
  • R 1 is preferably a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 alkoxy, and 4 to 10 membered saturation And C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of heterocycles. More preferably, a hydrogen atom, halogen, or cyano is mentioned. More preferably, a hydrogen atom, chlorine, or cyano is mentioned. Most preferably, a hydrogen atom or chlorine is mentioned.
  • R 2A , R 2B , R 2C , R 2D and R 5 are preferably the same or different and include a hydrogen atom, fluorine, a hydroxyl group or C 1-6 alkyl.
  • R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl optionally substituted with 1 to 5 fluorines, the two alkyls together To form a ring different from the ring to which the alkyl is bonded.
  • R 2A , R 2B , R 2C , R 2D and R 5 are more preferably the same or different and include a hydrogen atom or C 1-6 alkyl.
  • R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl
  • the two alkyls are joined together to form a ring to which the alkyl is bonded Another ring may be formed.
  • R 2A , R 2B , R 2C , R 2D and R 5 are more preferably a hydrogen atom.
  • R 3A , R 3B and R 4A are preferably the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring).
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a halogen, a hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl optionally substituted with 1-5 substituents independently selected from the group consisting of: 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl Or a hydrogen atom, wherein (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously a hydrogen atom, (3) B is B-3, and W is An oxygen atom, X- When -Z is N-COR 4A is, R 4A is not methyl, (4) A a is unsubstituted phenyl, B is B-4, W is an oxygen atom, X-Y- When Z is N—COR 4A , R 4A is not C 3 alkyl substituted with 1 to 5 fluorines.
  • R 3A , R 3B and R 4A are the same or different and are 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl C 1-6 alkyl optionally substituted with 1-6 alkyls independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, where (1) R 4A is not a hydrogen atom and (2) R 3A and R 3B are simultaneously a hydrogen atom And (3) when B is B-3, W is an oxygen atom, and XYZ is N—COR 4A , R 4A is not methyl and (4) A is unsubstituted Phenyl, B is B-4, W is An atom, X-Y-Z is and when is N-COR 4A, R 4A is not C 3 alkyl substituted with 1-5 fluorine.
  • R 3A , R 3B and R 4A are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl which may be substituted ; a 4 to 10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom .
  • R 3A and R 4A the same or different, fluorine and C 1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C 3-10 Examples include cycloalkyl or a 4- to 10-membered saturated heterocyclic ring.
  • R 3B includes a hydrogen atom.
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines means that “R 4A is substituted with 1 to 5 fluorines, It is not C 3 alkyl not substituted with a substituent ”.
  • R 4B is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group.
  • C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl which may be substituted with a 4-10 membered saturated heterocyclic ring which may be substituted with C 1-6 alkyl.
  • fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; or 4-10 membered saturation Heterocycles are mentioned. More preferable examples include C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl. It is done. Most preferred is C 1-6 alkyl optionally substituted with 1 to 5 fluorines.
  • R 6 is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group.
  • C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl
  • fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; A ring; or a hydrogen atom. More preferably, fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino C 1-6 alkyl optionally substituted with a substituent selected independently from the group consisting of cycloalkyl; or A hydrogen atom is mentioned. Most preferably, a hydrogen atom is mentioned.
  • preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.
  • (A) is mentioned as a preferable aspect.
  • (A) XYZ is N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B ;
  • A is phenyl or pyridyl (the phenyl and the pyridyl may each be substituted with halogen, hydroxyl group, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine; And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
  • B is B-1, B-2, B-3, B-4 or B-5,
  • W is an oxygen atom or a sulfur atom
  • R 1 is a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 al
  • R 3A , R 3B and R 4A are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring).
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a group consisting of halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl
  • a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from: a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; or (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms, (3) B is B-3, and W is an oxygen atom.
  • X-Y-Z is N-COR
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines
  • 1 to 5 R 4B independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group substituted halogen, hydroxyl, with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; the optionally substituted with a substituent C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; or a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; 1 to 5 R 6 independently selected from the group
  • (B) is mentioned as a more preferable aspect.
  • (B) XYZ is N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B ;
  • A is phenyl or pyridyl (each said phenyl and said pyridyl fluorine, chlorine, from one to five fluorines optionally substituted C 1-6 alkyl, optionally substituted with 1-5 fluorine Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
  • B is B-1, B-2, B-3, B-4 or B-5, W is an oxygen atom or a sulfur atom,
  • R 1 is a hydrogen atom, halogen or cyano
  • R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R
  • R 4A is not a hydrogen atom
  • R 3A and R 3B are not simultaneously a hydrogen atom
  • B is B-3, W is an oxygen atom and XYZ is N-COR 4A , R 4A is not methyl and (4) A is unsubstituted phenyl; B is B-4, W is an oxygen atom, XY
  • Z is N-COR 4A is, R 4A is not C 3 alkyl substituted with 1-5 fluorine, R 4B is selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting
  • (C) is N—CO—NR 3A R 3B or N—COR 4A ;
  • A is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy Which may be phenyl, B is B-1, B-4 or B-5, W is an oxygen atom,
  • R 1 is a hydrogen atom, chlorine or cyano
  • R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
  • R 3A , R 3B and R 4A are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl; a 4-10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen
  • the most preferable embodiment includes the following (D).
  • (D) XYZ is N—CO—NR 3A R 3B or N—COR 4A ;
  • A is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy;
  • B is B-1 or B-4, W is an oxygen atom,
  • R 1 is a hydrogen atom or chlorine;
  • R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
  • R 3A and R 4A are the same or different and each is a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy;
  • a 4-10 membered saturated heterocycle A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3B is a hydrogen atom.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) means a salt formed by adding a pharmaceutically acceptable acid or base to the compound of the formula (I).
  • a pharmaceutically acceptable acid or base When the compound of the present invention represented by the formula (I) has a basic functional group such as an amino group, it can form salts with various acids.
  • acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, and malonic acid.
  • Salt maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane
  • organic acid salts such as sulfonate
  • amino acid salts such as glutamate and aspartate.
  • salts When the compound of the present invention represented by the formula (I) has an acidic functional group such as a carboxyl group, it can form salts with various bases.
  • pharmaceutically acceptable salts include alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as calcium salt, or triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt. Examples thereof include organic base salts such as salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (I) with a base.
  • the method for producing the compound of the present invention is described below.
  • the compound of the present invention represented by the formula (I) can be produced, for example, by the following production methods A to M.
  • Production method A production method of synthetic intermediate
  • synthetic intermediates a6, a8 and a10 of a compound in which B is B-1 can be produced, for example, by the following production method.
  • P X represents a protecting group of amino
  • R X represents a hydrogen atom, alkyl or phenyl
  • R 1X represents halogen
  • R 1Y represents the term 1 R 1 as defined is not halogen
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound a1 can be synthesized by a known method such as a halogenation reaction of imidazole, or can be purchased as a commercial product.
  • Step A-1 This step is a step of obtaining compound a2 by reacting compound a1 with an appropriate boronic acid derivative in the presence of an appropriate transition metal reagent.
  • An example of the transition metal reagent used in this step is copper acetate.
  • Examples of the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably dichloroethane or methanol.
  • a similar reaction for example, a method described in Journal of Medicinal Chemistry, 2009, 52 (11), 3441-3444 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-2 This step is a step of obtaining compound a4 by reacting compound a2 obtained in step A-1 with compound a3 in the presence of an appropriate transition metal reagent.
  • the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane.
  • a similar reaction for example, a method described in Journal of Organic Chemistry, 2010, 75 (5), 1733-1739 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-3 This step is a step of obtaining compound a5 by reacting compound a4 obtained in step A-2 with a suitable transition metal reagent in a hydrogen atmosphere.
  • the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol.
  • a similar reaction for example, a method described in Journal of Medicinal Chemistry, 2012, 55 (1), 115-125, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 60 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-4 This step is a protecting group P X of the amino compound a5 prepared in the above Preparation Method A-3, by deprotection, to give compound compound a6.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step A-5 This step is a step of obtaining compound a7 by reacting compound a5 obtained in step A-3 with various halogenating agents in a suitable solvent in the presence of a suitable acid.
  • the halogenating agent used in this step is, for example, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane.
  • the acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid.
  • a similar reaction for example, a method described in Bioorg. Med. Chem.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-6 This step is a step of obtaining compound a8 from compound a7 obtained in step A-5, under the same conditions as in step A-4.
  • Step A-7 This step is a step of obtaining compound a9 by reacting compound a7 obtained in step A-5 with a suitable boronic acid derivative in a suitable solvent in the presence of a suitable transition metal reagent.
  • a suitable transition metal reagent examples include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 180 ° C., more preferably room temperature to 150 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-8 This step is a step of obtaining compound a10 from compound a9 obtained in step A-7, under the same conditions as in step A-4.
  • Production method B (Production method of synthetic intermediate) Among the compounds represented by formula (I), a synthetic intermediate b7 of a compound in which B is B-2 and W is an oxygen atom can be produced, for example, by the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step B-1 This step is a step of obtaining compound b2 by reacting compound b1 with nitromethane in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and preferably tert-butoxy potassium.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably a mixed solvent of tetrahydrofuran and tert-butanol.
  • a similar reaction for example, a method described in International Publication No. 2007/41061 pamphlet or the like is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-2 This step is a step of obtaining compound b3 by reacting compound b2 obtained in B-1 above in a hydrogen atmosphere using an appropriate transition metal catalyst.
  • the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol. As similar reactions, for example, the methods described in Bioorganic and Medicinal Chemistry Letters, 2004, 14 (13), 3419-3424, International Publication No. 2006/19768, etc. are known and can be synthesized similarly. .
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-3 In this step, compound b3 obtained in B-2 above is reacted with carboxylic acid b8 or acid chloride b9 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • compound b4 is obtained.
  • the condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • the base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-4 This step is a step of obtaining compound b5 by reacting compound b4 obtained in B-3 with an appropriate oxidizing agent.
  • the oxidizing agent used in this step include a desmartin reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or DMSO.
  • a similar reaction for example, a method described in International Publication No. 2010/138589 pamphlet is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-5 This step is a step of obtaining compound b6 by reacting compound b5 obtained in B-4 with an appropriate dehydrating reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • Examples of the dehydrating reagent used in this step include Burgess reagent.
  • a similar reaction for example, a method described in Synlett, 1999, 10, 1642-1644 is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-6 This step is a step of obtaining the compound b7 from the compound b6 obtained in the step B-5 under the conditions according to the step A-4.
  • c2 which is a synthetic intermediate of a compound in which B is B-2 and W is a sulfur atom can be produced, for example, by the following production method.
  • A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Step C-1 This step is a step of obtaining compound c1 by reacting compound b5 obtained in step B-4 with an appropriate thiocarbonylating reagent.
  • the thiocarbonylation reagent used in this step include Lawson's reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • a similar reaction for example, a method described in US Publication No. 2010/261617, etc. is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step C-2 In this step, compound c2 is obtained from compound c1 obtained in step C-1 under the same conditions as in step A-4.
  • d4 that is a synthetic intermediate of a compound in which B is B-3 and W is an oxygen atom can be produced, for example, by the following production method.
  • A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound d1 can be synthesized by a known method such as oxidation of the corresponding alcohol or aldehyde or corresponding ester hydrolysis, or can be purchased as a commercial product.
  • Step D-1 This step is a step in which compound d1 and compound d5 are reacted under the same conditions as in step B-3 to obtain compound d2.
  • Step D-2 This step is a step of obtaining a compound d3 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step B-5.
  • Step D-3 This step is a step of obtaining a compound d4 by reacting the compound d3 obtained in the step D-2 with the conditions according to the step A-4.
  • Production method E (Production method of synthetic intermediate) Among the compounds represented by the formula (I), e2 which is a synthetic intermediate of a compound in which B is B-3 and W is a sulfur atom can be produced by, for example, the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Step E-1 This step is a step of obtaining a compound e1 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step C-1.
  • Step E-2 This step is a step of obtaining a compound e2 by reacting the compound e1 obtained in the step E-1 with the conditions according to the step A-4.
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound f1 can be purchased as a commercial product.
  • Compound f4 can be synthesized by known methods such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step F-1 compound f2 is obtained by reacting compound f1 with a diazotizing reagent using an appropriate base.
  • the diazotizing reagent used in this step include 4-toluenesulfonyl azide.
  • the base used in this step is selected from the bases exemplified below, and is preferably sodium hydride.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • the methods described in Bioorganic and Medicinal Chemistry Letters, 2013, 23 (19), 5267-5269, etc. are known, and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-2 This step is a step of obtaining compound f3 by reacting compound f2 obtained in step F-1 with compound b1 in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and is preferably potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol.
  • a similar reaction for example, a method described in Journal of the American Chemical Society, 2003, 125 (13), 3714-3715 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-3 This step is a step of reacting compound f4 and hydroxylamine to obtain compound f5.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol.
  • a similar reaction for example, a method described in Organic Letters, 2001, 3 (26), 4209-4211, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-4 This step is a step of reacting the compound f5 obtained in the step F-3 with a chlorinating reagent to obtain the compound f6.
  • chlorinating reagent used in this step include N-chlorosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably DMF. Similar reactions are described in, for example, Bioorganic and Medicinal Chemistry Letters, 2006, 16 (21), 5576-5579, Journal of Heterocyclic Chemistry, 1996, 33 (6), 1583-1592, and the like. It can be synthesized similarly. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-5 In this step, compound f3 obtained in step F-2 and compound f6 obtained in step F-4 are reacted in the presence of a suitable base to obtain compound f7.
  • the base used in this step is selected from the bases exemplified below, but is preferably triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • the methods described in Journal of Medicinal Chemistry, 2003, 46 (2), 284-302, European Journal of Medicinal Chemistry, 2012, 54, 324-342, and the like are known. can do.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-6 This step is a step of obtaining compound f8 by reacting compound f7 obtained in step F-5 with the conditions according to step A-4.
  • Production method G (Production method of synthetic intermediate) Among the compounds represented by the formula (I), g5 which is a synthetic intermediate of a compound in which B is B-5 and W is an oxygen atom can be produced, for example, by the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound f4 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step G-1 This step is a step of obtaining compound g1 by reacting compound f4 with compound f2 obtained in Step F-1 under the same conditions as in Step F-2.
  • Step G-2 This step is a step of obtaining compound g2 by reacting compound b1 under the conditions according to the above F-3 step.
  • Step G-3 This step is a step of obtaining compound g3 by reacting compound g2 obtained in the above step G-2 under the same conditions as in the above step F-4.
  • Step G-4 This step is a step of obtaining compound g4 by reacting compound g3 obtained in step G-3 and g1 obtained in step G-1 under the same conditions as in step F-5.
  • Step G-5 This step is a step of obtaining compound g5 by reacting compound g4 obtained in the above step G-4 with the conditions according to the above step A-4.
  • Manufacturing method H Of the compounds represented by the formula (I), the compounds represented by the formulas [H1], [H2] and [H3], wherein B is B-1 and XYZ is N—CO—NR 3A R 3B
  • the compounds to be prepared (hereinafter also referred to as compounds H1, H2, and H3) can be produced, for example, by the following production method. Further, using the same production method, compounds represented by the formulas [H2] and [H3] can be produced using the intermediates a8 and a10 obtained by the intermediate production method A as starting materials. Further, using the same production method, the intermediates B7, c2, d4, e2, f8 and g5 obtained by the above intermediate production methods B, C, D, E, F and G are used as starting materials.
  • XYZ is N-CO-NR 3A R 3B
  • W is an oxygen atom or a sulfur atom.
  • A, R 2A , R 2B , R 2C , R 2D , R 3A and R 3B are as defined in item 1; R Y represents hydrogen, nitro or cyano; and R 1X represents halogen. And R 1Y means a non-halogen among R 1 defined in item 1)
  • Step H-1 This step is a step of obtaining Compound H1 by reacting Compound a6 obtained in Step A-4 with h1 or h2 which is a urea agent in a suitable solvent in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methylene chloride. Similar reactions include, for example, J. Org. Chem. 1995, 60 (25), 8262-8266, Bioorg. Med. Chem. Lett.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step H-2 This step is a step for obtaining compound H2 by reacting compound H1 obtained in step H-1 with various halogenating agents in a suitable solvent in the presence of a suitable acid.
  • the halogenating agent used in this step is preferably N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane.
  • the acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid.
  • a similar reaction for example, methods described in Bioorg. Med. Chem. Lett.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step H-3 This step is a step of obtaining compound H3 by reacting compound H2 obtained in step H-2 with an appropriate boronic acid derivative in an appropriate solvent in the presence of an appropriate transition metal reagent.
  • the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 180 ° C., more preferably room temperature to 150 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • XYZ is N-COR 4A
  • W is an oxygen atom or a sulfur atom. it can.
  • R 1Y represents a non-halogen of R 1 defined in item 1.
  • R 1X means halogen
  • Step I-1 In this step, compound a6 obtained in step A-4 is reacted with carboxylic acid i1 or acid chloride i2 in the presence of a suitable base in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • the condensing agent used in this step is, for example, EDCI (including hydrochloride) or HBTU.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step I-2 This step is a step of obtaining compound I2 by reacting compound I1 obtained in the above step I-1 under the same conditions as in the above step H-2.
  • Step I-3 This step is a step of obtaining compound I3 by reacting compound I2 obtained in the above step I-2 with the conditions according to the above step H-3.
  • Manufacturing method J Of the compounds represented by formula (I), the formulas [J1] [J2] [J3] and [J4] wherein B is B-4 and XYZ is CR 5 —NR 6 —COR 4B (Hereinafter also referred to as compounds J1, J2, J3, and J4) can be produced, for example, by the following production method according to the intermediate production method F. Further, by combining the following production method J and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —NR 6 —COR 4B ; Is a corresponding compound group in which is B-1, B-2, B-3 and B-5, and W is an oxygen atom or a sulfur atom.
  • R 1X represents halogen
  • R 1Y represents item 1
  • R 1 which is not halogen among the defined R 1 represents R Z represents a leaving group such as halogen
  • P X represents an amino protecting group
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound j1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step J-1 This step is a step wherein compound j2 is obtained by reacting compound j1 under the same conditions as in Step F-2.
  • Step J-2 This step is a step of obtaining compound j3 by reacting compound j2 obtained in step J-1 under the same conditions as in step F-5.
  • Step J-3 This step is a protecting group P X of the amino compound j3 prepared in the above Preparation Method J-2, is deprotected, to give compound compound j4.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step J-4 In this step, compound j4 obtained in J-3 above is reacted with carboxylic acid j5 or acid chloride j6 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • compound J1 is obtained.
  • the condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • the base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step J-5 This step is a step of obtaining compound J2 by reacting compound J1 obtained in the above step J-4 under the conditions according to the above step H-2.
  • Step J-6 In this step, compound J2 obtained in step J-5 is reacted under the same conditions as in step H-3 to obtain compound J3.
  • Step J-7 This step is a step of obtaining compound J4 by reacting compound j7 obtained in step J-6 with compound j7 in the presence of various bases in an appropriate solvent.
  • the base used in this step is selected from the bases exemplified below, and preferably sodium hydride or diisopropylamine.
  • the solvent used in this step is selected from the solvents exemplified below and preferably dimethylformamide or tetrahydrofuran.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 30 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably 0 ° C. to 80 ° C.
  • the reaction time is usually about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Manufacturing method K Of the compounds represented by formula (I), the compounds of formula [K1] [K2] [K3] and [K3] wherein B is B-4 and XYZ is CR 5 —NR 6 —CONR 3A R 3B
  • the compound represented by K4] (hereinafter also referred to as compounds K1, K2, K3 and K4) can be produced, for example, by the following production method.
  • XYZ is CR 5 —NR 6 —CONR 3A R 3B by combining the following production method K and production methods according to the above intermediate production methods A, B, C, D, E and G.
  • B is B-1, B-2, B-3 and B-5, and corresponding compounds can be produced wherein W is an oxygen atom or a sulfur atom.
  • R 1X represents halogen
  • R 1Y represents R 1 defined in Item 1 is not halogen
  • R Y represents hydrogen, nitro or cyano
  • R Z represents a leaving group such as halogen
  • Step K-1 This step is a step of obtaining compound K1 by reacting compound j4 obtained in the above step J-3 under the conditions according to the above step H-1.
  • Step K-2 This step is a step of obtaining compound K2 by reacting compound K1 obtained in the above step K-1 under the same conditions as in the above step J-7.
  • Step K-3 This step is a step of obtaining a compound K3 by reacting the compound K2 obtained in the step K-2 with the conditions according to the step H-2.
  • Step K-4 This step is a step of obtaining a compound K4 by reacting the compound K3 obtained in the step K-3 with the conditions according to the step H-3.
  • Manufacturing method M Of the compounds represented by the formula (I), the compounds represented by the formulas [M1] [M2] and [M3], wherein B is B-4 and XYZ is CR 5 —CO—NR 3A R 3B
  • the compounds to be produced (hereinafter also referred to as compounds M1, M2 and M3) can be produced, for example, by the following production method according to the intermediate production method F. Further, by combining the following production method M and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —CO—NR 3A R 3B , Corresponding compound groups in which B is B-1, B-2, B-3 and B-5 and W is an oxygen atom or a sulfur atom can be produced.
  • R 1X represents halogen
  • R 1Y represents item 1 R 1 which is not halogen among the defined R 1 represents P Y represents a protecting group for a carboxyl group
  • the protective group P Y Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group of a carboxylic acid .
  • Compound m1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step M-1 This step is a step of obtaining compound m2 by reacting compound m1 under the same conditions as in Step F-2.
  • Step M-2 This step is a step of obtaining a compound m3 by reacting the compound m2 obtained in the step M-1 with the conditions according to the step F-5.
  • This step is a step of obtaining the compound m4 by deprotecting the protecting group P Y of the carboxylic acid of the compound m3 obtained in the step M-2.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step M-4 This step is a step of obtaining compound M1 by reacting compound m4 obtained in step M-3 with amine m5 in the presence of a suitable condensing agent and in the presence of a suitable base in a suitable solvent.
  • a suitable condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • the base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step M-5 In this step, compound M1 obtained in step M-4 is reacted under the same conditions as in step H-2 to obtain compound M2.
  • Step M-6 In this step, compound M2 obtained in step M-5 is reacted under the same conditions as in step H-3 to obtain compound M3.
  • alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate and potassium carbonate
  • Alkali carbonates such as sodium hydride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metals such as sodium methoxide and sodium t-butoxide Alkoxides, organometallic bases such as butyllithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene ( Organic bases such as DBU) That.
  • DMAP 4-dimethylaminopyridine
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • the solvent used in each of the above steps should be appropriately selected depending on the reaction and the type of raw material compound.
  • alcohols such as methanol, ethanol and isopropanol
  • ketones such as acetone and ethyl methyl ketone.
  • Halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, Esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), nitriles such as acetonitrile
  • solvents can be used alone There can be used as a mixture of two or more kinds. Depending on the type of reaction, organic bases may be used as a solvent.
  • the compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art.
  • separation or purification methods include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization.
  • recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • a spectroscopic method such as nuclear magnetic resonance, infrared absorption, circular dichroism spectrum analysis, And mass spectrometry.
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • optical isomers exist.
  • the compounds of the present invention include mixtures of these isomers and isolated ones, and can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process, the optical properties of the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof Isomers can be obtained.
  • the solvent is an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol).
  • An ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent thereof), an optically active acid (for example, mandelic acid, N-benzyloxyalanine or monocarboxylic acid such as lactic acid, tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid) Stereomer method can be mentioned.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine or strychnine
  • the optical resolution can also be carried out by forming a salt using an organic amine).
  • the temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • Crystals in an inert solvent as necessary for example, alcohol solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. And a high purity optically active salt can be obtained. Further, if necessary, an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.
  • an inert solvent for example, alcohol solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc.
  • an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.
  • an optically active amine for example, 1-phenylethylamine etc.
  • an optically active amine for example, 1-phenylethylamine etc.
  • the compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine.
  • diseases caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease.
  • neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy.
  • the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • CIAS cognitive dysfunction associated with schizophrenia
  • schizophrenia Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • the compounds of the present invention are also useful for treating and / or preventing negative and / or positive symptoms associated with schizophrenia.
  • the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention.
  • the pharmaceutical agent in the case where the compound of the present invention or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug are used in combination may be a single compounding agent, or simultaneously, separately and continuously. Or multiple formulations administered at regular intervals.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coating agents, patches, inhalants and the like.
  • These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain pharmaceutically acceptable additives.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • the compound of the present invention can be used in combination with an atypical antipsychotic drug.
  • atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • Me means a methyl group
  • Et means an ethyl group
  • Ph means a phenyl group
  • Ts means a tosyl group.
  • TFA means trifluoroacetic acid.
  • s is a single line
  • d is a double line
  • dd is a double double line
  • t is a triple line
  • td is a triple double line
  • q is a quadruple line
  • m is Multiple lines
  • br means broad
  • brs means broad single line
  • brd means broad double line
  • brt means broad triple line
  • J means coupling constant.
  • High-performance liquid chromatographic mass spectrometer The measurement conditions of LCMS are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH +, and the retention time is represented by Rt (min, min). In each actual measurement value, any one of A to H is added as a measurement condition used for the measurement.
  • Reference example 1 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride a) Preparation of 4-bromo-1- (3-fluorophenyl) -1H-imidazole (compound Q1) 4-Fluoroimidazole (50 g) in methylene chloride solution (1500 mL) at room temperature with 3-fluorophenylboronic acid ( 94.0 g), copper (II) acetate (91.0 g) and pyridine (50 mL) were added, and the mixture was stirred at 30 ° C. for 48 hours.
  • Reference example 2 4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride a) Preparation of tert-butyl 4- [1- (3-fluorophenyl) -5-iodo-1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q5) Compound Q3 (5.0 g) in acetonitrile N-iodosuccinimide (3.6 g) and trifluoroacetic acid (0.05 mL) were added to the solution (30 mL) at room temperature, and the mixture was stirred at room temperature for 72 hours under light shielding.
  • Reference example 3 4- ⁇ 3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl ⁇ piperidine dihydrochloride a) Preparation of tert-butyl 4-ethiylpiperidine-1-carboxylate (Compound Q7) To a methanol solution (50 mL) of tert-butyl 4-formylpiperidine-1-carboxylate (7.8 g) at 0 ° C. Potassium carbonate (11 g) and dimethyl (acetyldiazomethyl) phosphonate (8.6 g) were added and stirred at 0 ° C. for 2 hours.
  • Reference example 4 4- ⁇ 5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl ⁇ piperidine dihydrochloride a) Preparation of tert-butyl 4-[(hydroxyimino) methyl] piperidine-1-carboxylate (Compound Q11) Methanol / water solution of tert-butyl 4-formylpiperidine-1-carboxylate (11 g) (80 mL / 80 mL) To the mixture, sodium carbonate (2.7 g) and hydroxylamine hydrochloride (4.3 g) were added at room temperature, and the mixture was stirred at room temperature for 16 hours.
  • Tetrahydrofuran 40 mL was added to the reaction solution, and then a tetrahydrofuran solution (20 mL) of compound Q12 (2.9 g) and triethylamine (5.6 g) was added at room temperature.
  • the reaction solution was heated to 60 ° C. and stirred for 2 hours, and then the solvent was distilled off under reduced pressure.
  • the residue was extracted with ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 8 4- [5- (4-Fluorophenyl) -1,3-thiazol-2-yl] piperidine hydrochloride (Reference Example 8) a) Preparation of tert-butyl 4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate (Compound Q22) Compound Q19 (2 g) in tetrahydrofuran (50 mL) After adding Lawson's reagent (1.7 g) at room temperature, the mixture was heated to 70 ° C. and stirred for 4 hours.
  • Example 1 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide Phenyl 4,4-difluorocyclohexylcarbamate (272 mg) and triethylamine (0.50 mL) were added to a methylene chloride solution (8 mL) of the compound of Reference Example 1 (198 mg) at room temperature, and the temperature was raised to 38 ° C. Stir for 48 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 1 (200 mg) was obtained by purification by preparative HPLC.
  • Example 2 ⁇ 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidin-1-yl ⁇ (4,4-difluorocyclohexyl) methanone
  • a methylene chloride solution (4 mL) of the compound of Reference Example 1 (198 mg), 4,4-difluorocyclohexanecarboxylic acid (175 mg), HBTU (540 mg) and triethylamine (0.50 mL) were added at room temperature. Stir for 24 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 2 (100 mg) was obtained by purification by preparative HPLC.
  • Example 3 4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide
  • the compound of Example 3 (26 mg) was obtained by the method according to Example 1 using the compound of Reference Example 2 (259 mg).
  • Example 4 N- (Tetrahydro-2H-pyran-4-yl) -4- ⁇ 3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl ⁇ piperidine-1-carboxamide
  • the compound of Example 4 (90 mg) was obtained by the method according to Example 1 using the compound of Reference Example 3 (327 mg).
  • Example 5 N- (Tetrahydro-2H-pyran-4-yl) -4- ⁇ 5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl ⁇ piperidine-1-carboxamide
  • the compound of Example 5 (85 mg) was obtained by the method according to Example 1 using the compound of Reference Example 4 (247 mg).
  • Example 6 N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-oxazol-5-yl] piperidine-1-carboxamide
  • the compound of Example 6 (38 mg) was obtained by the method according to Example 1 using the compound of Reference Example 5 (290 mg).
  • Example 7 N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-oxazol-2-yl] piperidine-1-carboxamide
  • the compound of Example 7 (200 mg) was obtained by the method according to Example 1 using the compound of Reference Example 6 (300 mg).
  • Example 8 N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] piperidine-1-carboxamide
  • the compound of Example 8 (35 mg) was obtained by the method according to Example 1 using the compound of Reference Example 7 (120 mg).
  • Example 9 N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxamide Triethylamine (0.46 mL) was added to a solution of the compound of Reference Example 8 (340 mg) and phenyl 4,4-diphenylcyclohexanecarbamate (434 mg) in acetonitrile (5 mL) at room temperature, and the temperature was raised to 55 ° C. Stir for hours.
  • Example 10 4- [4-Chloro-5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide N-chlorosuccinimide (38 mg) and trifluoroacetic acid (0.05 mL) were added to an acetonitrile solution (5 mL) of the compound of Example 9 (100 mg) at room temperature, and then the mixture was heated to 55 ° C. and stirred for 4 hours. did. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • Examples 11 to 39 The compounds shown in Table 1 were obtained by the method according to Example 1 or 3 using the corresponding raw material compounds.
  • Examples 40-50 The compounds shown in Table 2 were obtained by the method according to Example 2 using the corresponding raw material compounds.
  • Examples 51-91 The compounds shown in Table 3 were obtained by the method according to Example 4 using the corresponding starting compounds.
  • Examples 92-98 The compounds shown in Table 4 were obtained by the method according to Reference Example 3 and Example 2 using the corresponding starting compounds.
  • Examples 101-142 The compounds shown in Table 6 were obtained by the method according to Example 5 using the corresponding starting compounds.
  • Examples 143-148 The compounds shown in Table 7 were obtained by the method according to Reference Example 4 and Example 2 using the corresponding starting compounds.
  • Example 149 The compounds shown in Table 8 were obtained by the method according to Example 6 using the corresponding starting compounds.
  • Examples 150-151 The compounds shown in Table 9 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
  • Examples 152-154 The compounds shown in Table 10 were obtained by the method according to Example 7 using the corresponding starting compounds.
  • Examples 155 to 156 The compounds shown in Table 11 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
  • Examples 157 to 159 The compounds shown in Table 12 were obtained by the method according to Example 8 using the corresponding starting compounds.
  • Examples 160-161 The compounds shown in Table 13 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
  • Examples 162-163 The compounds shown in Table 14 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
  • Examples 164 to 165 The compounds shown in Table 15 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
  • Examples 166-175 The compounds shown in Table 16 were obtained by the method according to Example 6 using the corresponding starting compounds.
  • Examples 176-184 The compounds shown in Table 17 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
  • Examples 185-191 The compounds shown in Table 18 were obtained by the method according to Example 7 using the corresponding starting compounds.
  • Example 192 The compounds shown in Table 19 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
  • Examples 193-198 The compounds shown in Table 20 were obtained by the method according to Example 8 using the corresponding starting compounds.
  • Examples 199-210 The compounds shown in Table 21 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
  • Examples 211-214 The compounds shown in Table 22 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
  • Examples 215 to 219 The compounds shown in Table 23 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
  • Test Example 1 PAM activity evaluation using human ⁇ 7 nACh receptor stable expression cells
  • Human ⁇ 7 nAChR stable expression cells Human ⁇ 7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat. No. CCL-82.2, ATCC, USA) were used as host cells.
  • Introduction of pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted, and introduction of pcDNA3.1 vector into which the human ⁇ 7 nAChR gene was inserted (cat. No.
  • V790-20, invitrogen, Carlsbad, CA, USA Thus, aequorin and human ⁇ 7 nAChR stably expressing cells were obtained.
  • Zeocin catalog. No. R25001, invitrogen, Carlsbad, CA, USA
  • Geneticin catalog. No. 10131-027, invitrogen, Carlsbad, CA, USA
  • Medium includes 2.5% fetal bovine serum (cat. No. 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat. No. 26050-088, invitrogen, Carlsbad, CA, USA), 1 ⁇ g / ML Geneticin, F-10 Nutrient Mixture (Ham) medium (cat. No.
  • test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mmol / L HEPES / 0.2% BSA (cat. No. A3803, Sigma, St. Louis, MO, USA) and adjusted to 6 times the final concentration.
  • PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by ⁇ 7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicating EC 20 was added alone after 150 seconds. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after the addition of ACh to calculate RLU (Max-Min), and the ratio of RLU (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Data of ⁇ 7 PAM activity of representative compounds is shown in Table 24, Table 25 and Table 26.
  • Test Example 2 Evaluation of cognitive function using mouse novel object recognition test (hereinafter referred to as mORT) Decreased memory for known objects in a novel object recognition test using Slc: ddY mice (male, SLC Japan) weighing 25-30 g depending on the time interval between the first trial (training) and the second trial (test) When a second trial is performed 24 hours later, significant forgetting is observed. Therefore, the compound of the present invention was administered before the first trial, and the memory enhancing action in the second trial was evaluated. As a result, the compounds of Examples 1, 45, 51, 79 and 124 showed a significant memory enhancing action at 3 or 10 mg / kg (oral).
  • mORT mouse novel object recognition test
  • the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof has a strong ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7hnAChR) modulating action, and the central nervous system ( CNS) and / or peripheral nervous system (PNS) cholinergic diseases, smooth muscle contraction diseases, endocrine diseases, neurodegenerative diseases, diseases such as inflammation or pain, and withdrawal symptoms caused by addictive drug abuse It is useful for treatment and / or prevention of diseases and the like.

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Abstract

La présente invention concerne un composé qui présente un fort effet de régulation du récepteur nicotinique à l'acétylcholine α7 (nAChR α7) et est utile en tant que médicament thérapeutique des maladies associées à la capacité cholinergique du système nerveux central (SNC) et/ou du système nerveux périphérique (SNP), des maladies associées à la contraction des muscles lisses, des maladies endocriniennes, des maladies associées à une neurodégénérescence, etc. L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable dudit composé [Dans la formule, X-Y-Z représente N-CO-NR3AR3B ou analogue, A représente un phényle éventuellement substitué ou analogue, B représente un imidazole éventuellement substitué ou analogue, R2A, R2B, R2C et R2D peuvent être identiques ou différents et représentent des atomes d'hydrogène ou analogue, et R3A et R3B peuvent être identiques ou différents et représentent des cycloalkyles en C3-10 éventuellement substitués ou analogues].
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WO1993020061A1 (fr) * 1992-04-01 1993-10-14 The University Of Toledo Imidazoles substitues de 4-[4'-piperidinyl ou de 3'-pirrolidinyl] en tant qu'antagonistes du recepteur h3 et utilisations therapeutiques
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WO2007070433A2 (fr) * 2005-12-12 2007-06-21 Merck & Co., Inc. Derives de 2-arylthiazole en tant que modulateurs du recepteur cxcr3
WO2013083741A1 (fr) * 2011-12-08 2013-06-13 Boehringer Ingelheim International Gmbh 1,2,4-triazoles comme modulateurs allostériques de l'activité des récepteurs mglu5 pour le traitement de la schizophrénie ou de la démence
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WO1996016049A1 (fr) * 1994-11-23 1996-05-30 Glaxo Wellcome Inc. DERIVES OXAZOLES UTILISES EN TANT QU'ANTAGONISTES DES RECEPTEURS ADRENERGIQUES α-1 C
WO2007070433A2 (fr) * 2005-12-12 2007-06-21 Merck & Co., Inc. Derives de 2-arylthiazole en tant que modulateurs du recepteur cxcr3
WO2013083741A1 (fr) * 2011-12-08 2013-06-13 Boehringer Ingelheim International Gmbh 1,2,4-triazoles comme modulateurs allostériques de l'activité des récepteurs mglu5 pour le traitement de la schizophrénie ou de la démence
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