WO2012046882A1 - 1,4-oxazepane derivatives - Google Patents

1,4-oxazepane derivatives Download PDF

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Publication number
WO2012046882A1
WO2012046882A1 PCT/JP2011/073745 JP2011073745W WO2012046882A1 WO 2012046882 A1 WO2012046882 A1 WO 2012046882A1 JP 2011073745 W JP2011073745 W JP 2011073745W WO 2012046882 A1 WO2012046882 A1 WO 2012046882A1
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Prior art keywords
group
optionally substituted
compound
alkyl
ring
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English (en)
French (fr)
Inventor
Yuji Ishichi
Masami Yamada
Taku Kamei
Ikuo Fujimori
Yoshihisa Nakada
Tomoya Yukawa
Nobuki Sakauchi
Yusuke Ohba
Tetsuya Tsukamoto
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to EA201390491A priority Critical patent/EA201390491A1/ru
Priority to NZ60849911A priority patent/NZ608499A/en
Priority to GEAP201113078A priority patent/GEP20156295B/en
Priority to PH1/2013/500657A priority patent/PH12013500657A1/en
Priority to US13/877,810 priority patent/US20130267494A1/en
Priority to KR1020137011425A priority patent/KR20130116073A/ko
Priority to CA2813911A priority patent/CA2813911A1/en
Priority to SG2013015268A priority patent/SG188346A1/en
Priority to EP11778987.5A priority patent/EP2625170A1/en
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Priority to CN201180059036.1A priority patent/CN103261176B/zh
Priority to JP2013515601A priority patent/JP5873487B2/ja
Priority to AU2011313150A priority patent/AU2011313150A1/en
Priority to BR112013008420A priority patent/BR112013008420A2/pt
Priority to MX2013003749A priority patent/MX2013003749A/es
Publication of WO2012046882A1 publication Critical patent/WO2012046882A1/en
Priority to TNP2013000097A priority patent/TN2013000097A1/fr
Priority to IL225189A priority patent/IL225189A0/en
Priority to ZA2013/02112A priority patent/ZA201302112B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D413/06—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 only aliphatic carbon atoms
    • 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
    • C07D413/10—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 aromatic 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to heterocyclic compounds having a superior monoamine reuptake inhibitory activity, and useful as prophylactic or therapeutic drugs for depression, anxiety, attention deficit hyperactivity disorder, climacteric disorder, pain, stress urinary incontinence, mixed urinary incontinence and the like.
  • Serotonin (5-HT) , norepinephrine (NE) and dopamine (DA) which are monoamine neurotransmitters, are widely present in the brain, and have various functions such as
  • dopamine transporter DAT
  • Compounds showing a monoamine reuptake inhibitory activity are known to be effective for various diseases including psychoneurotic diseases such as . depression and the like, and widely used as therapeutic, drugs.
  • Compounds that inhibit reuptake of 3 kinds of serotonin, norepinephrine and dopamine are called Triple Reuptake Inhibitors, and expected to provide therapeutic drugs for psychoneurotic diseases and the like.
  • TCA selective serotonin reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • SNRI selective serotonin-norepinephrine reuptake inhibitor
  • norepinephrine-dopamine reuptake inhibitors such as bupropion and the like, monoamine oxidase inhibitor and the like have been used.
  • TCA selective serotonin reuptake inhibitor
  • SNRI selective serotonin-norepinephrine reuptake inhibitor
  • norepinephrine-dopamine reuptake inhibitors such as bupropion and the like
  • monoamine oxidase inhibitor and the like monoamine oxidase inhibitor and the like
  • TCA TCA, SSRI and SNRI have been reported to be useful for " improving the symptoms of psychoneurotic diseases such as depression as well as anxiety, attention deficit hyperactivity disorder and the like,, and neurodegenerative diseases such as Alzheimer's disease and the like; pain treatment of diabetic pain, muscle fibrosis and the like; or as therapeutic drugs for digestive tract diseases such as irritable bowel syndrome and the like.
  • psychoneurotic diseases such as depression as well as anxiety, attention deficit hyperactivity disorder and the like
  • neurodegenerative diseases such as Alzheimer's disease and the like
  • pain treatment of diabetic pain, muscle fibrosis and the like or as therapeutic drugs for digestive tract diseases such as irritable bowel syndrome and the like.
  • monoamine reuptake inhibitor is also effective as a therapeutic drug for lower urinary tract diseases such as overactive bladder, stress urinary incontinence and the like, particularly, stress urinary incontinence.
  • Stress urinary incontinence is a disease characterized by a symptom of urine leakage when intravesical pressure rises when the abdominal pressure rises transiently as a result of coughing, sneezing or light exercise. This . disease is often found in female, and considered to be
  • Patent document 1 (WO2009/056520) describes, as azabicyclo [3.2.1] octane derivatives having a monoamine reuptake inhibitory action and useful as an antidepressant, a compound represented by the formula:
  • Patent document 2 (WO97/30997) describes, as tropane derivatives having a monoamine reuptake inhibitory action and useful as therapeutic drugs for obesity and Parkinson' s disease, a compound represented by the formula:
  • Patent document 3 (US3018222) describes, as an oxazep derivative useful as a central nervous system stimulant or anorectic agent, the following compound:
  • Patent document 4 (US4010166) describes, as 1, -oxazepine derivatives useful as antidepressants, a compound represented by the formula:
  • Patent document 5 (WO2009/119528) describes, as a homopiperazinone derivative having a monoamine reuptake inhibitory action and useful as an antidepressant, a compound represented by the formula:
  • Patent document 6 describes, as a piperidine derivative having a monoamine reuptake inhibitory action, a compound represented by the formula:
  • patent document (EP109622A1) describes the following compounds :
  • non-patent document 1 Annual Reports in Medicinal Chemistry, 2007, vol. 42, p.13-26
  • non-patent document 2 The Annals of Pharmacotherapy, 2002, 20 vol. 36, No. 10, p.1577-1589
  • non-patent* document 3 The Journal of Family Practice, 1982, vol. 14, p.935-936
  • non-patent document 4 American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 2003, vol. 25 285, p.R356-R365
  • non-patent document 5 American Journal of Physiology-Renal Physiology, 2004, vol. 287, p.F434-F441
  • non-patent document 6 American Journal of Physiology-Renal Physiology, 2007, vol. 293, p.F920-F926
  • non-patent document 7 International Journal of Gynecology and Obstetrics, 2004, vol. 86, p.S38-S52 non-patent document 8: American Journal of Physiology-Renal
  • non-patent document 9 BJU International, 2004, vol. 93, p.311-318
  • non-patent document 10 BJU International, 2008, vol. 102, p.214-218
  • non-patent document 12 European Journal of Organic Chemistry, 2009, No. 22, p.3726-3731
  • incontinence mixed urinary incontinence and the like, and having superior properties in the efficacy, duration of action, specificity, lower toxicity and the like.
  • the present invention aims to provide a compound having a chemical structure different from the structures of known compounds including the aforementioned compounds, as well as a monoamine reuptake inhibitory activity and the like, and a novel prophylactic or therapeutic drug, for depression,
  • anxiety attention deficit hyperactivity disorder
  • climacteric disorder pain, stress urinary incontinence, mixed urinary incontinence and the like.
  • the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that a compound represented by the following formula (I) has a superior monoamine (serotonin, norepinephrine, dopamine etc.) reuptake inhibitory activity, which resulted in the completion of the present invention.
  • the present invention relates to:
  • ring A is an optionally substituted 6-membered aromatic and a group represented by
  • rings B 1 - B 6 are optionally further substituted provided a hydrogen atom bonded to a nitrogen atom
  • rings B 1 - B 6 is not substituted, and R is hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, an optionally substituted Ci-6 alkyl group, an optionally
  • Ci-6 alkoxy group an optionally substituted Ci_6 alkyl-carbonyl group, .an optionally substituted carbamoyl group, an optionally substituted C 6 -i2 aryloxy group, an optionally substituted aromatic heterocyclyl-oxy group, an optionally substituted aromatic heterocyclic group, or an optionally substituted nonaromatic heterocyclic group, wherein substituents on ring A are optionally bonded to form, together with ring A, optionally substituted 9- or 10-membered aromatic - fused ring,
  • ring A is a benzene ring
  • R is R X -CH 2 - (R x is a phenoxy group optionally substituted by. substituent (s) selected from a halogen atom and a methoxy group) ,
  • ring A is an optionally substituted 6-membered aromatic ring
  • rings B 1 - B 6 are optionally further substituted, provided a hydrogen atom bonded to a nitrogen atom
  • rings B 1 - B 6 is not substituted, and R' is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, an optionally substituted Ci_ 6 alkyl group, an optionally
  • Ci-e alkoxy group or an optionally substituted carbamoyl group
  • substituents on ring A are optionally bonded to form, together with ring A, optionally substituted 9- or 10-membered aromatic fused ring,
  • ring A is a benzene ring
  • R' is R X -CH 2 - (R x is a phenoxy group optionally substituted by substituent (s) selected from a halogen atom and a methoxy group) ,
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • the medicament of [13] which is a prophylactic or therapeutic drug for depression, anxiety, attention deficit hyperactivity disorder, climacteric disorder, pain, stress urinary incontinence or mixed urinary incontinence,
  • [17] use of the compound of [1] or [2] or a salt thereof for the production of a prophylactic or therapeutic drug for , depression, anxiety, attention deficit hyperactivity disorder, climacteric disorder, pain, stress urinary incontinence or mixed urinary incontinence,
  • [18] the compound of [1] or [2] or a salt thereof for the prophylaxis or treatment of depression, anxiety, attention deficit hyperactivity disorder, climacteric disorder, pain, stress urinary incontinence or mixed urinary incontinence, and the like.
  • the compound of the present invention has a superior monoamine (serotonin, norepinephrine, dopamine etc.) reuptake inhibitory activity, it is useful. as a prophylactic or therapeutic drug for, for example, depression, anxiety, attention deficit hyperactivity disorder, climacteric
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the "Ci_ 6 alkyl group” and “Ci_6 alkyl” in a substituent include a linear or branched chain Ci- 6 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1- methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2- dimethylpropyl, . hexyl, 2-methylpentyl, 3-methylpentyl, 1,2- dimethylbutyl, 1, 2, 2-trimethylpropyl and the like.
  • examples of the "Ci_ 6 alkoxy group” and “Ci-e alkoxy” in a substituent include linear or branched chain Ci-6 alkoxy ' group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy,
  • examples of the "C 3 -. 6 cycloalkyl group” and xv C 3- . 6 cycloalkyl" in a substituent include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • examples of the "C 3 - 6 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • examples of the "C 6 _i 2 aryl group” and “C6-12 aryl” in a substituent include phenyl, naphthyl (1-naphthyl, 2-naphthyl) and the like.
  • examples of the "C 7 _i 2 aralkyl group” and “C 7 -i2 aralkyl” in a substituent include benzyl, 2-phenylethyl, 1-phenylethyl , 3-phenylpropyl , 4- phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • substituents include a 4- to 7-membered (preferably 5- or 6- membered) monocyclic aromatic heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 - 4 hetero atoms selected from an oxygen atom, a sulfur atom (said sulfur atom is optionally oxidized) and a nitrogen atom, and a condensed aromatic heterocyclic group.
  • condensed aromatic heterocyclic group examples include groups wherein these 4- to 7-membered monocyclic aromatic heterocyclic groups are condensed with 1 or 2 selected from a 5- or 6-membered aromatic heterocycle (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle (e.g., thiophene) containing one sulfur atom, and a benzene ring and the like, and the like.
  • a 5- or 6-membered aromatic heterocycle e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle e.g., thiophene
  • pyridazinyl e.g., 3-pyridazinyl, 4-pyridazinyl
  • pyrazolyl e.g., 1-pyrazolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • isothiazolyl e.g., 3-isothiazolyl, 4-isothiazolyl, 5- isothiazolyl
  • oxazolyl e.g., 2-oxazolyl, 4-oxazolyl, 5- oxazolyl
  • isoxazolyl e.g., 3-isoxazolyl, 4-isoxazolyl, 5- isothiazolyl
  • oxazolyl e.g., 2-oxazolyl, 4-ox
  • triazinyl e.g., 1,2, 4- triazin-3-yl, 1, 2, 4-triazin-5-yl, 1, 2, 4-triazin-6-yl
  • triazinyl e.g., 1,2, 4- triazin-3-yl, 1, 2, 4-triazin-5-yl, 1, 2, 4-triazin-6-yl
  • condensed aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl) , isoquinolyl (e . g. , 3-isoquinolyl) , quinazolyl (e.g., 2-quinazolyl, 4- quinazolyl) , quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl) , • benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl, 4- benzofuranyl,—5-benzcfuranyl,—6-benzofuranyl , 7-benzofuranyl) , benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl) ,
  • benzoxazolyl e.g., 2-benzoxazolyl
  • benzisoxazolyl e.g., 7- benzisoxazolyl
  • benzothiazolyl e.g., 2-benzothiazolyl, 6- benzothiazolyl
  • benzimidazolyl e.g., benzimidazol-l-yl, benzimidazol-2-yl, benzimidazol-5-yl
  • benzotriazolyl e.g., lH-1, 2, 3-benzotriazol-l-yl, lH-1, 2, 3-benzotriazol-5-yl
  • indolyl e.g., indol-l-yl, indol-2-yl, indol-3-yl, indol-5- yl
  • indazolyl e.g., 2H-indazol-3-yl, lH-
  • heterocyclyl-" in a substituent include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic nonaromatic
  • heterocyclic group containing, as a ring constituting atom besides carbon atom, 1 - 4 hetero atoms selected from an oxygen atom, a sulfur atom (said sulfur atom is optionally oxidized) and a nitrogen atom, and a condensed nonaromatic heterocyclic group.
  • the condensed nonaromatic heterocyclic ⁇ group include groups wherein these 4- to 7- membered monocyclic nonaromatic heterocyclic groups are condensed with 1 or 2 selected from a 5- or 6-membered
  • aromatic or nonaromatic heterocycle e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • aromatic or nonaromatic heterocycle e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • heterocycle e.g., thiophene
  • the monocyclic nonaromatic heterocyclic group and condensed nonaromatic heterocyclic group may be crosslinked.
  • monocyclic nonaromatic heterocyclic groups such as azetidinyl (e.g., 2-azetidinyl) , pyrrolidinyl (e.g., 2-pyrrolidinyl, 3- pyrrolidinyl) , piperidyl (e.g., 2-piperidyl, 3-piperidyl, 4- piperidyl), homopiperidinyl (e.g., 2-homopiperidyl, 3- homopiperidyl, 4-homopiperidyl) , tetrahydropyridyl (e.g.,
  • dihydropyridyl e.g., 2,3- dihydropyridin-4-yl, 1, 2-dihydropyridin-l-yl, 1,2- dihydropyridin-3-yl
  • morpholinyl e.g., 2-morpholinyl
  • thiomorpholinyl e.g., 2-thiomorpholinyl
  • 1,1-dioxide- thiomorpholinyl e.g., 1, l-dioxide-thiomorpholin-2-yl
  • piperazinyl e.g., 2-piperazinyl
  • hexamethyleneiminyl e.g.,
  • 2-hexamet yleneiminyl 2-hexamet yleneiminyl
  • oxazolidinyl e.g., 2-oxazolidinyl
  • thiazolidinyl e.g., 2-thiazolidinyl
  • imidazolidinyl e.g., 2-imidazolidinyl
  • oxazolinyl e.g., 2-oxazolinyl
  • thiazolinyl e.g., 2-thiazolinyl
  • imidazolinyl e.g., 2- . imidazolinyl
  • dioxolyl e.g ' . , 1, 3-dioxol-4-yl
  • dioxolanyl e.g., 1, 3-dioxolan-4-yl
  • dihydrooxadiazolyl e.g., 4,5- dihydro-1, 2, -oxadiazol-3-yl, 2, 3-dihydro-l, 3, 4-oxadiazol-5- yl
  • pyranyl e.g., 2-pyranyl, 4-pyranyl
  • ' tetrahydropyranyl e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl , 4- tetrahydropyranyl
  • thiopyranyl e.g., 4-thiopyranyl
  • pyrazolidinyl e.g., 3-pyrazolidinyl
  • pyrazolinyl e.g., 3-pyrazolinyl
  • tetrahydropyrimidinyl e.g., 2-tetrahydropyrimidinyl
  • hexahydropyrimidinyl e.g., 2-hexahydropyrimidinyl
  • dihydrotriazolyl e.g., 2, 3-dihydro-lH-l, 2, 3-triazol-4-yl, 4, 5-dihydro-lH-l, 2, -triazol-3-yl
  • tetrahydrotriazolyl e.g., 2, 3, 4, 5-tetrahydro-lH-l, 2, 3-triazol-4-yl
  • thiazinyl e.g., 1, 4-thiazin-2-yl
  • 1, 1-dioxide-thiazinanyl e.g., 1,.1-dioxide- 1, 2-thiazinan-3-yl
  • dihydropyridazinyl e.g., 1,6- dihydropyridazin-3-yl, 2, 3-dihydropyridazin-3-yl
  • dihydropyridazinyl e.g., 1,6- dihydropyridazin-3-yl, 2, 3-dihydropyrida
  • tetrahydropyridazinyl e.g., 1, , 5, 6-tetrahydropyridazin-3- yl
  • dihydrothioxazinyl e.g., 2, 3-dihydro-l, 4-thioxazin-3- yl
  • dihydrothiazinyl e.g., 3, 4-dihydro-2H-l, 4-thiazin-5-yl
  • dioxanyl e.g., 1, 4-dioxan-2-yl
  • dihydroindolyl e.g., 2, 3-dihydro-lH-indol-2-yl
  • dihydroisoindolyl e.g., 2, 3-dihydro-lH-isoindol-l-yl, 1,3- dihydro-2H-isoindol-2-yl
  • dihydrobenzofuranyl e.g., 2,3- dihydro-l-benzofuran-5-yl
  • dihydrobenzodioxinyl e.g., 2,3- dihydro-1, 4-benzodioxinyl
  • dihydrobenzodioxepinyl e.g., 3,4- dihydro-2H-l, 5-benzodioxepin-7-yl
  • tetrahydrobenzofuranyl e.g., 4, 5, 6, 7-tetrahydro-l-benzofuran-3-yl
  • chromenyl e.g., 4H-chromen-2-yl, 2H-chromen-3-yl, 2H-chromen-7
  • dihydroquinolinyl e.g., 1, 2-dihydroquinolin-4-yl, 3,4- dihydroquinolin-2 (IH) -yl
  • tetrahydroquinolinyl e.g., 1, 2-dihydroquinolin-4-yl, 3,4- dihydroquinolin-2 (IH) -yl
  • tetrahydrobenzoazepinyl e.g., 2, 3, , 5-tetrahydro-lH- benzo [c] azepin-l-yl ⁇
  • benzodioxolyl e.g., 1 , 3-benzodioxol-5- yl
  • benzothiazine e.g., 3, 4-dihydro-2H-l, -benzothiazin-2- yl
  • examples of the- "cyclic amino" of the "cyclic amino group” and substituent include cyclic amino groups such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, homopiperidino, thiomorpholino, 1,1-dioxide- thiomorpholino, morpholino, 1-piperazinyl, 1-imidazolidinyl, 1-pyrrolyl, 1-imidazolyl, 1-dihydropyridazinyl (e.g., 2,3- dihydropyridazin-2-yl) , 1-hexahydropyrimidinyl,
  • cyclic amino groups such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, homopiperidino, thiomorpholino, 1,1-dioxide- thiomorpholino, morpholino, 1-piperazinyl, 1-imidazolidinyl, 1-pyrrolyl, 1-imidazolyl, 1-
  • tetrahydropyridyl e. g. , 1, 2, 3, 6-tetrahydropyridin-l-yl
  • 1-hexamethyleneiminyl 3-oxazolidinyl
  • 3-thiazolidinyl 1- imidazolinyl
  • 1-pyrazolidinyl 1-pyrazolinyl
  • 1- tetrahydropyrimidinyl dihydrotriazolyl (e.g., 2 , 3-dihydro-lH- 1, 2, 3-triazol-l-yl, 4 , 5-dihydro-lH-l, 2 , 4-triazol-l-yl)
  • tetrahydrotriazolyl e.g., 2, 3, 4, 5-tetrahydro-lH-1 , 2, 3- triazol-l-yl
  • 1-dioxide-thiazinanyl e.g., 1, 1-dioxide-l, 2- thiazirian-2-yl
  • 3- tetrahydroquinazolinyl e.g., 1, 2, 3, 4-tetrahydroquinazolin-3- yl
  • 3-tetrahydropyrido [3, 2-d] pyrimidinyl e.g., 1,2,3,4- tetrahydropyrido [3, 2-d] pyrimidin-3-yl
  • 3-tetrahydropteridinyl e.g., 1,2,3,4- tetrahydropyrido [3, 2-d] pyrimidin-3-yl
  • 6-membered aromatic ring for ring A include benzene ring, 6-membered aromatic heterocycle
  • nitrogen atoms e.g., pyridine, pyrazine, pyrimidine, pyridazine, triazine
  • nitrogen atoms e.g., pyridine, pyrazine, pyrimidine, pyridazine, triazine
  • a halogen atom e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
  • the number of the substituents is 1 to 5, preferably 1 to 3, more preferably 1 or 2.
  • Examples of the "9 or 10-membered aromatic fused ring" of the "optionally substituted 9 or 10-membered aromatic fused ring” formed, together with ring A, by the substituents on ring A bonded to each other include naphthalene, benzofuran, indazole and the like.
  • Examples of the substituent that the "9 or 10-membered aromatic fused ring” optionally has include those similar to the substituents that the 6-membered aromatic ring for ring A optionally has.
  • the number of the substituents is 1 to 5, preferably 1 to 3, more preferably 1 or 2.
  • Ring A is preferably an optionally substituted benzene ring.
  • benzene ring a benzene ring substituted by 1 to 3 ' (preferably 2) substituents
  • a halogen atom selected from a halogen atom, a Ci- 6 alkyl group and a Ci- 6 alkoxy group is preferable, and a benzene ring substituted by
  • ring A is preferably an optionally substituted benzene ring, more preferably, a benzene ring optionally substituted 1 to 3 (preferably 2) substituents selected from a halogen atom, a Ci- 6 alkyl group and a Ci-e alkoxy group, more preferably, a benzene ring optionally substituted 1 to 3 (preferably 1 or 2) halogen atoms
  • ring A is preferably an optionally substituted benzene ring, more preferably, a benzene ring optionally substituted by 1 to 3 (preferably 2) substituents selected from a halogen atom (preferably, a fluorine atom, a chlorine atom) and a Ci-e alkyl group (preferably, methyl) , more preferably, a benzene ring substituted by 2 substituents selected from a fluorine atom and a chlorine atom.
  • a halogen atom preferably, a fluorine atom, a chlorine atom
  • Ci-e alkyl group preferably, methyl
  • Preferable examples of ring A include ⁇ ⁇
  • preferable specific example ring A include,
  • Rings B 1 - B 6 are optionally further substituted.
  • rings B 1 - B 6 is not substituted.
  • substituents that rings B 1 - B 6 optionally further have include substituents selected from
  • a halogen atom e.g • r fluorine atom, a chlorine atom, bromine atom, an iodine atom
  • Ci-g alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci_ 6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • the number of the substituents is 1 to 5, preferably 1 to 3, more preferably 1 or 2.
  • rings B 1 - B 6 optionally further have are preferably a hydroxy group and a Ci-. 6 alkoxy group (preferably, methoxy).
  • rings B 1 - B 6 is preferably one wherein they are substituted by a hydroxy group or a Ci_ 6 alkoxy group (preferably, methoxy) besides ring A and R or one wherein they do not have substituent other than ring A and R, more
  • rings B - B are more preferably substituted by a hydroxy group or a Ci- 6 alkoxy group
  • rings B 1 - B 6 preferably do not have substituent other than ring A and R' .
  • the "optionally substituted carboxy group" for R is preferably a carboxy group or a Ci- 6 alkoxy-carbonyl group (preferably, ethoxycarbonyl) .
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • R D and R E are each independently,
  • examples of the substituent that the cyclic amino group" of the "optionally substituted cyclic amino group” optionally has include substituents selected from .
  • (31) a C3-6 cycloalkylsulfonyl group
  • the number of the substituents is 1 to 4, preferably 1 to 3.
  • the "optionally substituted amino group" for R is preferably
  • a mono- or di- (Ci_ 6 alkylsulfonyl) amino group preferably, methylsulfonylamino, ethylsulfonylamino
  • a mono- or di- (aromatic heterocyclyl-sulfonyl) amino group preferably, pyridylsulfonylamino (preferably, pyridin-3- ylsulfonylamino) ,
  • Ci-6 alkyl group preferably, methyl, ethyl
  • 1 to 3 preferably, 1 or 2
  • halogen atom preferably, fluorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • an aromatic heterocyclic group preferably, triazolyl (preferably, 1, 2, 4-triazol-l-yl) )
  • dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • Ci_6 alkyl-carbonyl group preferably, acetyl
  • Ci-6 alkoxy-carbonyl group preferably, ethoxycarbonyl
  • Ci-6 alkylsulfonylamino group preferably, methylsulfonylamino
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a C 7 _i2 aralkyl group preferably, benzyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro- 1, 2, 4-oxadiazol-3-yl)
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro- 1, 2, 4-oxadiazol-3-yl)
  • Ci-6 alkyl group preferably, methyl
  • R D and R E are each independently,
  • Ci-6 alkyl group preferably, methyl, ethyl
  • an optionally substituted cyclic amino group preferably, a cyclic amino group (preferably, 1-imidazolidinyl ) optionally substituted by 1 or 2 oxo groups) .
  • the "optionally substituted amino group" for R is preferably
  • a mono- or di-(Ci-6 alkyl-carbonyl) amino group preferably, acetylamino
  • a mono- or di-(Ci-6 alkyl-carbonyl) amino group preferably, acetylamino
  • Ci-6 alkyl group of the "optionally substituted Ci_ 6 alkyl group” for R is preferably methyl, ethyl, propyl or isopropyl .
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl
  • a nonaromatic heterocyclic group optionally substituted by an oxo group or a thioxo group
  • (21) a mono- or di-Ci- 6 alkylsulfamoyl group
  • Ci-6 alkyl group optionally .substituted by a hydroxy group, or
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 3 _ 6 cycloalkyl group, (5) a C3-6 cycloalkyloxy group,
  • R 1 is
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • R K and R L are each independently,
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a Ci- 6 alkoxy group, or
  • Ci-6 alkyl group (ii) a Ci-6 alkyl group, and R w and R° are each independently,
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a carboxy group,
  • Ci-6 alkoxy group optionally substituted by a Ci-6 alkoxy group
  • the number of the substituents is 1 to 4, preferably 1 to 3.
  • Ci_6 alkyl group for R is preferably a Ci- 6 alkyl group (preferably, methyl, ethyl, propyl,, isopropyl) optionally substituted by 1 to 4
  • a halogen atom preferably, a fluorine atom
  • Ci- 6 alkyl a mono- or di- (Ci- 6 alkyl) carbamoyl group (preferably, isopropylcarbamoyl) (said Ci- 6 alkyl is optionally substituted by a carboxy group) ,
  • Ci-6 alkoxy group preferably, methoxy, ethoxy, propoxy
  • 1 to 3 preferably, 1 or 2
  • Ci-6 alkoxy-carbonyl group preferably,
  • Ci-6 alkyl-carbonyloxy group preferably, acetyloxy
  • Ci-6 alkylsulfonyloxy group preferably,
  • a halogen atom preferably, a fluorine atom, a chlorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • Ci-6 alkoxy-carbonyl group preferably, methoxycarbonyl
  • Ci-6 alkylsulfonyl group (preferably,
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group or a thioxo group, and
  • a C7- 2 aralkyloxy group preferably, benzyloxy
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl)
  • oxo group optionally substituted by an oxo group
  • pyridyloxy (preferably, pyridin-2-yloxy) ) optionally
  • Ci-6 alkoxy-carbonyl group preferably, methoxycarbonyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, -oxadiazol-3- yl, 2, 3-dihydro-l, 3, 4-oxadiazol-5-yl )
  • a Ci_6 alkylthio group preferably, methylthio
  • Ci-6 alkylsulfinyl group preferably, methylsulfinyl
  • Ci-6 " alkylsulfonyl group preferably, methylsulfonyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • an aromatic heterocyclyl-amino group preferably, pyridylamino (preferably, pyridin-2-ylamino) , pyrimidinylamino (preferably, pyrimidin-2-ylamino) , benzooxazolylamino
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl)
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl)
  • optionally substituted by an oxo group preferably,
  • Ci-6 alkyl group preferably, methyl, ethyl
  • a Ci-6 alkyl group optionally, substituted by a hydroxy group
  • Ci-6 alkyl group preferably, methyl, ethyl, propyl, isopropyl
  • a Ci-6 alkyl group optionally substituted by 1 to 3
  • a halogen atom preferably, a fluorine atom
  • a cyano group preferably, a hydroxy group
  • Ci-6 alkoxy group ' preferably, methoxy, ethoxy, isopropoxy, isobutoxy
  • 1 to 3 substituents selected from a halogen atom (preferably, a fluorine atom) and a C 3 - 6 cycloalkyl group (preferably,
  • an aromatic heterocyclyl-oxy group preferably, pyridyloxy (preferably, pyridin-2-yloxy) , pyrimidinyloxy
  • a halogen atom preferably, a fluorine atom, a chlorine atom
  • a cyano group preferably, a carboxy group
  • a mono- or di-Ci- 6 alkylamino group (preferably, methylamino, dimethylamino)
  • N-(aromatic heterocyclyl-carbonyl) -N- (Ci_6 alkyl)amino group preferably, N- (pyridylcarbonyl) -N-.
  • Ci- 6 ' alkylthio group preferably, methylthio
  • Ci-6 alkylsulfonyl group (preferably,
  • a Ci-6 alkyl-carbonyloxy group preferably, acetyloxy
  • a C 6 -i2 aryloxy group preferably, phenoxy
  • 1 to 3 preferably, 1 substituents selected from a nonaromatic heterocyclic group (preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group, and a carboxy group
  • an aromatic heterocyclic group preferably, pyridyl (preferably, pyridin-2-yl) , pyrazolyl (preferably, pyrazol-l-yl) , isoxazolyl (preferably, isoxazol-5-yl) , triazolyl (preferably, lH-1, 2, 4-triazol-l-yl) , tetrazolyl
  • a cyclic amino group preferably, 1- pyrrolidinyl, piperidino, 1-imidazolidinyl, morpholino, 8-oxa- 3-azabicyclo [3.2.1] octan-3-yl
  • 1 to 3 preferably, 1 or 2
  • substituents selected from a halogen atom preferably, a fluorine atom, a chlorine atom
  • a nonaromatic heterocyclic group preferably, dihydropyridyl (preferably, 1, 2-dihydropyridin-l-yl) ,
  • dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally . substituted by 1 to 3 (preferably, 1 or 2) substituents selected from a halogen atom (preferably, a chlorine atom) and an oxo group,
  • Ci-6 alkoxy group preferably, methoxy, isopropoxy
  • a halogen atom preferably, a. fluorine atom, a chlorine atom
  • Ci-6 alkyl group preferably, methyl, tert- butyl
  • a nbnaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5- dihydro-1, 2, -oxadiazol-3-yl)
  • oxo group optionally substituted by an oxo group
  • Ci-6 alkoxy group preferably, methoxy, ethoxy
  • Ci-6 alkylsulfonyl group (preferably,
  • an aromatic heterocyclic group preferably, oxadiazolyl (preferably, 1, 2, 4-oxadiazol-3-yl) , tetrazolyl
  • Ci_ 6 alkyl group preferably, methyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a C 7 -i2 aralkyl group preferably, benzyl
  • a C 7 -i2 aralkyl group preferably, benzyl
  • optional-ly—subs-t-i-truted—by—a-nonaromat c—heterocyctrc ⁇ grOup preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro-
  • an aromatic heterocyclic group preferably, pyridyl (preferably, pyridin-2-yl, pyridin-3-yl) , thiazolyl (preferably, thiazol-5-yl) ) optionally substituted by 1 to 3 (preferably, 1) substituents selected from
  • Ci_6 alkyl group preferably, methyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a cyclic amino group preferably, 1- pyrrolidinyl, morpholino, 1 , 1-dioxide-thiomorpholino
  • a nonaromatic heterocyclic group preferably, dihydropyridyl (preferably, 1, 2-dihydropyridin-3-yl) ,
  • tetrahydrofuryl preferably, tetrahydrofuran-2-yl
  • Ci-6 alkyl-carbonyl group preferably, acetyl, ethylcarbonyl
  • (x) a cyclic amino-carbonyl group (preferably, pyrrolidin-l-ylcarbonyl) ,
  • Ci-6 alkyl group preferably, methyl
  • Ci-6 alkyl group preferably, methyl, ethyl, isopropyl
  • a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • a halogen atom preferably, a fluorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • a cyclic amino group preferably, morpholino
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, -oxadiazo ⁇ -J- yl) ) optionally substituted by an oxo group, or
  • an aromatic heterocyclic group preferably, pyridyl (preferably, pyridin-2-yl, pyridin-3-yl) , furyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • Ci-6 alkyl group preferably, methyl, ethyl
  • a hydroxy group preferably, methyl, ethyl
  • R K and R L are each independently,
  • Ci_6 alkyl group preferably, methyl, ethyl, tert-butyl
  • 1 to 3 preferably, 1 substituents selected from a hydroxy group and a Ci_ 6 alkoxy group (preferably, methoxy) , or.
  • Ci-6 alkoxy group preferably, methoxy
  • Ci-6 alkyl group preferably, methyl
  • R and R° are each independently,
  • Ci-6 alkyl group preferably, methyl
  • Ci-6 alkoxy group preferably, methoxy
  • an aromatic heterocyclic group preferably, pyrazolyl (preferably, pyrazol-l-yl, pyrazol-3-yl) , oxadiazolyl
  • Ci-6 alkyl group preferably, methyl
  • substituents selected from a halogen atom (preferably, a fluorine atom) , a hydroxy group and a carboxy group,
  • Ci-6 alkoxy group preferably, ethoxy, tert- butoxy
  • Ci_ 6 alkoxy group optionally substituted by a Ci_ 6 alkoxy group
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a cyclic amino group preferably, 1-azetidinyl, 1- pyrrolidinyl, piperidino, 1-imidazolidinyl, 1- dihydropyridazinyl (preferably, 2 , 3-dihydropyridazin-2-yl ) , 1- hexahydropyrimidinyl, 2-dihydroisoindolyl (preferably, 1,3- dihydro-2H-isoindol-2-yl) , 3-dihydroquinazolinyl (preferably, 3, -dihydroquinazolin-3-yl) , 3-tetrahydroquinazolinyl
  • Ci-6 alkyl group preferably, methyl
  • Ci-6 alkoxy-carbonyl group preferably, ethoxycarbonyl
  • a nonaromatic heterocyclic group " preferably, dih ' ydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group, , and
  • nonaromatic heterocyclic group preferably, 1- dihydropyridyl (preferably, 1, 2-dihydropyridin-l-yl) ,
  • dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by 1 to 3 substituents selected from
  • halogen atom preferably, a chlorine atom
  • Ci-6 alkoxy-carbonyl group preferably, methoxycarbonyl
  • an aromatic heterocyclic group preferably, triazolyl (preferably, 1, 2, 4-triazol-3-yl) , tetrazolyl
  • Ci_ 6 alkyl group preferably, methyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, , 5-dihydro-l , 2 , -oxadiazol-3- yl, 4 , 5-dihydro-l, 3, 4-oxadiazol-2-yl) , dihydrotriazolyl
  • the "optionally, substituted Ci_ 6 alkyl group" for R is preferably a C ⁇ s alkyl group (preferably, methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents selected from
  • Ci_6 alkoxy-Ci-6 alkyl-carbonylamino group preferably, (2- methoxyacetyl) amino, (2-ethoxyacetyl) amino, (2- isopropoxyacetyl) amino
  • Ci- 6 alkylsulfonylamino group preferably,
  • Ci-6 alkoxy-Ci- 6 alkyl-carbonylamino group means a Ci- 6 alkyl-carbonylamino group substituted by a Ci_ 6 alkoxy group.
  • Ci-6 alkoxy group of the "optionally substituted Ci_ 6 alkoxy group” for R is preferably methoxy or ethoxy.
  • substituted Ci_ 6 alkyl group optionally has.
  • the number of the substituents is 1 to 4, preferably 1 to 3, more preferably 1.
  • the number of the substituents that the "Ci-6 alkoxy group" optionally has is preferably 1 or 2.
  • the "optionally substituted Ci- 6 alkoxy group" for R is preferably a Ci-6 alkoxy group, more preferably, methoxy or ethoxy.
  • Ci_ 6 alkyl-carbonyl group for R is preferably acetyl.
  • Ci- 6 alkyl group of the aforementioned "optionally substituted Ci-e alkyl group” optionally has.
  • the number of the substituents is 1 to 4, preferably 1 to 3, more preferably 1.
  • the number of the substituents. that the "Ci_ 6 alkyl-carbonyl group” optionally has is
  • Ci- 6 alkyl-carbonyl group for R is preferably a Cx- 6 alkyl-carbonyl group, more preferably, acetyl.
  • the "optionally substituted carbamoyl group" for R is -CO-NR p R Q
  • R p and R Q are each independently,
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to
  • the "optionally substituted carbamoyl group" for R is preferably -CO-NR p R Q wherein
  • R p and R Q are each independently,
  • Ci-6 alkyl group preferably, methyl, ethyl, isobutyl
  • 1 to 3 preferably 1 or 2 , more preferably 1 substituents selected from
  • Ci-6 alkylsulfonyl group preferably,
  • Ci- 6 alkoxy group preferably, methoxy
  • Ci-6 alkoxy group preferably, methoxy
  • Ci-6 alkylsulfonyl " group preferably, methylsulfonyl
  • C 6 -i2 arylsulfonyl group preferably, phenylsulfonyl
  • Ci-6 alkyl group preferably, methyl
  • halogen atoms preferably, a fluorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • halogen atoms preferably, a fluorine atom
  • C 6 -i2 aryloxy group" for R is preferably phenoxy.
  • Examples of the substituent that the "C 6 -i2 aryloxy group” optionally has include those similar to the substituents that the "Ci-6 alkyl group” of the aforementioned “optionally substituted Ci- 6 alkyl group” optionally has.
  • the number of the substituents is 1 to 4, preferably 1 to 3, more preferably 1.
  • the "optionally substituted C 6 -i2 aryloxy group" for R is preferably a C6-12 aryloxy group (preferably, phenoxy)
  • nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-
  • aromatic heterocyclyl-oxy group of the "optionally substituted aromatic heterocyclyl-oxy group" for R is
  • pyridyloxy preferably, pyridin-3-yloxy, pyridin-4- yloxy
  • heterocyclyl-oxy group optionally has include those similar to the substituents that the "Ci- 6 alkyl group" of the
  • aforementioned "optionally substituted Ci- 6 alkyl group” optionally has.
  • the number of the substituents is 1 to 4, preferably 1 to 3, more preferably 1.
  • aromatic heterocyclyl-oxy group for R is preferably an aromatic heterocyclyl-oxy group (preferably, pyridyloxy (preferably, pyridin-3-yloxy, pyridin- 4-yloxy) ) optionally substituted by 1 to 3 (preferably, 1) substituents selected from
  • Ci-6 alkyl is optionally substituted by a hydroxy group
  • an aromatic heterocyclic group preferably, triazolyl (preferably, lH-1, 2, 4-triazol-3-yl) , tetrazolyl (preferably, tetrazol-5-yl) ) optionally substituted by a Ci-6 alkyl group (preferably, methyl), and
  • dihydrooxadiazolyl preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl
  • dihydrotriazolyl preferably, 4, 5-dihydro-lH-l, 2, 4- triazol-3-yl
  • aromatic heterocyclic group of the "optionally substituted aromatic heterocyclic group” for R is preferably thiazolyl (preferably, thiazol-2-yl) .
  • heterocyclic group optionally has include those similar to the substituents that the "Ci_ 6 alkyl group" of the
  • aforementioned "optionally substituted s alkyl group” optionally has.
  • the number of the substituents is 1 to 4,
  • 0 preferably 1 to 3, more preferably 1.
  • the "optionally substituted aromatic heterocyclic group" for R is preferably an aromatic heterocyclic group
  • thiazolyl preferably, thiazol-2-yl
  • optionallys substituted by a carboxy group preferably, thiazolyl (preferably, thiazol-2-yl)
  • nonaromatic heterocyclic group of the "optionally substituted nonaromatic heterocyclic group" for R is
  • dihydropyridyl preferably, 1 , 2-dihydropyridin-l-0 yl
  • dihydrooxadiazolyl preferably, 4, 5-dihydro-l, 2, 4- oxadiazol-3-yl
  • the number of the substituents is 1 to 4, preferably 1 to 3, more preferably 1.
  • D group" for R is preferably a nonaromatic heterocyclic group (preferably, dihydropyridyl (preferably, 1, 2-dihydropyridin-l- yl) , dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2 , 4- oxadiazol-3-yl) ) optionally substituted by 1 to 3 (preferably, - 1 or 2) substituents selected from
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) , and
  • R is preferably
  • Ci-6 alkoxy-carbonyl group preferably, ethoxycarbonyl
  • amino group an amino group
  • a mono- or di- (Ci_ 6 alkylsulfonyl) amino group preferably, methylsulfonylamino, ethylsulfonylamino
  • a mono- or di- (aromatic heterocyclyl-sulfonyl ) amino group preferably, pyridylsulfonylamino' (preferably, pyridin-3- ylsulfonylamino) ) ,
  • Ci-6 alkyl group preferably, methyl
  • Ci-6 alkyl group preferably, methyl, ethyl
  • 1 to 3 preferably, 1 or 2
  • halogen atom preferably, fluorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • aromatic heterocyclic group preferably, triazolyl (preferably, 1, 2, 4-triazol-l-yl)
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4, 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4 , 5-dihydro-l, 2, 4-oxadiazol-3- yl) ) optionally substituted by an oxo group,
  • a C7-12 aralkyl group preferably, benzyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro- 1, 2, 4-oxadiazol-3-yl)
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro- 1, 2, 4-oxadiazol-3-yl)
  • Ci-6 alkyl group preferably, methyl, ethyl
  • an optionally substituted cyclic amino group preferably, a cyclic amino group (preferably, imidazolidinyl (preferably, imidazolidin-l-yl) ) optionally substituted by 1 or 2 oxo groups, and
  • Ci-6 alkyl group preferably, methyl, ethyl, propyl, isopropyl
  • 1 to 4 preferably 1 to 3, . more preferably 1 or 2
  • Ci_6 alkyl is optionally substituted by a carboxy group
  • Ci-6 alkoxy group preferably, methoxy, ethoxy, propoxy
  • 1 to 3 preferably, 1 or 2 substituents selected from
  • a mono- or di- (Ci_ 6 alkylsulfonyl) amino group preferably, methylsulfonylamino
  • a Ci-6 alkoxy-carbonyl group preferably, ethoxycarbonyl
  • a cyclic amino-carbonyl group preferably, azetidin-l-ylcarbonyl, 1, 1-dioxide-thiomorpholinocarbonyl
  • a cyclic amino-carbonyl group optionally substituted by a hydroxy group
  • Ci_6 alkyl-carbonyloxy group preferably, acetyloxy
  • Ci-6 alkylsulfonyloxy group preferably, methylsulfonyloxy
  • a C 6 -i2 aryloxy group preferably, phenoxy
  • 1 to 3 preferably, 1 or 2
  • a halogen atom preferably, a fluorine atom, a chlorine atom
  • Ci-6 alkoxy group preferably, methoxy
  • Ci-6 alkoxy-carbonyl group preferably, methoxycarbonyl
  • Ci-6 alkylsulfonyl group preferably, methylsulfonyl
  • a nonaromatic heterocyclic group preferably, dihydrooxadiazolyl (preferably, 4,5-dihydro-

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GEAP201113078A GEP20156295B (en) 2010-10-07 2011-10-05 1,4-oxazepane derivatives
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US10065955B2 (en) 2014-12-10 2018-09-04 Ono Pharmaceutical Co., Ltd. Dihydroindolizinone derivative
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US10414723B2 (en) 2015-05-08 2019-09-17 Vertellus Holdings Llc Processes for converting carboxamides to thiocarboxamides
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KR20140103286A (ko) * 2011-12-21 2014-08-26 오노 야꾸힝 고교 가부시키가이샤 인자 ＸＩａ 억제제로서 피리디논 및 피리미디논 유도체
CN104136431A (zh) * 2011-12-21 2014-11-05 小野药品工业株式会社 作为凝血因子XIa抑制剂的吡啶酮和嘧啶酮衍生物
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DOP2013000074A (es) 2014-07-31
CN103261176B (zh) 2015-06-03
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TW201242956A (en) 2012-11-01
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UY33650A (es) 2012-04-30
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US8722662B2 (en) 2014-05-13
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