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WO2011078143A1 - Pyrimidine derivatives and pharmaceutical composition containing same - Google Patents

Pyrimidine derivatives and pharmaceutical composition containing same Download PDF

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Publication number
WO2011078143A1
WO2011078143A1 PCT/JP2010/072951 JP2010072951W WO2011078143A1 WO 2011078143 A1 WO2011078143 A1 WO 2011078143A1 JP 2010072951 W JP2010072951 W JP 2010072951W WO 2011078143 A1 WO2011078143 A1 WO 2011078143A1
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Prior art keywords
substituted
unsubstituted
substituent
group
aromatic heterocyclic
Prior art date
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PCT/JP2010/072951
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French (fr)
Japanese (ja)
Inventor
努 桝田
裕樹 立花
雅好 宮川
剛 長谷川
裕之 飛永
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Publication of WO2011078143A1 publication Critical patent/WO2011078143A1/en
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving histamine H4 receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical composition containing them.
  • Histamine interacts with four receptors of the G-protein coupled superfamily (histamine H1, H2, H3 and H4 receptors), allergic reaction through H1 receptor, gastric acid secretion through H2 receptor, H3 receptor It expresses various physiological functions such as neurotransmission in the central nervous system through the body.
  • the histamine H4 receptor is a 7-transmembrane G protein-coupled receptor consisting of 390 amino acids with about 40% homology to the H3 receptor. It is mainly expressed in blood cells such as eosinophils, mast cells, dendritic cells, and T cells, and particularly highly expressed in eosinophils and mast cells (Non-patent Documents 1 and 2). .
  • histamine H4 receptor has been confirmed to be expressed in synovial cells collected from rheumatic patients (Non-patent Documents 3 and 4), and is also expressed in synovial cells collected from osteoarthritis patients. It has been confirmed (Non-Patent Document 5), and expression has also been confirmed in intestinal cells (Non-Patent Document 6). Furthermore, it has been reported that the expression level of histamine H4 receptor is also increased in intranasal polyps (Non-patent Document 7). The pharmacological properties of the histamine H4 receptor have also been revealed by several specific ligands.
  • eosinophil migration and morphological changes, and increased expression of CD11b / CD18 and CD54 are known to be effects caused by binding of histamine to the H4 receptor (Non-patent Document 8).
  • the histamine H4 receptor is also known to be involved in calcium influx in mast cells (Non-patent Document 9), to be involved in regulation of cytokine production in dendritic cells (Non-patent Document 10), and the like. The action is various.
  • histamine H4 receptor is involved in the accumulation of mast cells induced by histamine (Non-patent document 9), peritonitis model induced by zymosan (Non-patent document 11) and pleurisy model (non-patent document) Involvement in neutrophil infiltration in literature 12), involvement in eosinophil infiltration in an asthma model by ovalbumin (Non-patent document 10), and involvement in itch (non-patent document 13) have been reported. Yes. It has been described in Patent Document 1, Patent Document 2, Patent Document 3, Non-Patent Document 14, and Non-Patent Document 15 that an aromatic heterocyclic derivative acts on a histamine H4 receptor. Inventive compounds are neither described nor suggested.
  • the present invention provides a novel compound having an action of regulating histamine H4 receptor.
  • the present inventors have an action of regulating histamine H4 receptor, and are useful for the prevention and / or treatment of diseases mediated by histamine H4 receptor.
  • the inventors discovered a new compound and completed the invention described below.
  • the present invention relates to the following (1) to (15).
  • X 1 is N
  • X 2 is N
  • X 3 is C (R x3 )
  • X 4 is C (R x4 )
  • R x3 and R x4 are each together with an adjacent ring member atom.
  • X 1 is N
  • X 2 is C (R x2 )
  • X 3 is C (R x3 )
  • X 4 is N
  • R x2 and R x3 are adjacent to each other Together with the ring atoms to form a C ring
  • Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfony
  • Ring C is (Wherein W 1 , W 2 , R 1a , R 1b , n 1 , n 2 , n 3 and n 4 have the same meaning as (1) above), and the compound according to (2) above Or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Ring C is (Wherein W 1 , R 1a and n 1 have the same meanings as (1) above), or a pharmaceutically acceptable salt thereof or a solvate thereof. .
  • R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, Hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyl
  • X 1 is N
  • X 2 is N
  • X 3 is C (R x3 )
  • X 4 is C (R x4 )
  • X 1 is N
  • X 2 is C (R x2 )
  • X 1 is N
  • X 2 is C (R x2 )
  • X 3 is C (R x3 )
  • X 4 is C (R x4 ), or X 1 is C (R x1 ),
  • B 2 is, (Wherein R 10 , R 11 , and p are as defined in (1) above), or a pharmaceutically acceptable compound thereof Salts or solvates thereof.
  • Y is sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A, substituted or unsubstituted alkylsulfonyl Amino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocycle Sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or nitrogen-containing
  • Y is sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from Substituent Group A (9)
  • (11) The compound according to any one of the above (1) to (10), wherein m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (11) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a disease involving histamine H4 receptor comprising administering a compound according to any one of (1) to (11) above, a pharmaceutically acceptable salt thereof, or a solvate thereof; How to treat and / or prevent a condition.
  • Ring A is an aromatic 6-membered ring;
  • X 1 is N or C (R x1 );
  • X 2 is N or C (R x2 );
  • X 3 is N or C (R x3 );
  • X 4 is N or C (R x4 );
  • R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy
  • R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl Hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • X 1 is N
  • X 2 is N
  • X 3 is C (R x3 )
  • X 4 is C (R x4 ), or X 1 is N and X 2 is C (R x2 ) , X 3 is C (R x3 ), and X 4 is N, or a compound according to (1 ′) or (2 ′), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (4 ′) B 2 is (Wherein R 10 , R 11 , and p have the same meanings as (1 ′) above), or a compound according to any one of (1 ′) to (3 ′) above, A pharmaceutically acceptable salt or a solvate thereof.
  • X 1 is N
  • X 2 is N
  • X 3 is C (R x3 )
  • X 4 is C (R x4 )
  • R x3 and R x4 are each together with an adjacent ring member atom.
  • X 1 is N
  • X 2 is C (R x2 )
  • X 3 is C (R x3 )
  • X 4 is N
  • R x2 and R x3 is a group that forms a C ring together with adjacent ring members
  • Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted
  • Ring C is (Wherein W 1 , W 2 , R 1a , R 1b , n 1 , n 2 , n 3 and n 4 have the same meaning as the above (1 ′)); Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, un
  • (7 ′) B 2 is (Wherein R 10 , R 11 , and p are as defined in (1 ′) above), or a compound described in (1 ′), (5 ′) or (6 ′) above, or The pharmaceutically acceptable salt or solvate thereof.
  • Y is sulfamoyl substituted with a substituent selected from Substituent Group A, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, Substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonyl Amino or a nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent selected from Sub
  • a histamine H4 receptor characterized by administering a compound according to any one of (1 ′) to (10 ′) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method of treating and / or preventing a disease involved.
  • R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalky
  • R a1 and R a2 are groups that together form a ring A together with the carbon atoms to which they are bonded (wherein the A ring is as defined above (1 ′′)), (1 ′′) or (2 ′′) a compound or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Y is substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted cycloalkylsulfonyl Amino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino or substituted or unsubstituted heteroarylsulfonylamino (1 ′ The compound according to any one of ') to (3' ') or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Alkyl includes linear or branched monovalent hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • Examples of “alkyl” in R x1 , R x2 , R x3 and R x4 include methyl, ethyl, n-propyl, isopropyl and the like.
  • Examples of “alkyl” in R 9a , R 9b , R 10 and R 11 include methyl, ethyl, n-propyl, isopropyl and the like.
  • Alkyl such as “haloalkyl”, “alkylamino”, “alkylimino”, “alkylsulfinyl”, “alkylsulfonyl”, “alkylsulfonyloxy”, “alkylsulfamoyl”, “arylalkyl”, “arylalkylamino”, etc.
  • the moiety is as defined above for “alkyl”.
  • alkyl part of “alkyloxy” has the same meaning as the above “alkyl”. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • Alkyloxy ” in R x1 , R x2 , R x3 and R x4 includes methoxy, ethoxy, propoxy, isopropoxy and the like.
  • alkyloxy moiety such as “haloalkyloxy” and “alkyloxyimino” has the same meaning as the above “alkyloxy”.
  • alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.
  • “Alkylthio” in R x1 , R x2 , R x3 and R x4 includes methylthio, ethylthio, n-propylthio, isopropylthio and the like.
  • alkyloxycarbonyl has the same meaning as the above “alkyloxy”. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
  • Alkyloxycarbonyl ” in R x1 , R x2 , R x3 and R x4 includes methyloxycarbonyl, ethyloxycarbonyl and the like.
  • alkyl part of “alkylcarbamoyl” has the same meaning as the above “alkyl”.
  • examples thereof include mono- or dialkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl and the like.
  • Examples of the “alkylcarbamoyl” in R x1 , R x2 , R x3 and R x4 include methylcarbamoyl, ethylcarbamoyl and the like.
  • Alkenyl includes straight or branched alkenyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more double bonds at any position. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl and the like. “Alkenyl” in R x1 , R x2 , R x3 and R x4 includes vinyl, propenyl, isopropenyl, butenyl, isobutenyl and the like.
  • alkenyl part of “alkenyloxy” has the same meaning as the above “alkenyl”.
  • alkenyl part of “alkenylthio” has the same meaning as the above “alkenyl”. Examples thereof include vinylthio, propenylthio, isopropenylthio, butenylthio, isobutenylthio, prenylthio, butadienylthio, pentenylthio, isopentenylthio, pentadienylthio, hexenylthio, isohexenylthio, hexadienylthio and the like.
  • alkenyloxy part of “alkenyloxycarbonyl” has the same meaning as the above “alkenyloxy”.
  • alkenyl moiety such as “haloalkenyl”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkenylsulfonyloxy”, “alkenylsulfamoyl” has the same meaning as the above “alkenyl”.
  • Alkynyl includes linear or branched alkynyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more triple bonds at any position. These have one or more triple bonds at arbitrary positions, and may further have a double bond. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, various pentynyl isomers, and the like.
  • alkynyl part of “alkynyloxy” has the same meaning as the above “alkynyl”.
  • alkynyl For example, ethynyloxy, propynyloxy, butynyloxy, pentynyloxy and the like can be mentioned.
  • C2-C6 alkynyloxy is used.
  • Alkynylthio has the same meaning as the above “alkynyl” in the alkynyl moiety.
  • alkynyl in the alkynyl moiety.
  • ethynylthio, propynylthio, butynylthio, pentynylthio and the like can be mentioned.
  • C2-C6 alkynylthio is used.
  • alkynyloxycarbonyl has the same meaning as the above “alkynyloxy”. Examples include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, and the like. Preferably, C2-C6 alkynyloxycarbonyl is used.
  • Alkynyl moieties such as “alkynylsulfinyl”, “alkynylsulfonyl”, “alkynylsulfonyloxy”, “alkynylsulfamoyl” and the like are synonymous with the above “alkynyl”.
  • Acyl is R—C ( ⁇ O) — (for example, R is “alkyl”, “alkenyl” or “alkynyl”, or “cycloalkyl”, “cycloalkenyl”, “aryl”, “ A heteroaryl ”or a“ non-aromatic heterocyclic group ”).
  • acyl part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.
  • Unsubstituted sulfamoyl means a group represented by —S ( ⁇ O) 2 —NH 2 .
  • “Sulphamoyl substituted with a substituent selected from Substituent Group A” means a group represented by —S ( ⁇ O) 2 —NR X R Y.
  • R X and R Y is a substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted Or a group selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • substituent group A substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted Or a group selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substitute
  • “sulfamoyl substituted with a substituent selected from Substituent Group A” includes unsubstituted alkyl, Substituent Group C (Substituent Group C: hydroxy, halogen, substituted or unsubstituted alkoxy, Alkyl substituted with one or more substituents selected from substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted aryl) Selected from substituent group B (substituent group B: hydroxy, substituted or unsubstituted alkyl, halogen and carbamoyl), one or more substituted aryls, unsubstituted aryl, substituent group B Heteroaryl substituted with one or more substituents, unsubstituted heteroaryl, substituent group D (substituent
  • “Unsubstituted aminosulfonylamino” means a group represented by —NH—S ( ⁇ O) 2 —NH 2 . “Substituted aminosulfonylamino” means a group represented by —NR z —S ( ⁇ O) 2 —NR X R Y , and at least one of R X , R Y and R z is represented by “ The meaning is the same as the substituent of “substituted amino”.
  • R X and R Y are substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or non-substituted Substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Group.
  • R z has the same meaning as the substituent of “substituted amino” shown below.
  • “Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms.
  • Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.
  • Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.
  • Cycloalkyl includes a monovalent group derived from the above “cycloalkane”.
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, adamantyl and the like.
  • “Cycloalkanediyl” includes a divalent group derived from the above “cycloalkane”.
  • Examples of the monocyclic cycloalkanediyl include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, cyclooctanediyl, cyclononanediyl, cyclodecandidiyl and the like.
  • Examples of polycyclic cycloalkanediyl include norbornanediyl, adamantanediyl and the like.
  • cycloalkyl part of “cycloalkyloxy” has the same meaning as the above “cycloalkyl”.
  • cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, cyclodecyloxy and the like can be mentioned.
  • polycyclic cycloalkyloxy include norbornyloxy, tetrahydronaphthalen-5-yloxy, tetrahydronaphthalen-6-yloxy, adamantaneoxy and the like.
  • cycloalkyloxy part of “cycloalkyloxycarbonyl” has the same meaning as the above “cycloalkyloxy”. Examples include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, cyclooctyloxycarbonyl, cyclononyloxycarbonyl, cyclodecyloxycarbonyl, and the like.
  • polycyclic cycloalkyloxycarbonyl examples include norbornyloxycarbonyl, tetrahydronaphthalen-5-yloxycarbonyl, tetrahydronaphthalen-6-yloxycarbonyl and the like.
  • “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond.
  • Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene.
  • Examples of the polycyclic cycloalkene include norbornene and indene.
  • Cycloalkenyl includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.
  • Cycloalkenediyl includes a divalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenediyl include cyclopentenediyl, cyclohexenediyl and the like. Examples of polycyclic cycloalkenediyl include norbornene diyl.
  • cycloalkenyl part of “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”.
  • cycloalkenyloxy examples include norbornenyloxy and indenyloxy.
  • cycloalkenyloxycarbonyl has the same meaning as the above “cycloalkenyloxy”.
  • examples of the monocyclic cycloalkenyloxycarbonyl include cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl, and the like.
  • examples of the polycyclic cycloalkenyloxycarbonyl include norbornenyloxycarbonyl, indenyloxycarbonyl and the like.
  • aromatic carbocycle includes a monocyclic or condensed aromatic hydrocarbon ring.
  • a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned.
  • Aryl means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like.
  • aryl part of “arylsulfonyloxy” has the same meaning as the above “aryl”.
  • aryl For example, phenylsulfonyloxy, 1-naphthylsulfoneoxy and the like can be mentioned.
  • aryl part of “aryloxy”, “aryloxycarbonyl”, “arylalkylamino”, “arylsulfinyl” and “arylalkyl” has the same meaning as the above “aryl”.
  • “Aromatic carbocyclic diyl” includes a divalent group derived from the above “aromatic carbocycle”. For example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like can be mentioned.
  • Heterocycle means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring, A ring in which two or more of them are independently fused, or A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”.
  • An aromatic or non-aromatic fused ring derived from the above ring.
  • monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc.
  • heterocyclic group includes a monovalent group derived from the above “heterocycle”.
  • Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl
  • a ring group For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic groups
  • the “aromatic heterocycle” includes the above “heterocycle” which is an aromatic ring.
  • a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic ring in which two or more of them are independently fused, An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • indole isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo
  • examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.
  • Heteroaryl includes a monovalent group derived from the above “aromatic heterocycle”.
  • a 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic cyclic group in which two or more of them are independently fused, An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • Aryl For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.
  • aromatic 6-membered ring includes the above-mentioned “benzene ring” and “aromatic heterocycle” which are 6-membered aromatic rings.
  • non-aromatic heterocycle includes those that are non-aromatic rings among the above-mentioned “heterocycle”.
  • a 5- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring A non-aromatic ring in which two or more of them are independently fused,
  • a ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
  • a 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”.
  • fused rings For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydro Monocyclic non-aromatic heterocycles such as thiazoline, tetrahydroisothiazoline, Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophen
  • non-aromatic heterocyclic group includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
  • non-aromatic sulfur-containing heterocyclic group includes at least one sulfur atom in the ring, and may further include one or more atoms arbitrarily selected from an oxygen atom and a nitrogen atom in the ring. It includes a group derived from a non-aromatic 4- to 7-membered ring or a ring in which two or more thereof are condensed. Examples thereof include thiomorpholinyl, thiomorpholino, thianyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl and the like.
  • non-aromatic heterocyclic moiety of “non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic alkylamino” and “non-aromatic heterocyclic alkyl” Synonymous with “heterocycle”.
  • Substituents for “substituted amino” and “substituted aminosulfonylamino” include, but are not limited to, one or more of the same or different substituents selected from the following group: Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.), haloalkyloxy (eg
  • Substituted or unsubstituted alkylsulfonylamino substituted or unsubstituted aminosulfonylamino
  • substituted or unsubstituted cycloalkylsulfonylamino substituted or unsubstituted nonaromatic heterocyclic sulfonylamino
  • amino in “substituted or unsubstituted arylsulfonylamino” or “substituted or unsubstituted heteroarylsulfonylamino” may also be substituted with the substituent represented by the above “substituted amino”.
  • Substituents for “substituted aryl” and “substituted heteroaryl” include halogen, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, mekyloxy, ethyloxy, n-propyloxy, isopropyloxy, trifluoromethyloxyhalogen, Hydroxy, carbamoyl and the like can be mentioned.
  • halogen, methyl, isopropyl, hydroxy, carbamoyl and the like can be mentioned.
  • one or more hydrogen, carbon or other atoms of the compound of general formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • the compound of general formula (I) includes all radiolabeled compounds of the compound of general formula (I). Such “radiolabeled”, “radiolabeled” and the like of compounds of general formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. is there. Examples of isotopes that can be incorporated into the compound of the general formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, and 35, respectively.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium-labeled compound of general formula (I) can be prepared by introducing tritium into a specific compound of formula I, for example, by a catalytic dehalogenation reaction using tritium. This process comprises reacting a compound of general formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It may be included.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • the compound of the present invention represented by the above general formula (I) or a salt thereof may be converted into a hydrate or a solvate by a known method.
  • Suitable solvates include solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether and the like.
  • non-toxic and water-soluble hydrates or solvates for example, ethanol and the like
  • the compounds according to the present invention include pharmaceutically acceptable salts.
  • alkali metals such as lithium, sodium or potassium
  • alkaline earth metals such as magnesium or calcium
  • ammonium salts with organic bases and amino acids
  • inorganic acids hydroochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid
  • organic acids acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, and salts with p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.
  • hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable.
  • “Modulators” include agonists, partial agonists, inverse agonists and antagonists.
  • “Histamine H4 modulator” includes histamine H4 receptor modulators, ie, histamine H4 receptor agonists, histamine H4 receptor partial agonists, histamine H4 receptor inverse agonists, histamine H4 receptor antagonists To do.
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alken
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy; n 1 is an integer from 0 to 4; -B 1 is represented by the formula: -X- (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonyla
  • R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substitu
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substituted or unsubstituted alkyl; m is an integer from
  • R x2 and R x3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substitu
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substituted or unsubstituted alkyl; m is an integer from
  • R x1 , R x2 and R x3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or Unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substitu
  • R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; m is an integer from 1 to 5: Y is substituted or unsubstituted alkyl; m is an integer from
  • R 1b is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 3 is an integer from 0 to 2;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is a substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 3 is an integer from 0 to 2;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • R 1b is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 3 is an integer from 0 to 2;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsub
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;
  • n 3 is an integer from 0 to 2;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfon
  • R 1b is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group; n 3 is an integer from 0 to 2; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group; n 3 is an integer from 0 to 2; —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen; R 8a and R 8b are hydrogen; m is an integer from 1 to 5: Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or
  • R 1b is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 4 is an integer of 0 or 1;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsub
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 4 is an integer of 0 or 1;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsub
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or un
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsub
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • R 1a is a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or un
  • R 1b is a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
  • Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • n 1 is an integer from 0 to 4;
  • —B 1 represents the formula: —X— (CR 8a R 8b ) mY (Where X is N (R 7c ); R 7c is hydrogen;
  • R 8a and R 8b are hydrogen;
  • m is an integer from 1 to 5:
  • Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfony
  • Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include each substituent represented by the following general formula (IA) or (IB). Or a pharmaceutically acceptable salt or solvate thereof shown in all possible combinations of all options.
  • R 2a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylsulfonyl or substituted or Examples include unsubstituted acyl.
  • W 2 includes N (R 2a ) or S
  • R 2a is hydrogen or substituted or unsubstituted alkyl.
  • W 2 N (R 2a ) and R 2a are hydrogen or substituted or unsubstituted alkyl.
  • W 2 it includes S is.
  • R 1b halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalken
  • R 1b includes halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group.
  • n2 is an integer of 0 to 2.
  • n2 is 0.
  • R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
  • X N (R 7c ) and R 7c include hydrogen or substituted or unsubstituted alkyl.
  • NH is exemplified as X.
  • m is an integer of 1 to 3.
  • 2 is mentioned as m.
  • substituted or unsubstituted cycloalkylthio substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Sulfinyl substituted with a substituent selected from Substituent Group A, Sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, substituted with a substituent selected from Substituent Group A Sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted amino
  • Y unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the
  • Y includes sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, or sulfamoyl substituted with a substituent selected from Substituent Group A.
  • Y may be unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from substituent group A.
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
  • R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
  • p is an integer from 0 to 4
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include all the options of each substituent represented by the following general formula (IC). Or a pharmaceutically acceptable salt thereof or a solvate thereof is also included.
  • R 1c halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy.
  • R 1c includes halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, and hydroxy.
  • R 1c includes halogen or hydroxy.
  • R 1c includes hydroxy.
  • R 1c includes halogen.
  • fluorine is mentioned as R1c .
  • R 1d halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy.
  • R 1d includes halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or hydroxy.
  • R 1d is bonded to the carbon atom to which R 1c is bonded, and includes halogen or substituted or unsubstituted alkyl.
  • n3 is an integer of 0 to 3.
  • n3 is 0 or 1.
  • R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
  • N (R 7c ) and R 7c include hydrogen or substituted or unsubstituted alkyl.
  • NH is exemplified as X.
  • m is an integer of 1 to 3.
  • 2 is mentioned as m.
  • substituted or unsubstituted cycloalkylthio substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio
  • Substituent group A substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Substituted sulfinyl substituted with a substituent selected from a substituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl),
  • Y unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the
  • Examples of Y include unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, or sulfonyl substituted with a substituent selected from substituent group A.
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
  • R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
  • p is an integer from 0 to 4
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include all the options of each substituent represented by the following general formula (ID). Or a pharmaceutically acceptable salt thereof or a solvate thereof is also included.
  • R 1a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalken
  • R 1a halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, sulfonyl substituted with a substituent selected from substituent group A, or substituted or An unsubstituted non-aromatic heterocyclic group is mentioned.
  • R 1a one R 1a is bonded to the 6-position nitrogen atom constituting the ring in formula (ID), and is halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted acyl, And substituted or unsubstituted cycloalkyl, sulfonyl substituted with a substituent selected from Substituent Group A, or substituted or unsubstituted non-aromatic heterocyclic group.
  • R 1a one R 1a is bonded to the 6-position nitrogen atom constituting the ring in Formula (ID), and is substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a group of substituents And sulfonyl substituted with a substituent selected from A.
  • n1 is an integer of 1 to 4.
  • n1 is 1.
  • R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
  • N (R 7c ) and R 7c may be hydrogen or substituted or unsubstituted alkyl.
  • X is NH.
  • m is an integer of 1 to 3.
  • 2 is mentioned as m.
  • substituted or unsubstituted cycloalkylthio substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Sulfinyl substituted with a substituent selected from Substituent Group A, Sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, substituted with a substituent selected from Substituent Group A Sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted amino
  • Y unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the
  • Y includes sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, or sulfamoyl substituted with a substituent selected from Substituent Group A.
  • Y may be unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from substituent group A.
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
  • R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl
  • R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
  • p is an integer from 0 to 4
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • a B 2 wherein R 10 is substituted or unsubstituted alkyl; R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; p is an integer from 0 to 4) The group shown by these is mentioned.
  • R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalky
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B'
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5: —X— represents —NH—; Y is
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B 'and -B 2 is -B''
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5:
  • —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulf
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B "and -B 2 is -B '
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5:
  • —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulfam
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B'
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5: —X— represents —NH—; Y is
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B 'and -B 2 is -B''
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5:
  • —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulf
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • —W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —
  • R 2 is hydrogen, substituted or unsubstituted alkyl or acyl
  • -B 1 is -B "and -B 2 is -B '
  • —B ′ has the formula: —X— (CH 2 ) m —Y; m is an integer from 1 to 5:
  • —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulfam
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • -B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B'
  • —B ′ has the formula: —X— (CH 2 ) 2 —Y;
  • —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
  • Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
  • R 11 is hydrogen or substituted or unsubstituted
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • -B 1 is -B 'and -B 2 is -B''
  • —B ′ has the formula: —X— (CH 2 ) 2 —Y; —X— represents —NH—;
  • Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A; -B ''
  • Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
  • R 11 is hydrogen or substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt thereof, or a solvate
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy
  • n is an integer from 0 to 2
  • -B 1 is -B "and -B 2 is -B '
  • —B ′ has the formula: —X— (CH 2 ) 2 —Y
  • —X— represents —NH—
  • Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
  • Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino
  • R 11 is hydrogen or substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof
  • histamine H4 receptor agonist, partial agonist, inverse agonist and antagonist, particularly antagonist
  • histamine H4 receptor is It is useful as a therapeutic agent for diseases involved.
  • respiratory diseases such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD); rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus Inflammatory diseases such as atherosclerosis; effective for pain relief including neuropathic pain and nociceptive pain.
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the following synthesis route.
  • R a1 and R a2 are as defined above (1)
  • R 14 is a leaving group such as halogen, substituted or unsubstituted alkyloxy or cyano
  • R 15 is substituted or unsubstituted alkyl or substituted or Unsubstituted aryl.
  • the compound represented by the general formula (iii) can be synthesized by allowing the compound represented by the general formula (ii) to act on the compound represented by the general formula (i) in the presence of a base.
  • reaction solvent examples include THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • sodium hydride and potassium hydride examples of the reaction solvent
  • 1 to 10 molar equivalents can be used relative to compound (i).
  • reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (iii) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (iii) can be synthesized by condensing the compound represented by the general formula (iii) with urea.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the obtained compound represented by the general formula (iv) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • Z is substituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group, and other symbols are as defined above.
  • the compound represented by the general formula (vi) can be synthesized.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • Examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (iii).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (vi) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (vii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (iv).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride and the like, and 1 equivalent to a solvent amount can be used with respect to compound (iv). Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (vii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (viii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (vi).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride and the like, and 1 equivalent to a solvent amount can be used with respect to compound (vi).
  • dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (viii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • R 16 is substituted alkyl, Z ′ is a substituted or unsubstituted non-aromatic heterocyclic group, and other symbols are as defined above.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (ix). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xi) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (vii) By reacting the compound represented by the general formula (vii) with the amine represented by the general formula (x) in the presence or absence of a base, the compound represented by the general formula (xii) is obtained.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (vii). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (xii) By reacting the compound represented by the general formula (xii) with the amine represented by the general formula (xiii) in the presence or absence of a base, the compound represented by the general formula (xiv) is obtained.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used relative to compound (xii). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xiv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • P 1 is a common amine protecting group such as Boc, benzyloxycarbonyl or benzyl, Is a non-aromatic nitrogen-containing heterocyclic group, and other symbols are as defined above.
  • An amine represented by the general formula (xvi) is obtained by subjecting the compound represented by the general formula (xv) to a known deprotection reaction (see: Green's Protective Groups in Organic Synthesis, Wiley). The resulting compound represented by the general formula (xv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 18 is hydrogen or substituted or unsubstituted alkyl, Is a non-aromatic heterocyclic group, and other symbols are as defined above.
  • An amine represented by the general formula (xviii) is obtained by subjecting the compound represented by the general formula (xvii) to a known deprotection reaction (see: Green's Protective Groups in Organic Synthesis, Wiley).
  • the resulting compound represented by the general formula (xv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 19 is hydrogen or substituted or unsubstituted alkyl
  • R 20 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or (Unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.)
  • the compound represented by the general formula (xxv) is obtained by allowing the compound represented by the general formula (xxiv) to act on the amine represented by the general formula (xxiii) in the presence of a base.
  • reaction solvent examples include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (xxv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xxvii) is obtained by allowing a compound represented by the general formula (xxiv) to act on the amine represented by the general formula (xxvi) in the presence of a base.
  • the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (xxvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xxix) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (xxviii).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, and the like, and 1 equivalent to a solvent amount can be used with respect to compound (xxviii). Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive. With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 21 and R 22 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted And cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • base examples include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxx).
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xxxiv) is obtained by allowing an acid to act on the compound represented by the general formula (xxxiii).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • the acid include trimethylsilane iodide, boron tribromide, and the like. The acid can be used at 1 to 30 molar equivalents relative to the compound (xxxiii). With respect to the reaction temperature, it can be ⁇ 78 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (xxxvi) is obtained by allowing 1-chloroethyl chloroformate to act on the compound represented by the general formula (xxxv) in the presence of a base.
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxxv).
  • the reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 24 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • the compound represented by the general formula (xxxviii) is obtained by allowing the compound represented by the general formula (xxxvii) to act on the compound represented by the general formula (xxxvi) in the presence of a base.
  • reaction solvent examples include dichloromethane, 1,2-dichloroethane, chloroform, THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, which can be used alone or in combination.
  • base examples include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like, and 1 to 20 molar equivalents are used with respect to the compound (xxxvi). it can. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • Z 2 and Z 3 are a leaving group such as bromine atom, chlorine atom, tosylate, mesylate, alkylsulfone, arylsulfone, R 31 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, X 1 , X 2 , X 3 and X 4 are the same as defined in (1) above.)
  • the compound (xli) represented by the general formula is obtained.
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (ixl). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xli) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 32 is hydrogen, substituted or unsubstituted alkyl, or R 32 and Z 4 may be combined to form a ring
  • Z 4 is hydrogen, substituted or unsubstituted alkyl or acyl, or other symbols. Is as defined above.)
  • the compound represented by the general formula (xliii) is obtained by allowing the compound represented by the general formula (xlii) to act on the compound represented by the general formula (xli) in the presence or absence of a base.
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (xli). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xliii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 33 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 34 is hydrogen, or two R 34 are bonded to each other, and- (CR 60a R 60b ) t-, t is 1 to An integer of 3, R 60a and R 60b are each independently hydrogen or alkyl.)
  • a metal catalyst and a boronic acid or boronic acid ester represented by the general formula (xliv) By reacting a metal catalyst and a boronic acid or boronic acid ester represented by the general formula (xliv) with the compound represented by the general formula (xl
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF, NMP and the like, and these can be used alone or in combination.
  • metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like.
  • the compound can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound (xli).
  • An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus Examples thereof include potassium oxyhydrogen, cesium carbonate, and the like, and can be used at 1 to 10 molar equivalents relative to the compound (xli).
  • Boronic acid or boronic acid ester (xliv) can be used at 1 to 10 molar equivalents relative to compound (xli). With respect to the reaction temperature, it can be 20 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound represented by the general formula (xlv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 35 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, etc.
  • R 36 and R 37 are each independently hydrogen, R 35 and R 36 may be combined to form a ring, such as substituted or unsubstituted alkyl, substituted or unsubstituted amino, etc., and other symbols are as defined above.
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, formic acid and the like, and these can be used alone or in combination.
  • metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (xlvi). Can do.
  • the hydrogen pressure is 1 to 50 atm. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the obtained compound (xlvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 38 is substituted or unsubstituted alkylene or substituted or unsubstituted alkenylene
  • R 39 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or Z 4 and R 39 May be combined to form a non-aromatic heterocycle
  • P 1 is a suitable protecting group for an amino group, and other symbols are as defined above.
  • trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid and the like can be used at 1 molar equivalent to a solvent amount.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
  • the reaction temperature include 0 ° C. to 100 ° C.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (il) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • R 40 is (CR 8a R 8b ) m, CR 8a , R 8b and m are the same as (1) above,
  • R 41 is a carbamate group such as Boc and benzyloxycarbonyl
  • R 42 and R 43 are Each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 42 and R 43 may be cyclic together, and other symbols are as defined above.
  • diazocarboxylic acid esters examples include diazocarboxylic acid alkyl esters such as diethyl azodicarboxylate and diisopropylcarboxylate.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (xliii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 45 is hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or An unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 46 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It may be cyclic with acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, and
  • Substituted alkyl, substituted or unsubstituted alkenyl, substituted or It may be cyclic with unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl.
  • the compound represented by the general formula (lv) is obtained by allowing the compound represented by the general formula (lv) to act on the compound represented by the general formula (lib).
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and can be used at 1 to 10 molar equivalents relative to the compound (lib). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lvi) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (lvii) By treating the compound (lvi) with an acid, a compound represented by the general formula (lvii) can be synthesized.
  • the compound (lvi) 1 molar equivalent to a solvent amount of trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid and the like can be used.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
  • the reaction temperature include 0 ° C. to 100 ° C.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (lx) can be synthesized by allowing the compound represented by the general formula (lix) to act on the compound represented by the general formula (lviii) in the presence of a base.
  • the reaction solvent include THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, hydrogen
  • Examples thereof include sodium hydride and potassium hydride, and 1 to 10 molar equivalents can be used with respect to compound (lviii).
  • the reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lx) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (lxi) By reacting the compound represented by the general formula (lx) with urea in the presence of a base, the compound represented by the general formula (lxi) can be synthesized.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lxi) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • Z 5 is nitrogen, sulfur atom, R 50 is alkyl, aryl group, and other symbols are as defined above.
  • the compound represented by the general formula (lxii) can be synthesized.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (lx).
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (lxiv) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (lxi).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, phenyl dichloride diphosphoric acid, and the like. Can be used. Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • Compound (lxvi) can be synthesized by allowing a halogenating reagent to act on compound (lxv).
  • the reaction solvent include methylene chloride, chloroform, toluene and the like, and these can be used alone or in combination.
  • halogenating reagent examples include diethylaminosulfur trifluoride, morpholinosulfur trifluoride, bis (2-methoxyethyl) aminosulfur trifluoride, 2,2-difluoro-1,3-dimethylimidazolidine, phosphorus pentachloride, Phosphorus chloride, tungsten hexachloride and the like can be mentioned, and 1 to 10 molar equivalents can be used with respect to compound (lxv).
  • the reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound (lxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (lxviii) By reacting the compound represented by the general formula (lxviii) with the compound represented by the general formula (xlii) in the presence or absence of a base, the compound represented by the general formula (lxviii) is obtained.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (lxvii). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
  • the metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I) and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxix). Can do.
  • the hydrogen pressure is 1 to 50 atm. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 72 hours.
  • the obtained compound (lxx) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (lxxii) is obtained by allowing the compound represented by the general formula (lxxii) to act on the compound represented by the general formula (lxxii).
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (lxxi). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (lxxiv) can be synthesized by allowing a base to act on the compound represented by the general formula (lxxiii).
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, hydrogen phosphate
  • Examples thereof include sodium, potassium phosphate, potassium hydrogen phosphate, cesium carbonate and the like, and the compound can be used at 1 to 10 molar equivalents relative to the compound represented by the general formula (lxxiii). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 49 and R 50 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Z 8 is bromine atom, chlorine atom, tosylate, mesylate, alkylsulfone, arylsulfone Etc., and other symbols are as defined above.) In the presence of a base, the compound represented by the general formula (lxxvi) is allowed to act on the compound represented by the general formula (lxxv) to obtain the compound represented by the general formula (lxxvi).
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, acetone and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, phosphoric acid
  • Sodium hydrogen, potassium phosphate, potassium hydrogen phosphate, cesium carbonate and the like can be mentioned, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (lxxiv).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (lxxvi) is heated, the compound represented by the general formula (lxxvii) is obtained.
  • the reaction solvent include toluene, water, DMF, NMP and the like, and they can be used alone or in combination.
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (lxxvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
  • metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxxvii). Can do.
  • the hydrogen pressure is 1 to 50 atm.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the obtained compound (lxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (lxxix) By treating the compound (lxxviii) with an acid, a compound represented by the general formula (lxxix) can be synthesized.
  • 1 molar equivalent to a solvent amount of trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like can be used.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lxxix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 51 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, e is an integer of 1 to 2, f is an integer of 1 to 3, and other symbols are as defined above.
  • a compound represented by the general formula (lxxxii) is obtained by allowing a compound represented by the general formula (lxxxi) to act on the amine represented by the general formula (lxxx) in the presence of a base.
  • the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (lxxxii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 52 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic groups, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • the compound represented by the general formula (lxxxiii) When the compound represented by the general formula (lxxxiii) is allowed to act on the amine represented by the general formula (lxxxii) in the presence of a base, the compound represented by the general formula (xxxiv) is obtained.
  • the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (lxxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the azide represented by the general formula (lxxxv) is obtained.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
  • Sodium azide can be used at 1 to 10 molar equivalents relative to compound (lxxxiv). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (lxxxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
  • metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I) and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxxxv). Can do.
  • the hydrogen pressure is 1 to 50 atm.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the obtained compound (lxxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 53 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 52 and R 53 may be combined to form a ring
  • P 2 is Boc, benzyloxy Protecting groups for general amines such as carbonyl and benzi i, and other symbols are as defined above.)
  • An amine represented by the general formula (lxxxviii) is obtained by performing a known deprotection reaction (see Green's Protective Groups in Organic Synthesis, Wiley) on the compound represented by the general formula (lxxxvii). The resulting compound represented by the general formula (lx
  • R 54 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, g is 0 to 2, and the symbols are as defined above.
  • a compound represented by the general formula (xc) is obtained by allowing a compound represented by the general formula (lxxxix) to act on the amine represented by the general formula (lxxxviii) in the presence of a base.
  • the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (xc) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • R 55 is (CR 8a R 8b ) m, and the symbols are as defined above.
  • a compound represented by the general formula (xcii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (xci).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, sulfuryl chloride and the like, and 1 equivalent to a solvent amount is used with respect to the compound (xci). it can. Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive. With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xcii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • R 56 and R 57 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, the symbols thereof are as defined above.
  • the compound represented by the general formula (xcii) By reacting the compound represented by the general formula (xcii) with the amine represented by the general formula (xciii) in the presence of a base, the compound represented by the general formula (xciv) is obtained.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xciv).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xciv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • the general synthesis method of the compound included in the present invention is shown below, but is not limited to this synthesis method.
  • Y is a leaving group such as bromine, chlorine, tosylate, mesylate, alkylsulfonyl, arylsulfonyl, and other symbols are as defined above.
  • a compound represented by the general formula (xcv) can be converted into a compound represented by the general formula (xcvi) with a halogenating agent.
  • the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine, iodine and the like. An equivalent amount can be used.
  • reaction solvent examples include methylene chloride and chloroform, and these can be used alone or in combination.
  • reaction temperature it can be -20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the obtained carboxylic acid compound (xcvi) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (xcvii) can be converted into the alcohol compound represented by the general formula (xcviii) by a reducing agent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like.
  • the reducing agent can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by the general formula (xcvii).
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
  • reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xcviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 61 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 62 represents hydrogen, or substituted or unsubstituted benzyl, and other symbols are as defined above.
  • the compound represented by the general formula (c) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (ic).
  • a halogenating agent examples include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
  • the halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, phenyl dichloride phosphoric acid, and the like. Can be used.
  • dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (c) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • the epoxide represented by the general formula (cii) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (c).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
  • the peroxide include metachloroperbenzoic acid, performic acid, dimethyldioxolane, hydrogen peroxide and the like, and 1 to 20 equivalents can be used with respect to the compound (c).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (cii) can be converted into the alcohol compound represented by the general formula (civ) by a reducing agent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cii).
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
  • the reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (civ) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • Ar 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 63 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkyl non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 64 is hydrogen, or two R 64 is bonded to- (CR 65a R 65b ) t-, R 65a and R 65b are each independently hydrogen or alkyl, t is an integer of 1 to 3, and other symbols are as defined above.
  • the metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to the compound ().
  • An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus
  • Examples thereof include potassium oxyhydrogen, cesium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to the compound ().
  • Boronic acid or boronic acid ester (cvi) can be used in an amount of 1 to 10 molar equivalents relative to compound (cv). With respect to the reaction temperature, it can be 20 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cvii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (cix) can be synthesized by reducing the compound represented by the general formula (cviii) with hydrogen in the presence of a metal catalyst.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate and the like, and these can be used alone or in combination.
  • the metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like. 5 weight percent can be used.
  • the hydrogen pressure is 1 to 50 atm. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (cix) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • R 67 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, Other symbols are as defined above.
  • a compound represented by the general formula (cix) can be converted to an amide compound represented by the general formula (cxi) by an acylating agent.
  • the acylating agent include acid anhydrides such as acetic anhydride and acid chlorides such as acetyl chloride.
  • the acylating agent can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by the general formula (cix).
  • the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride and the like.
  • 1 to 10 molar equivalents can be used.
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound represented by the general formula (cxi) can be isolated and purified by the known means (eg, chromatography, recrystallization and the like).
  • the compound represented by the general formula (cix) can be converted to a sulfonamide compound represented by the general formula (cxiii) with a sulfonylating agent.
  • a sulfonylating agent include sulfonic acid anhydrides and sulfonic acid chlorides, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cix).
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like (compix) 1 to 10 molar equivalents can be used.
  • Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (cix) can be converted to the compound represented by the general formula (cxv) with an alkylating agent.
  • alkylating agent include alkyl chloride, alkyl bromide, alkyl iodide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cix).
  • Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like (compix) 1 to 10 molar equivalents can be used.
  • Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound represented by the general formula (cxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 68 is substituted or unsubstituted benzyl
  • R 69 and R 70 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group
  • Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R 69 and R 70 may form a ring together.
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (cxx) can be synthesized by reducing the compound represented by the general formula (cxix) with hydrogen in the presence of a metal catalyst.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate and the like, and these can be used alone or in combination.
  • the metal catalyst examples include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.000 with respect to the compound represented by the general formula (cxix). 5 weight percent can be used.
  • the hydrogen pressure is 1 to 50 atm. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (cxx) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 71 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted And cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • organophosphorus reagent examples include alkyl or aryl phosphines such as triphenylphosphine and tributylphosphine, and 1 to 10 molar equivalents can be used with respect to the compound (cxxi).
  • diazocarboxylic acid esters examples include diazocarboxylic acid alkyl esters such as diethyl azodicarboxylate and diisopropylcarboxylate.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (cxxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (cxxv) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (cxxiv).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
  • peroxides include metachloroperbenzoic acid, formic acid, dimethyldioxolane, hydrogen peroxide, and the like, and 1 to 20 equivalents can be used with respect to compound (cxxiv).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cxxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (cxxvii) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (cxxvi).
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
  • the peroxide include metachloroperbenzoic acid, performic acid, dimethyldioxolane, hydrogen peroxide, and the like, and 1 to 1.5 equivalents can be used with respect to the compound (cxxvi).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (cxxvii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • One embodiment of the compound of the present invention has the following group in the following general formula (II).
  • AC, Ba, Bb (AC1, Ba1, Bb1), (AC1, Ba1, Bb2), (AC1, Ba1, Bb3), (AC1, Ba1, Bb4), (AC1, Ba1, Bb5), (AC1 , Ba1, Bb6), (AC1, Ba2, Bb1), (AC1, Ba2, Bb2), (AC1, Ba2, Bb3), (AC1, Ba2, Bb4), (AC1, Ba2, Bb5), (AC1, Ba2 , Bb6), (AC1, Ba3, Bb1), (AC1, Ba3, Bb2), (AC1, Ba3, Bb3), (AC1, Ba3, Bb4), (AC1, Ba3, Bb5), (AC1, Ba3, Bb6 ), (AC1, Ba4, Bb1), (AC1, Ba4, Bb2), (AC1, Ba4, Bb3), (AC1, Ba4, Bb4), (AC1, Ba4, Bb5), (AC1, Ba4, Bb6), (AC1, Ba4, Bb5), (AC1, Ba4, Bb6), (AC1, Ba4, Bb5),
  • One embodiment of the compound of the present invention has the following group in the following general formula (III).
  • the compound whose combination of AC, Ba, and Bb is the following (AC, Ba, Bb).
  • (AC, Ba, Bb) (AC1, Ba1, Bb1), (AC1, Ba1, Bb2), (AC1, Ba1, Bb3), (AC1, Ba1, Bb4), (AC1, Ba1, Bb5), (AC1 , Ba1, Bb6), (AC1, Ba2, Bb1), (AC1, Ba2, Bb2), (AC1, Ba2, Bb3), (AC1, Ba2, Bb4), (AC1, Ba2, Bb5), (AC1, Ba2 , Bb6), (AC1, Ba3, Bb1), (AC1, Ba3, Bb2), (AC1, Ba3, Bb3), (AC1, Ba3, Bb4), (AC1, Ba3, Bb5), (AC1, Ba3, Bb6 ), (AC1, Ba4, Bb1), (AC1, Ba4, Bb2), (AC1, Ba4, Bb3), (AC1,
  • One embodiment of the compound of the present invention has the following groups in the following general formulas (IV) and (V).
  • AAC, Ba, Bb (AAC1, BBa1, BBb1), (AAC1, BBa1, BBb2), (AAC1, BBa1, BBb3), (AAC1, BBa2, BBb1), (AAC1, BBa2, BBb2), (AAC1 , BBa2, BBb3), (AAC1, BBa3, BBb1), (AAC1, BBa3, BBb2), (AAC1, BBa3, BBb3), (AAC1, BBa4, BBb1), (AAC1, BBa4, BBb2), (AAC1, BBa4 , BBb3), (AAC1, BBa5, BBb1), (AAC1, BBa5, BBb2), (AAC1, BBa5, BBb3), (AAC2, BBa1, BBb1), (AAC1, BBa5, BBb1), (AAC1, BBa5, BBb1), (AAC1, BBa5,
  • histamine H4 receptor agonist, partial agonist, inverse agonist and antagonist, particularly antagonist
  • histamine H4 receptor is It is useful as a therapeutic agent for diseases involved.
  • respiratory diseases such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD); rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus Inflammatory diseases such as atherosclerosis; effective for pain relief including neuropathic pain and nociceptive pain.
  • the compounds of the present invention have a high affinity for histamine receptors, in particular histamine H4 receptors, subtype selectivity (selectivity for histamine H1, H2, and H3 receptors, in particular selectivity for H3 receptors) and Since it has high selectivity for other receptors, it can be a medicament with reduced side effects (for example, influence on motor function).
  • the compound of the present invention has high stability, high oral absorption, high solubility, good bioavailability, low clearance, long half-life, high sustained efficacy, and / or liver enzyme There are also advantages such as low inhibitory activity.
  • the present invention provides a pharmaceutical composition comprising a combination of an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
  • compositions for example, excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, surfactants, and the like
  • pharmaceutically acceptable carriers well known in the art Can be used to produce a pharmaceutical composition according to a conventional method.
  • the dosage unit dosage form can be appropriately selected depending on the therapeutic purpose and administration route. Specifically, oral preparations such as tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions, and parenterals such as injections, suppositories, ointments, patches, aerosols, etc. Agents. These dosage unit forms are formulated according to methods well known in the art.
  • the amount of the compound of the present invention to be contained in the above preparation can be appropriately changed depending on the dosage form, administration route, administration schedule and the like.
  • the administration method of the pharmaceutical composition according to the present invention is appropriately determined according to the dosage form of the preparation, the age, sex, weight, symptom level and other conditions of the patient, and is oral, subcutaneous, transdermal, rectal, nasal It can be selected from various routes such as inner and oral cavity.
  • the dose of the compound of the present invention contained in the pharmaceutical composition of the present invention depends on the selected route of administration, patient age, sex, weight, disease state, type of the compound administered, other conditions, etc. Although it is appropriately selected, in the case of oral administration to adults, it is usually 0.05 to 1000 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 100 mg / kg / day, preferably 0.01 to 1 mg / kg / day. These pharmaceutical compositions of the present invention can be administered once a day or divided into a plurality of times.
  • reaction solution was poured into water, washed with ethyl acetate, neutralized with sodium bicarbonate with stirring, and the aqueous layer was adjusted to pH 8.
  • the aqueous layer was extracted again with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain compound (4) (48.8 mg, 94% yield).
  • reaction solution was poured into ice water-2 mol / l hydrochloric acid and extracted with ethyl acetate.
  • organic layer was washed with aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran.
  • the organic layer was washed with water and dried over anhydrous sodium sulfate.
  • the organic layer was concentrated under reduced pressure to obtain yellow compound 39 (8.4 g, crude yield 98%). Used in the next step without purification.
  • Step 5 Compound 41 (2.37 g, 5.83 mmol) was dissolved in ethanol-tetrahydrofuran (3: 1) (75 mL), 20 w / w% palladium hydroxide on carbon (460 mg) was added, and 1 The mixture was stirred at room temperature for 2.5 hours under atmospheric hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain yellow compound 42 (1.36 g, yield 57%).
  • Step 7 Compound 43 (50 mg, 0.297 mmol) was dissolved in phenylphosphoric dichloride (232 mg, 1.189 mmol), and the mixture was heated and stirred at 140 ° C. for 1.5 hours and 160 ° C. for 2 hours. The reaction mixture was poured into water, basified with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain white compound 44 (15.9 mg, yield 26%).
  • Step 2 Compound 48 (1.7 mL) was added to a solution of compound 47 (5.27 g, 20.1 mmol) and triethylamine (5.6 mL, 40.3 mmol) in dichloromethane-tetrahydrofuran (1: 1, 60 mL). 22.1 mmol) was added under ice cooling, followed by stirring for 2.5 hours under ice cooling. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 49 was used in the next step without purification.
  • Step 4 To a solution of compound 51 (0.40 g, 1.40 mmol) in ethanol-tetrahydrofuran-formic acid (5: 1: 0.1, 12 mL) was added palladium / carbon (0.30 g, 0.279 mmol). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was dissolved in chloroform and washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 7 To a compound 66 (40 mg, 0.076 mmol) was added a 4 mol / L ethyl acetate solution (0.5 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and recrystallized with ethyl acetate to obtain Compound 67 (33.2 mg, total yield 94.4%).
  • tert-butyl piperazine-1-carboxylate (Compound 74, 245 mg, 1.32 mmol) was added, and the mixture was further stirred for 45 minutes.
  • the reaction mixture was poured into ice water and extracted with ethyl acetate.
  • the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Compound 80 (I-304) Compound 80 was synthesized by the method described in International Publication No. WO03 / 088381A1. This was carried out using Escherichia coli BL21 (DE3) into which an expression vector into which the CYP146 gene derived from Amycolatopsis orientalis was inserted was introduced.
  • Sterilized seed culture medium (6.78 g / L Na 2 HPO 4 (anhydrous), 3 g / L KH 2 PO 4 , 0.5 g / L NaCl, 1 g / L NH 4 Cl, 10 g / L casamino acid, 4 g / L Glucose, 20 mg / L thymine, 11 mg / L CaCl 2 , 95 mg / L MgCl 2 , 28 mg / L FeSO 4 , 100 mg / L Carbicillin) and cultured at 25 ° C. for 24 hours on a reciprocating shaker at 300 rpm Was the seed mother.
  • Sterilized main culture medium (6.78 g / L Na 2 HPO 4 (anhydrous), 3 g / L KH 2 PO 4 , 0.5 g / L NaCl, 1 g / L NH 4 Cl, 10 g / L casamino acid, 20 mg / L Thymine, 11 mg / L CaCl 2 , 28 mg / L FeSO 4 , 80 mg / L 5-aminolevulinic acid, 100 mg / L Carbillillin, Merck's 0 version AutoInduction System-Solution I 20 ml / L, -Solution III 50 1 ml / L) was dispensed 3 L at a time into two 5 L aeration and agitation culture apparatuses, then 15 ml of the seed mother was inoculated and aerated (3 L / min) at 25 ° C.
  • the culture broth was collected in a centrifuge tube, centrifuged at 4000 rpm for 10 minutes, and the supernatant was removed. Then, 1.2 L of sodium phosphate buffer (50 mmol / L sodium phosphate (pH 7.4), 2% glycerol, 50 mg / LC Carbicillin, 24 mg / L isopropyl- ⁇ -thiogalactopyranoside) was added and suspended to prepare a 5-fold concentrated bacterial solution.
  • sodium phosphate buffer 50 mmol / L sodium phosphate (pH 7.4)
  • 2% glycerol 50 mg / LC Carbicillin, 24 mg / L isopropyl- ⁇ -thiogalactopyranoside
  • Step 6 To a solution of compound 95 (94 mg, 0.40 mmol) in N-methylpyrrolidone (1.5 mL), 2-amino-N-isopropylethanesulfonamide hydrochloride (98 mg, 0.48 mmol), N, N-di After adding isopropyl ethylamine (0.169 mL, 0.97 mmol), the mixture was stirred at 100 ° C. for 30 minutes. Further, tert-butyl piperazine-1-carboxylate (376 mg, 2.02 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation.
  • Step 4 Compound 102 (159 mg, 0.36 mmol) in 1,4-dioxane (3 mL) was added to triphenylphosphine (123 mg, 0.47 mmol), 2.2 M diethylazodicarboxylate / toluene solution (0.213 mL). , 0.47 mmol), and a solution of compound 100 (72 mg, 0.43 mmol) in 1,4-dioxane (0.5 mL) were added and stirred at room temperature for 2 hours.
  • triphenylphosphine (123 mg, 0.47 mmol), 2.2 M diethylazodicarboxylate / toluene solution (0.213 mL, 0.47 mmol), compound 100 (72 mg, 0.43 mmol) in 1,4-dioxane (0 0.5 mL) solution was added twice every hour and stirred at room temperature for 1 hour.
  • the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution.
  • tert-butyl piperazine-1-carboxylate (212 mg, 1.14 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation.
  • the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution.
  • the extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from chloroform to give Compound 110 (152 mg, yield 75%) as a white solid.
  • Nonspecific binding was determined by incubating in the presence of 100 ⁇ mol / L unlabeled histamine dihydrochloride (Nakalai Tesque). Membrane fractions were collected on 0.5% PEI coated Unifilterplate GF / B (PerkinElmer) by rapid filtration using a PerkinElmer cell harvester and washed 6 times with 350 ⁇ L ice-cold 50 mmol / L Tris-HCl, pH 7.4. . The filter was air-dried, mixed with a scintillation cocktail Microscinti-MS (PerkinElmer), and the radioactivity trapped on the filter was measured with a Topcount liquid scintillation counter (PerkinElmer).
  • the results of the histamine H4 receptor binding test of the compounds of the present invention are shown in the following table.
  • the unit nM in the table indicates nmol / L.
  • Test Example Histamine H3 receptor binding test Human-derived histamine H3 receptor forced expression CHO-K1 cell membrane fraction (PerkinElmer), radioligand [3H] -histamine (PerkinElmer), binding buffer (50 mmol / L Tris) Receptor binding assays were performed in HCl pH 7.4, 5 mmol / L EDTA). [3H] -Histamine with a final concentration of 15 nmol / L was added to a binding buffer in which 15 ⁇ g of the histamine H3 receptor-expressing membrane fraction was suspended, and incubated at room temperature for 60 minutes at a reaction volume of 150 ⁇ L.
  • Nonspecific binding was determined by incubating in the presence of 100 ⁇ mol / L unlabeled histamine dihydrochloride (Nakalai Tesque). Membrane fractions were collected on 0.5% PEI coated Unifilterplate GF / B (PerkinElmer) by rapid filtration using a PerkinElmer cell harvester and washed 6 times with 350 ⁇ L ice-cold 50 mM Tris-HCl, pH 7.4. The filter was air-dried, mixed with a scintillation cocktail Microscinti-MS (PerkinElmer), and the radioactivity trapped on the filter was measured with a Topcount liquid scintillation counter (PerkinElmer).
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (BFC) as a CYP3A4 enzyme using E. coli-expressed CYP3A4 as an enzyme.
  • BFC 7-benzyloxytrifluoromethylcoumarin
  • the reaction is debenzylated to produce a metabolite 7-hydroxytrifluoromethylcoumarin (HFC) that emits fluorescence.
  • the reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C.
  • the fluorescence value of 7-HFC which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • DMSO a solvent in which the drug was dissolved
  • Test Example CYP Inhibition Test O-deethylation of 7-ethoxyresorufin (CYP1A2) as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes ), Methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the amount of product produced is inhibited by the test compound is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multilabel counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. Used to calculate IC 50 by inverse estimation with a logistic model.
  • Test example Metabolic stability test Using pooled rat liver microsomes prepared according to the literature (Japanese journal of pharmacology, 33 (1), p.41-56, Feb 1983) or commercially available pooled human liver microsomes The reaction is performed for a certain period of time, the residual rate is calculated by comparing the reaction sample and the unreacted sample, and the degree of metabolism in the liver is evaluated. 1 mmol / L NADPH in 0.2 mL buffer (50 mmol / L tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL rat or human liver microsomes The reaction is carried out at 37 ° C.
  • the test compound in the centrifugal supernatant is quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction is calculated with the amount of the compound at 0 minute reaction as 100%.
  • the hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • Test example hERG test A delay that plays an important role in the ventricular repolarization process using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of risk assessment of ECG QT interval prolongation
  • I Kr rectified K + current
  • a +50 mV depolarization stimulus was further applied for 2 seconds. Record the I Kr elicited when a 50 mV repolarization stimulus is applied for 2 seconds.
  • the absolute value of the maximum tail current is measured using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the test substance on I Kr is evaluated. (Result) The inhibition rate at a compound concentration of 1 ⁇ mol / l is shown.
  • I-005 1% I-065: 1% I-067: 7% I-212: 4% I-236: 1% I-279: 3% I-301: 2% I-342: 8%
  • Test example Powder solubility test Put an appropriate amount of sample in a suitable container, JP-1 solution (2.0 g sodium chloride, 7.0 mL hydrochloric acid to 1000 mL), JP-2 solution (pH 6.8 phosphate buffer) Add 500 mL of water to 500 mL of solution), and add 200 ⁇ L of 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (add water to 1.08 g of TCA to make 100 mL). If dissolved after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C for 1 hour. Filter, add 100 ⁇ L of methanol to 100 ⁇ L of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. Quantify using HPLC with the absolute calibration curve method.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • HPC-L low-viscosity hydroxypropylcellulose
  • aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1mm), and dry.
  • the obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg
  • the compound of formula (I), lactose is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate 5 mg
  • the compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 5 A haptic agent containing the following components is produced.
  • Ingredient Compound represented by formula (I) 50 mg Aqueous base (5% ethanol / 5% butylene glycol / 90% purified water) 950 mg Glycerin Kaolin Polyvinyl alcohol aqueous solution
  • the compound represented by the formula (I) is added to an aqueous base, and after ultrasonic irradiation for about 15 minutes, the mixture is sufficiently stirred to obtain a solution. 5 parts of glycerin, 1 part of kaolin and 5 parts of an aqueous polyvinyl alcohol solution are uniformly mixed, and 1 part of the prepared solution is added.
  • the compound of the present invention has a modulatory action on the histamine H4 receptor, and diseases or conditions involving the histamine H4 receptor such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), etc. Diseases; rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus, atherosclerosis, and other inflammatory diseases; pain relief including neuropathic or nociceptive pain Useful for.
  • diseases or conditions involving the histamine H4 receptor such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), etc. Diseases; rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus, atherosclerosis, and other inflammatory diseases; pain relief including

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Abstract

Disclosed is a novel compound which has histamine H4 receptor modulating activity. Specifically disclosed is a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt. (In the formula, ring A represents an aromatic heterocyclic ring; -B1 represents a group represented by -X-(CR8aR8b)m-Y; X represents a group represented by N(R7c) or the like; R7c represents a hydrogen atom, a substituted or unsubstituted alkyl group or the like; R8a and R8b each independently represents a hydrogen atom, a halogen atom or the like; m represents an integer of 0-5; Y represents a substituted or unsubstituted cycloalkylthio group or the like; and -B2 represents a group represented by formula (II) (wherein R10s each independently represents a substituted or unsubstituted alkyl group or the like; R11 represents a hydrogen atom, a substituted or unsubstituted alkyl group or the like; and p represents an integer of 0-4) or the like.)

Description

ピリミジン誘導体およびそれらを含有する医薬組成物Pyrimidine derivatives and pharmaceutical compositions containing them

　本発明は、ヒスタミンＨ４受容体が関与する疾患または状態を治療するのに有用な化合物もしくはその製薬上許容される塩またはそれらの溶媒和物、およびそれらを含有する医薬組成物に関する。 The present invention relates to a compound useful for treating a disease or condition involving histamine H4 receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical composition containing them.

　ヒスタミンは、Ｇ－タンパク質結合スーパーファミリーの４つの受容体（ヒスタミンＨ１、Ｈ２、Ｈ３およびＨ４受容体）と相互作用し、Ｈ１受容体を介するアレルギー反応、Ｈ２受容体を介する胃酸分泌作用、Ｈ３受容体を介する中枢神経系における神経伝達作用などの、種々の生理機能を発現する。
　ヒスタミンＨ４受容体は、Ｈ３受容体に約４０％の相同性を持つ３９０個のアミノ酸からなる７回膜貫通型Ｇタンパク質結合受容体である。主に好酸球、肥満細胞、樹状細胞、Ｔ細胞などの血球系細胞に発現しており、特に好酸球、肥満細胞において高発現している（非特許文献１、非特許文献２）。
　また、ヒスタミンＨ４受容体は、リウマチ患者より採取した滑膜細胞における発現が確認されており（非特許文献３、非特許文献４）、変形性関節症患者より採取した滑膜細胞においても発現が確認されており（非特許文献５）、腸管細胞においても発現が確認されている（非特許文献６）。さらに、鼻腔内ポリープにおいても、ヒスタミンＨ４受容体の発現量が増加していることが報告されている（非特許文献７）。
　ヒスタミンＨ４受容体の薬理学的性質は、幾つかの特異的なリガンドによっても明らかにされている。例えば、好酸球の遊走および形態変化、ならびにＣＤ１１ｂ／ＣＤ１８、ＣＤ５４の発現上昇などは、ヒスタミンがＨ４受容体に結合することによって惹起される作用であることが知られている（非特許文献８）。また、ヒスタミンＨ４受容体は、肥満細胞におけるカルシウムの流入に関与すること（非特許文献９）、樹状細胞におけるサイトカイン産生調節に関与すること（非特許文献１０）なども知られており、その作用は多彩である。
　ｉｎ　ｖｉｖｏにおいては、ヒスタミンＨ４受容体は、ヒスタミンによって誘発される肥満細胞の集積に関与すること（非特許文献９）、ｚｙｍｏｓａｎによって誘発される腹膜炎モデル（非特許文献１１）および胸膜炎モデル（非特許文献１２）における好中球浸潤に関与すること、卵白アルブミンによる喘息モデルにおける好酸球浸潤に関与すること（非特許文献１０）、ならびに痒みに関与すること（非特許文献１３）が報告されている。
　ヒスタミンＨ４受容体に芳香族複素環誘導体が作用することは、特許文献１、特許文献２、特許文献３、非特許文献１４および非特許文献１５に記載されているが、いずれの文献にも本発明化合物は記載も示唆もされていない。 Histamine interacts with four receptors of the G-protein coupled superfamily (histamine H1, H2, H3 and H4 receptors), allergic reaction through H1 receptor, gastric acid secretion through H2 receptor, H3 receptor It expresses various physiological functions such as neurotransmission in the central nervous system through the body.
The histamine H4 receptor is a 7-transmembrane G protein-coupled receptor consisting of 390 amino acids with about 40% homology to the H3 receptor. It is mainly expressed in blood cells such as eosinophils, mast cells, dendritic cells, and T cells, and particularly highly expressed in eosinophils and mast cells (Non-patent Documents 1 and 2). .
In addition, histamine H4 receptor has been confirmed to be expressed in synovial cells collected from rheumatic patients (Non-patent Documents 3 and 4), and is also expressed in synovial cells collected from osteoarthritis patients. It has been confirmed (Non-Patent Document 5), and expression has also been confirmed in intestinal cells (Non-Patent Document 6). Furthermore, it has been reported that the expression level of histamine H4 receptor is also increased in intranasal polyps (Non-patent Document 7).
The pharmacological properties of the histamine H4 receptor have also been revealed by several specific ligands. For example, eosinophil migration and morphological changes, and increased expression of CD11b / CD18 and CD54 are known to be effects caused by binding of histamine to the H4 receptor (Non-patent Document 8). ). The histamine H4 receptor is also known to be involved in calcium influx in mast cells (Non-patent Document 9), to be involved in regulation of cytokine production in dendritic cells (Non-patent Document 10), and the like. The action is various.
In vivo, histamine H4 receptor is involved in the accumulation of mast cells induced by histamine (Non-patent document 9), peritonitis model induced by zymosan (Non-patent document 11) and pleurisy model (non-patent document) Involvement in neutrophil infiltration in literature 12), involvement in eosinophil infiltration in an asthma model by ovalbumin (Non-patent document 10), and involvement in itch (non-patent document 13) have been reported. Yes.
It has been described in Patent Document 1, Patent Document 2, Patent Document 3, Non-Patent Document 14, and Non-Patent Document 15 that an aromatic heterocyclic derivative acts on a histamine H4 receptor. Inventive compounds are neither described nor suggested.

国際公開第２００９／０８３０８６号明細書International Publication No. 2009/083086 国際公開第２００８／００８３５９号明細書International Publication No. 2008/008359 Specification 国際公開第２００９／１５２３２５号明細書International Publication No. 2009/152325

Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，２０００，２７５，３６７８J. et al. Biol. Chem. 2000, 275, 3678 ＭｏｌＰｈａｒｍａｃｏｌ．，２００１，５９，４２７．MolPharmacol. , 2001, 59, 427. Ａｎｎ．Ｒｈｅｕｍ．Ｄｉｓ．，２００６，６５（Ｓｕｐｐｌ　ＩＩ），　１２９Ann. Rheum. Dis. 2006, 65 (Suppl II), 129 Ｂｉｏ．Ｐｈａｒｍ．Ｂｕｌｌ．，２００５，２８，２０１６．Bio. Pharm. Bull. 2005, 28, 2016. Ｅｕｒｏｐｅａｎ　Ｈｉｓｔａｍｉｎｅ　Ｒｅｓｅａｒｃｈ　Ｓｏｃｉｅｔｙ　ＸＸＸＶＩ　Ａｎｎｕａｌ　ｍｅｅｔｉｎｇ，　Ｆｌｏｒｅｎｃｅ，　Ｉｔａｌｙ，　２００７，Ｐ－１１European Histamine Research Society XXXVI Annual meeting, Florence, Italy, 2007, P-11 Ｇｕｔ，２００６，５５，４９８．Gut, 2006, 55, 498. Ｃｅｌｌ　Ｂｉｏｌ．　Ｉｎｔ．，２００７，３１，１３６７．Cell Biol. Int. 2007, 31, 1367. Ｂｒ．　Ｊ．　Ｐｈａｒｍａｃｏｌ．，２００４，１４２，１６１．Br. J. Pharmacol. , 2004, 142, 161. Ｊ．Ｐｈａｒｍｃｏｌ．Ｅｘｐ．Ｔｈｅｒ．，２００３，３０５，１２１２．J. et al. Pharmcol. Exp. Ther. 2003, 305, 1212. Ｊ．Ｉｍｍｕｎｏｌ．，２００６，１７６，７０６２．J. et al. Immunol. 2006, 176, 7062. Ｊ．Ｐｈａｒｍｃｏｌ．Ｅｘｐ．Ｔｈｅｒ．，２００４，３０９，４０４．J. et al. Pharmcol. Exp. Ther. , 2004, 309, 404. Ｊ．Ｐｈａｒｍｃｏｌ．Ｅｘｐ．Ｔｈｅｒ．，２００３，３０７，　１０７２．J. et al. Pharmcol. Exp. Ther. , 2003, 307, 1072. Ｊ．Ａｌｌｅｒｇｙ．　Ｃｌｉｎ．　Ｉｍｍｕｎｏｌ．，２００７，１１９，１７６．J. et al. Allergy. Clin. Immunol. , 2007, 119, 176. Ｊ．Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ，　２００８，　５１，　７８５５－７８６５J. et al. Medicinal Chemistry, 2008, 51, 7855-7865 Ｊ．Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ，　２０１０，　５３，　２３９０－２４００J. et al. Medicinal Chemistry, 2010, 53, 2390-2400

　本発明は、ヒスタミンＨ４受容体を調節する作用を有する新規な化合物を提供する。 The present invention provides a novel compound having an action of regulating histamine H4 receptor.

　本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、ヒスタミンＨ４受容体を調節する作用を有し、ヒスタミンＨ４受容体により仲介される疾患の予防および／または治療に有用な新規化合物を見出し、以下に記載する発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have an action of regulating histamine H4 receptor, and are useful for the prevention and / or treatment of diseases mediated by histamine H4 receptor. The inventors discovered a new compound and completed the invention described below.

　本発明は、以下の（１）～（１５）に関する。
（１）　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000011

［式中、
環Ａは、芳香族複素環；
Ｘ１は、ＮまたはＣ（Ｒｘ１）；
Ｘ２は、ＮまたはＣ（Ｒｘ２）；
Ｘ３は、ＮまたはＣ（Ｒｘ３）；
Ｘ４は、ＮまたはＣ（Ｒｘ４）；
ただし、Ｘ１、Ｘ２、Ｘ３およびＸ4の少なくとも１つは、窒素原子である；
Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；または、
Ｒｘ２およびＲｘ３、またはＲｘ３およびＲｘ４は、それぞれ隣接する環構成原子と一緒になってＣ環を形成してもよく；
Ｃ環は、
Figure JPOXMLDOC01-appb-C000012
（式中、
Ｗ１は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ａ）、Ｓ、Ｓ（Ｏ）またはＳ（Ｏ）２；
Ｗ２は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ｂ）またはＳ；
Ｒ２ａおよびＲ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニルまたは置換もしくは非置換のアシル；
ｎ１は、０～４の整数；
ｎ２は、０～３の整数；
ｎ３は、０～２の整数；
ｎ４は、０または１の整数；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、
ａ）ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
Ｒ１aは、以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、０～５の整数、
ただし、Ｙが、置換基群Ａから選択される置換基で置換されたスルホニルによって環を構成する窒素原子が置換されている含窒素非芳香族複素環基以外の基である場合は、ｍは１～４の整数である；
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000013
（式中、
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のシクロアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン］で示される化合物（ただし、
（i）Ａ環がＣ環と縮合せず、Ｙが置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである化合物、
（ii）ｍが０であり、ＸがＮ（Ｒ７ｃ）であり、Ｒ７ｃが水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシルであり、Ｙが置換もしくは非置換のヘテロアリールまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換されたインドリンである化合物、
（iii）Ｒ１１がヘテロアリールで置換されたアミノおよびチオキソで置換されたアルキルである化合物、
および
（iv）以下に示す化合物：
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
（式中、Ｍｅはメチルであり、Ｅｔはエチルである）
を除く。）、もしくはその製薬上許容される塩またはそれらの溶媒和物。 The present invention relates to the following (1) to (15).
(1) Formula (I):
Figure JPOXMLDOC01-appb-C000011
[Where:
Ring A is an aromatic heterocycle;
X 1 is N or C (R x1 );
X 2 is N or C (R x2 );
X 3 is N or C (R x3 );
X 4 is N or C (R x4 );
Provided that at least one of X 1 , X 2 , X 3 and X 4 is a nitrogen atom;
R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyl Ruoxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A (substituent group A: Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted Or substituted aryl or substituted heteroaryl), carbamoyl substituted with a substituent selected from substituents selected from substituent group A, sulfamoyl substituted with substituent selected from substituent group A, substituent group A Sulfur substituted with a substituent selected from Nyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or non-substituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy; or
R x2 and R x3 , or R x3 and R x4 , together with adjacent ring members, may form a C ring;
Ring C is
Figure JPOXMLDOC01-appb-C000012
(Where
Each W 1 is independently O, N (R 2a ), S, S (O) or S (O) 2 ;
Each W 2 independently represents O, N (R 2b ) or S;
R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, unsubstituted sulfamoyl, a sulfamoyl substituted with a substituent selected from substituent group A, or a substituent selected from substituent group A A sulfinyl substituted with a group, a sulfonyl substituted with a substituent selected from Substituent Group A, or a substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
n 2 is an integer from 0 to 3;
n 3 is an integer from 0 to 2;
n 4 is an integer of 0 or 1;
R 1a and R 1b are each independently
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxy From sulfonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, carbamoyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, substituent group A Sulfamoyl substituted with a selected substituent, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Oxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted Heteroaryloxy or
R 1a may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x— or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 0 to 5,
However, when Y is a group other than a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the ring is substituted by a sulfonyl substituted with a substituent selected from the substituent group A, m is An integer from 1 to 4;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl Sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Nitrogen-containing non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from substituent group A A group represented by
B 2 is,
Figure JPOXMLDOC01-appb-C000013
(Where
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer of 0 to 4) or a alkylene represented by a substituted or unsubstituted amino group] (provided that,
(I) a compound wherein A ring is not fused to C ring and Y is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
(Ii) m is 0, X is N (R 7c ), R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl, and Y is substituted or unsubstituted heteroaryl or A compound in which the nitrogen atom constituting the ring is an indoline substituted with a sulfonyl substituted with a substituent selected from the substituent group A;
(Iii) the compound wherein R 11 is amino substituted with heteroaryl and alkyl substituted with thioxo,
And (iv) the following compounds:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
(Wherein Me is methyl and Et is ethyl)
except for. Or a pharmaceutically acceptable salt thereof or a solvate thereof.

（２）Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であり、Ｒｘ３およびＲｘ４が、それぞれ隣接する環構成原子と一緒になってＣ環を形成するか、またはＸ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮであり、Ｒｘ２およびＲｘ３が、それぞれ隣接する環構成原子と一緒になってＣ環を形成し；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基であり；
Ｂ２が、

Figure JPOXMLDOC01-appb-C000016

（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは上記（１）と同意義）で示される基である上記（１）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (2) X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), and R x3 and R x4 are each together with an adjacent ring member atom. To form a C ring, or X 1 is N, X 2 is C (R x2 ), X 3 is C (R x3 ), and X 4 is N, and R x2 and R x3 are adjacent to each other Together with the ring atoms to form a C ring;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent;
B 2 is,
Figure JPOXMLDOC01-appb-C000016
(Wherein R 9a , R 9b , R 10 , R 11 and p are as defined in (1) above), or a pharmaceutically acceptable salt thereof or a compound thereof Solvates.

（３）Ｃ環が、

Figure JPOXMLDOC01-appb-C000017

（式中、Ｗ１、Ｗ２、Ｒ１ａ、Ｒ１ｂ、ｎ１、ｎ２、ｎ３およびｎ４は、上記（１）と同意義）で示される環である上記（２）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (3) Ring C is
Figure JPOXMLDOC01-appb-C000017
(Wherein W 1 , W 2 , R 1a , R 1b , n 1 , n 2 , n 3 and n 4 have the same meaning as (1) above), and the compound according to (2) above Or a pharmaceutically acceptable salt thereof or a solvate thereof.

（４）Ｃ環が、

Figure JPOXMLDOC01-appb-C000018

（式中、Ｗ１、Ｒ１ａおよびｎ１は、上記（１）と同意義）で示される環である上記（２）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (4) Ring C is
Figure JPOXMLDOC01-appb-C000018
(Wherein W 1 , R 1a and n 1 have the same meanings as (1) above), or a pharmaceutically acceptable salt thereof or a solvate thereof. .

（５）Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４が、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｘが、Ｎ（Ｒ７ｃ）（式中、Ｒ７ｃは上記（１）と同意義）；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
Ｂ２が、

Figure JPOXMLDOC01-appb-C000019

（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは上記（１）と同意義）で示される基である請求項１記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (5) R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, Hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cyclo Substitution selected from lukenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A Selected from carbamoyl substituted with a group, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A, sulfinyl substituted with a substituent selected from Substituent Group A, Substituent Group A Substituted sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Of cycloalkenyl, substituted or Substituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
X is N (R 7c ) (wherein R 7c is as defined in (1) above);
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent;
B 2 is,
Figure JPOXMLDOC01-appb-C000019
(Wherein R 9a , R 9b , R 10 , R 11 and p are the same as defined in (1) above), or a pharmaceutically acceptable salt thereof or a salt thereof Solvate.

（６）Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であるか、または
Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮである、上記（５）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (6) X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), or X 1 is N, X 2 is C (R x2 ), The compound of the above-mentioned (5), wherein X 3 is C (R x3 ), and X 4 is N, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（７）Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であるか、または
Ｘ１がＣ（Ｒｘ１）、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）である、上記（５）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (7) X 1 is N, X 2 is C (R x2 ), X 3 is C (R x3 ), and X 4 is C (R x4 ), or X 1 is C (R x1 ), X The compound according to the above (5), wherein 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（８）Ｂ２が、

Figure JPOXMLDOC01-appb-C000020

（式中、Ｒ１０、Ｒ１１、およびｐは上記（１）と同意義）で示される基である、上記（１）～（７）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (8) B 2 is,
Figure JPOXMLDOC01-appb-C000020
(Wherein R 10 , R 11 , and p are as defined in (1) above), or a pharmaceutically acceptable compound thereof Salts or solvates thereof.

（９）Ｙが、置換基群Ａから選択される置換基で置換されたスルホニル、非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基である、上記（１）～（８）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１０）Ｙが、置換基群Ａから選択される置換基で置換されたスルホニル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルファモイルである、上記（１）～（９）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１１）ｍが、１～３の整数である上記（１）～（１０）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１２）上記（１）～（１１）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。

（１３）ヒスタミンＨ４調節剤である、上記（１２）記載の医薬組成物。

（１４）上記（１）～（１１）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ヒスタミンＨ４受容体が関与する疾患または状態の治療および／または予防方法。

（１５）ヒスタミンＨ４受容体が関与する疾患または状態の治療および／または予防のための、上記（１）～（１１）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
(9) Y is sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A, substituted or unsubstituted alkylsulfonyl Amino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocycle Sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or nitrogen-containing nitrogen substituted with a sulfonyl substituted with a substituent selected from substituent group A A non-aromatic heterocyclic group, Serial (1) compound, or a pharmaceutically acceptable salt or solvate thereof according to any one of the - (8).

(10) Y is sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from Substituent Group A (9) The compound according to any one of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(11) The compound according to any one of the above (1) to (10), wherein m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(12) A pharmaceutical composition comprising the compound according to any one of (1) to (11) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(13) The pharmaceutical composition according to the above (12), which is a histamine H4 modulator.

(14) a disease involving histamine H4 receptor, comprising administering a compound according to any one of (1) to (11) above, a pharmaceutically acceptable salt thereof, or a solvate thereof; How to treat and / or prevent a condition.

(15) The compound according to any one of (1) to (11) above, a pharmaceutically acceptable salt thereof or a solvent thereof for the treatment and / or prevention of a disease or condition involving histamine H4 receptor Japanese products.

また、本発明は例えば、以下の項目に関する。
（１’）式（Ｉ）：

Figure JPOXMLDOC01-appb-C000021

［式中、
環Ａは、芳香族６員環；
Ｘ１は、ＮまたはＣ（Ｒｘ１）；
Ｘ２は、ＮまたはＣ（Ｒｘ２）；
Ｘ３は、ＮまたはＣ（Ｒｘ３）；
Ｘ４は、ＮまたはＣ（Ｒｘ４）；
Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；または、
Ｒｘ２およびＲｘ３、またはＲｘ３およびＲｘ４は、それぞれ隣接する環構成原子と一緒になってＣ環を形成してもよく；
Ｃ環は、
Figure JPOXMLDOC01-appb-C000022
（式中、
Ｗ１は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ａ）、Ｓ、Ｓ（Ｏ）またはＳ（Ｏ）２；
Ｗ２は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ｂ）またはＳ；
Ｒ２ａおよびＲ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
ｎ１は、０～４の整数；
ｎ２は、０～３の整数；
ｎ３は、０～２の整数；
ｎ４は、０または１の整数；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
Ｒ１aは、以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｃ（Ｒ７ａＲ７ｂ）、Ｎ（Ｒ７ｃ）、ＯまたはＳ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキル、シアノ、または一緒になってオキソもしくはチオキソ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、０～５の整数；
Ｙは、メルカプト、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、環内の窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000023
（式中、
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）で示される基）で示される化合物（ただし、
（i）Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４が、同時に２つ以上非置換スルファモイルである化合物、
（ii）Ａ環がＣ環と縮合せず、Ｙがメルカプト、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである化合物、
（iii）Ｙが置換もしくは非置換のアルキルおよび置換もしくは非置換のアルキルオキシカルボニルで置換されたチアゾリル、または置換もしくは非置換のピリジルで置換されたチアゾリルである化合物、
（iv）ｍが０であり、ＸがＮ（Ｒ７ｃ）、ＯまたはＳである化合物、
（v）ｍが１であり、Ｒ７ａまたはＲ７ｂがシアノであり、かつＹが非置換ベンゾチアゾリルである化合物、および
（vi）以下に示す化合物：
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
を除く。］、もしくはその製薬上許容される塩またはそれらの溶媒和物。 Moreover, this invention relates to the following items, for example.
(1 ′) Formula (I):
Figure JPOXMLDOC01-appb-C000021
[Where:
Ring A is an aromatic 6-membered ring;
X 1 is N or C (R x1 );
X 2 is N or C (R x2 );
X 3 is N or C (R x3 );
X 4 is N or C (R x4 );
R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyl Ruoxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A (substituent group A: Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted Or substituted aryl or substituted heteroaryl), carbamoyl substituted with a substituent selected from substituents selected from substituent group A, sulfamoyl substituted with substituent selected from substituent group A, substituent group A Sulfur substituted with a substituent selected from Nyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or non-substituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy; or
R x2 and R x3 , or R x3 and R x4 , together with adjacent ring members, may form a C ring;
Ring C is
Figure JPOXMLDOC01-appb-C000022
(Where
Each W 1 is independently O, N (R 2a ), S, S (O) or S (O) 2 ;
Each W 2 independently represents O, N (R 2b ) or S;
R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
n 2 is an integer from 0 to 3;
n 3 is an integer from 0 to 2;
n 4 is an integer of 0 or 1;
R 1a and R 1b are each independently
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl From bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, carbamoyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, substituent group A Sulfamoyl substituted with a selected substituent, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Oxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or non-substituted Substituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted hetero Aryloxy or
R 1a may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) Two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is C (R 7a R 7b ), N (R 7c ), O or S;
R 7a and R 7b are each independently hydrogen, substituted or unsubstituted alkyl, cyano, or together oxo or thioxo;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 0 to 5;
Y is mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted Non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, sulfinyl substituted with a substituent selected from Substituent Group A, substituent selected from Substituent Group A Substituted sulfonyl, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonyl Amino, substituted or non- Substituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or An unsubstituted heteroarylsulfonylamino, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a nitrogen atom in the ring substituted with a sulfonyl substituted with a substituent selected from Substituent Group A A nitrogen non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl);
B 2 is,
Figure JPOXMLDOC01-appb-C000023
(Where
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 is hydrogen or substituted or unsubstituted alkyl;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer of 0 to 4))
(I) the compound wherein R x1 , R x2 , R x3 and R x4 are simultaneously two or more unsubstituted sulfamoyl;
(Ii) ring A is not fused to ring C and Y is mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted cycloalkyl, substituted or A compound that is an unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocycle, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl,
(Iii) a compound wherein Y is thiazolyl substituted with substituted or unsubstituted alkyl and substituted or unsubstituted alkyloxycarbonyl, or thiazolyl substituted with substituted or unsubstituted pyridyl,
(Iv) a compound wherein m is 0 and X is N (R 7c ), O or S;
(V) a compound wherein m is 1, R 7a or R 7b is cyano, and Y is unsubstituted benzothiazolyl, and (vi) a compound shown below:
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
except for. Or a pharmaceutically acceptable salt or solvate thereof.

（２’）Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４が、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環内の窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
Ｂ２が、

Figure JPOXMLDOC01-appb-C000027

（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは上記（１）と同意義。）で示される基である上記（１’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (2 ′) R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl Hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cyclo Substituent selected from alkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A Selected from carbamoyl, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A, sulfinyl substituted with a substituent selected from Substituent Group A, Substituent Group A Substituted sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or Substituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl Sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a substituent in which the nitrogen atom in the ring is selected from substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a group;
B 2 is,
Figure JPOXMLDOC01-appb-C000027
(Wherein R 9a , R 9b , R 10 , R 11 and p are as defined in (1) above), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Or a solvate thereof.

（３’）Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であるか、またはＸ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮである、上記（１’）または（２’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (3 ′) X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), or X 1 is N and X 2 is C (R x2 ) , X 3 is C (R x3 ), and X 4 is N, or a compound according to (1 ′) or (2 ′), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（４’）Ｂ２が、

Figure JPOXMLDOC01-appb-C000028

（式中、Ｒ１０、Ｒ１１、およびｐは上記（１’）と同意義。）で示される基である、上記（１’）～（３’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (4 ′) B 2 is
Figure JPOXMLDOC01-appb-C000028
(Wherein R 10 , R 11 , and p have the same meanings as (1 ′) above), or a compound according to any one of (1 ′) to (3 ′) above, A pharmaceutically acceptable salt or a solvate thereof.

（５’）Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であり、Ｒｘ３およびＲｘ４が、それぞれ隣接する環構成原子と一緒になってＣ環を形成する基であるか、または、Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮであり、Ｒｘ２およびＲｘ３が、それぞれ隣接する環構成原子と一緒になってＣ環を形成する基であり；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環内の窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
Ｂ２が、

Figure JPOXMLDOC01-appb-C000029

（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは上記（１’）と同意義。）で示される基である上記（１’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (5 ′) X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), and R x3 and R x4 are each together with an adjacent ring member atom. Or X 1 is N, X 2 is C (R x2 ), X 3 is C (R x3 ), and X 4 is N, and R x2 and R x3 is a group that forms a C ring together with adjacent ring members;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl Sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a substituent in which the nitrogen atom in the ring is selected from substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a group;
B 2 is,
Figure JPOXMLDOC01-appb-C000029
(Wherein R 9a , R 9b , R 10 , R 11 and p are as defined in (1 ′) above), or a pharmaceutically acceptable compound thereof described above (1 ′) Salts or solvates thereof.

（６’）Ｒｘ２およびＲｘ３、またはＲｘ３およびＲｘ４が、それぞれ隣接する環構成原子と一緒になってＣ環を形成してもよく：
Ｃ環は、

Figure JPOXMLDOC01-appb-C000030

（式中、Ｗ１、Ｗ２、Ｒ１ａ、Ｒ１ｂ、ｎ１、ｎ２、ｎ３およびｎ４は、上記（１’）と同意義。）で示される環；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環内の窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000031
（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは上記（１）と同意義。）で示される基である上記（１’）または（５’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (6 ′) R x2 and R x3 , or R x3 and R x4 , together with adjacent ring members, may form a C ring:
Ring C is
Figure JPOXMLDOC01-appb-C000030
(Wherein W 1 , W 2 , R 1a , R 1b , n 1 , n 2 , n 3 and n 4 have the same meaning as the above (1 ′));
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl A sulfonylamino, a substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, a substituted or unsubstituted arylsulfonylamino, a substituted or unsubstituted heteroarylsulfonylamino or a substituent in which the nitrogen atom in the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with
B 2 is,
Figure JPOXMLDOC01-appb-C000031
(Wherein R 9a , R 9b , R 10 , R 11 and p have the same meanings as (1) above), or a compound thereof according to (1 ′) or (5 ′) or a pharmaceutical product thereof Top acceptable salts or solvates thereof.

（７’）Ｂ２が、

Figure JPOXMLDOC01-appb-C000032

（式中、Ｒ１０、Ｒ１１、およびｐは上記（１’）と同意義。）で示される基である、上記（１’）、（５’）または（６’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (7 ′) B 2 is
Figure JPOXMLDOC01-appb-C000032
(Wherein R 10 , R 11 , and p are as defined in (1 ′) above), or a compound described in (1 ′), (5 ′) or (6 ′) above, or The pharmaceutically acceptable salt or solvate thereof.

（８’）Ｙが、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環内の窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基である、上記（１’）～（７’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。 (8 ′) Y is sulfamoyl substituted with a substituent selected from Substituent Group A, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, Substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonyl Amino or a nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent selected from Substituent Group A in the nitrogen atom, (1 ′) to (7 ′) above Any one of the compounds or pharmaceutically acceptable salts thereof. The solvate thereof.

（９’）Ｙが、置換基群Ａから選択される置換基で置換されたスルファモイルである、上記（１’）～（８’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１０’）ｍが、１～３の整数である上記（１’）～（９’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１１’）上記（１’）～（１０’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。

（１２’）ヒスタミンＨ４調節剤である、上記（１１’）記載の医薬組成物。

（１３’）上記（１’）～（１０’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ヒスタミンＨ４受容体が関与する疾患の治療および／または予防方法。

（１４’）ヒスタミンＨ４受容体が関与する疾患の治療薬および／または予防薬の製造のための、上記（１’）～（１０’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。

（１５’）ヒスタミンＨ４受容体が関与する疾患の治療および／または予防のための、上記（１’）～（１０’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
(9 ′) The compound according to any one of the above (1 ′) to (8 ′), or a pharmaceutically acceptable salt thereof, wherein Y is sulfamoyl substituted with a substituent selected from Substituent Group A Salts or solvates thereof.

(10 ′) The compound according to any one of (1 ′) to (9 ′) above, wherein m is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(11 ′) A pharmaceutical composition comprising the compound according to any one of (1 ′) to (10 ′) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(12 ′) The pharmaceutical composition according to the above (11 ′), which is a histamine H4 modulator.

(13 ′) A histamine H4 receptor characterized by administering a compound according to any one of (1 ′) to (10 ′) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method of treating and / or preventing a disease involved.

(14 ′) The compound according to any one of the above (1 ′) to (10 ′) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving a histamine H4 receptor Salt or solvate thereof.

(15 ′) The compound according to any one of the above (1 ′) to (10 ′), or a pharmaceutically acceptable salt thereof, or the like thereof, for the treatment and / or prevention of a disease involving histamine H4 receptor Solvates.

また、本発明は例えば、以下の項目に関する。
（１’’）
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000033

［式中、Ｒａ１およびＲａ２は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、アシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；またはＲａ１およびＲａ２は、それらが結合する炭素原子と一緒になってＡ環を形成してもよく：
Ａ環は、
Figure JPOXMLDOC01-appb-C000034
（式中、
Ｒ１は、それぞれ独立して、以下のａ）群～ｅ）群からなる群から選択される１以上の基；
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、アシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、ならびに置換もしくは非置換のヘテロアリールオキシ、
ｂ）２つのＲ１が、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１が、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１が、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１が、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１は、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎは、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
[式中、
－Ｘ－は、単結合、－Ｎ（Ｒ７）－、－Ｏ－または－Ｓ－；
Ｒ７は、水素、置換もしくは非置換のアルキルまたはアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、メルカプト、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または置換もしくは非置換の非芳香族含硫黄複素環式基]で示される基；
－Ｂ’’は、
Figure JPOXMLDOC01-appb-C000035
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
Ｒ９aおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物（ただし、
Figure JPOXMLDOC01-appb-C000036
を除く。）もしくはその製薬上許容される塩またはそれらの溶媒和物。 Moreover, this invention relates to the following items, for example.
(1 '')
Formula (I ′):
Figure JPOXMLDOC01-appb-C000033
Wherein R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted Is an unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted Alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted nonaromatic heterocyclic sulfinyl, substituted Or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Ruoxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Or a substituted or unsubstituted heteroaryloxy; or R a1 and R a2 together with the carbon atom to which they are attached may form an A ring:
Ring A is
Figure JPOXMLDOC01-appb-C000034
(Where
Each R 1 independently represents one or more groups selected from the group consisting of the following groups a) to e);
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted Alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted Substituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted nonaromatic heterocyclic sulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroaryl Sulfinyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy , Cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, and substituted or unsubstituted Heteroaryloxy,
b) two R 1 are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1 are bonded to the same carbon atom-(CR 4a R 4b ) x-,
d) Two R 1 are bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) Two R 1 are bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1 is not selected from two or more of c), d) and e) at the same time;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ is represented by the formula: —X— (CR 8a R 8b ) mY
[Where
—X— represents a single bond, —N (R 7 ) —, —O— or —S—;
R 7 is hydrogen, substituted or unsubstituted alkyl or acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted Non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted Substituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroaryl Sulfinyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonyl Amino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted hetero Arylsulfonylamino, or a group represented by a substituted or unsubstituted non-aromatic sulfur-containing heterocyclic group];
-B ''
Figure JPOXMLDOC01-appb-C000035
Wherein R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is a ring represented by 0 to 4, and a compound represented by the formula:
Figure JPOXMLDOC01-appb-C000036
except for. Or a pharmaceutically acceptable salt thereof or a solvate thereof.

（２’’）Ｒａ１およびＲａ２が、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、アシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシである、上記（１’’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (2 ″) R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or Is an unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted Alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted Or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Oxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof or a solvate thereof. The compound according to the above (1 ″), which is an aryloxy of the above, or a substituted or unsubstituted heteroaryloxy.

（３’’）Ｒａ１およびＲａ２が、それぞれ結合する炭素原子と一緒になってＡ環（式中、Ａ環は上記（１’’）と同意義。）を形成する基である、上記（１’’）または（２’’）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (3 ″) R a1 and R a2 are groups that together form a ring A together with the carbon atoms to which they are bonded (wherein the A ring is as defined above (1 ″)), (1 ″) or (2 ″) a compound or a pharmaceutically acceptable salt thereof or a solvate thereof.

（４’’）Ｙが、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノまたは置換もしくは非置換のヘテロアリールスルホニルアミノである、上記（１’’）～（３’’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (4 ″) Y is substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted cycloalkylsulfonyl Amino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino or substituted or unsubstituted heteroarylsulfonylamino (1 ′ The compound according to any one of ') to (3' ') or a pharmaceutically acceptable salt thereof, or a solvate thereof.

（５’’）－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’である、上記（１’’）～（４’’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (5 ″) The compound according to any one of the above (1 ″) to (4 ″) or a pharmaceutically acceptable salt thereof, wherein —B 1 is —B ′ and —B 2 is —B ″. Salts or solvates thereof.

（６’’）－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’である、上記（１’’）～（４’’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (6 ″) The compound according to any one of the above (1 ″) to (4 ″) or a pharmaceutically acceptable salt thereof, wherein —B 1 is —B ″ and —B 2 is —B ′. Salts or solvates thereof.

（７’’）－Ｂ’’が、

Figure JPOXMLDOC01-appb-C000037

（式中、Ｒ１０、Ｒ１１、およびｐは上記（１’’）と同意義）である、上記（１’’）～（６’’）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 (7 ") -B"
Figure JPOXMLDOC01-appb-C000037
(Wherein R 10 , R 11 , and p are as defined above (1 ″)), or a pharmaceutically acceptable compound thereof according to any one of (1 ″) to (6 ″) above Salts or solvates thereof.

（８’’）上記（１’’）～（７’’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。

（９’’）ヒスタミンＨ４調節剤である、上記（８’’）記載の医薬組成物。

（１０’’）上記（１’’）～（７’’）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ヒスタミンＨ４受容体が関与する疾患の予防または治療方法。

（１１’’）ヒスタミンＨ４受容体が関与する疾患の治療薬および／または予防薬の製造のための、（１’’）～（７’’）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物の使用。

（１２’’）ヒスタミンＨ４受容体が関与する疾患の治療および／または予防のための、（１’’）～（７’’）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
(8 ″) A pharmaceutical composition comprising the compound according to any one of (1 ″) to (7 ″) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(9 ″) The pharmaceutical composition according to the above (8 ″), which is a histamine H4 modulator.

(10 ″) Histamine H4 receptor characterized by administering the compound according to any one of (1 ″) to (7 ″) above, a pharmaceutically acceptable salt thereof or a solvate thereof A method for preventing or treating diseases involving the body.

(11 ″) The compound according to any one of (1 ″) to (7 ″) for the manufacture of a therapeutic and / or prophylactic agent for diseases involving histamine H4 receptor, its pharmaceutically acceptable Salt or solvate thereof.

(12 ″) The compound according to any one of (1 ″) to (7 ″), a pharmaceutically acceptable salt thereof or a compound for the treatment and / or prevention of a disease involving histamine H4 receptor Their solvates.

　以下、本発明について実施形態を示しながら説明する。本明細書の全体にわたり、単数形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。従って、単数形の冠詞（例えば、英語の場合は「ａ」、「ａｎ」、「ｔｈｅ」など）は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、本明細書において使用される用語は、特に言及しない限り、当上記分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用される全ての専門用語および科学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。 Hereinafter, the present invention will be described with reference to embodiments. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the above field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

　本明細書中で用いる用語を以下に説明する。各用語は、特に記載しない限り以下の意味を有する。 The terms used in this specification are explained below. Each term has the following meaning unless otherwise specified.

　「ハロゲン」とはフッ素、塩素、臭素およびヨウ素を意味する。 “Halogen” means fluorine, chlorine, bromine and iodine.

　「ハロアルキル」、「ハロアルキルオキシ」のハロゲン部分は上記「ハロゲン」と同義である。 The halogen part of “haloalkyl” and “haloalkyloxy” has the same meaning as the above “halogen”.

　「アルキル」とは、炭素数１～１０、好ましくは炭素数１～６、さらに好ましくは炭素数１～３の直鎖または分枝鎖の１価の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル等が挙げられる。
　Ｒ９ａ、Ｒ９ｂ、Ｒ１０およびＲ１１における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル等が挙げられる。 “Alkyl” includes linear or branched monovalent hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
Examples of “alkyl” in R x1 , R x2 , R x3 and R x4 include methyl, ethyl, n-propyl, isopropyl and the like.
Examples of “alkyl” in R 9a , R 9b , R 10 and R 11 include methyl, ethyl, n-propyl, isopropyl and the like.

　「ハロアルキル」、「アルキルアミノ」、「アルキルイミノ」、「アルキルスルフィニル」、「アルキルスルホニル」、「アルキルスルホニルオキシ」、「アルキルスルファモイル」、「アリールアルキル」、「アリールアルキルアミノ」等のアルキル部分は、上記「アルキル」と同義である。 Alkyl such as “haloalkyl”, “alkylamino”, “alkylimino”, “alkylsulfinyl”, “alkylsulfonyl”, “alkylsulfonyloxy”, “alkylsulfamoyl”, “arylalkyl”, “arylalkylamino”, etc. The moiety is as defined above for “alkyl”.

　「アルキルオキシ」のアルキル部分は、上記「アルキル」と同義である。例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ヘキシルオキシ等が挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルキルオキシ」としては、メトキシ、エトキシ、プロポキシ、イソプロポキシ等が挙げられる。 The alkyl part of “alkyloxy” has the same meaning as the above “alkyl”. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
“ Alkyloxy ” in R x1 , R x2 , R x3 and R x4 includes methoxy, ethoxy, propoxy, isopropoxy and the like.

　「ハロアルキルオキシ」、「アルキルオキシイミノ」等のアルキルオキシ部分は、上記「アルキルオキシ」と同義である。 The alkyloxy moiety such as “haloalkyloxy” and “alkyloxyimino” has the same meaning as the above “alkyloxy”.

　「アルキルチオ」のアルキル部分は、上記「アルキル」と同義である。例えば、メチルチオ、エチルチオ、ｎ－プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、ｓｅｃ－ブチルチオ、ｔｅｒｔ－ブチルチオ、ペンチルチオ、イソペンチルチオ、ネオペンチルチオ、ヘキシルチオ等が挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルキルチオ」としては、メチルチオ、エチルチオ、ｎ-プロピルチオ、イソプロピルチオ等が挙げられる。 The alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.
“Alkylthio” in R x1 , R x2 , R x3 and R x4 includes methylthio, ethylthio, n-propylthio, isopropylthio and the like.

　「アルキルオキシカルボニル」のアルキルオキシ部分は、上記「アルキルオキシ」と同義である。例えば、メチルオキシカルボニル、エチルオキシカルボニル、ｎ－プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｎ－ブチルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、ｎ－ペンチルオキシカルボニル等が挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルキルオキシカルボニル」としては、メチルオキシカルボニル、エチルオキシカルボニル等が挙げられる。 The alkyloxy moiety of “alkyloxycarbonyl” has the same meaning as the above “alkyloxy”. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
“ Alkyloxycarbonyl ” in R x1 , R x2 , R x3 and R x4 includes methyloxycarbonyl, ethyloxycarbonyl and the like.

　「アルキルカルバモイル」のアルキル部分は、上記「アルキル」と同義である。例えば、メチルカルバモイル、エチルカルバモイル、ｎ－プロピルカルバモイル、イソプロピルカルバモイル、シクロプロピルカルバモイル、ｎ－ブチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル等のモノ又はジアルキルカルバモイルが挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルキルカルバモイル」としては、メチルカルバモイル、エチルカルバモイル等が挙げられる。
The alkyl part of “alkylcarbamoyl” has the same meaning as the above “alkyl”. Examples thereof include mono- or dialkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl and the like.
Examples of the “alkylcarbamoyl” in R x1 , R x2 , R x3 and R x4 include methylcarbamoyl, ethylcarbamoyl and the like.

　「アルケニル」とは、任意の位置に１以上の二重結合を有する炭素数２～６、好ましくは炭素数２～３の直鎖または分枝状のアルケニルを包含する。例えば、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル等が挙げられる。
　Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４における「アルケニル」としては、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル等が挙げられる。 “Alkenyl” includes straight or branched alkenyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more double bonds at any position. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl and the like.
“Alkenyl” in R x1 , R x2 , R x3 and R x4 includes vinyl, propenyl, isopropenyl, butenyl, isobutenyl and the like.

　「アルケニルオキシ」のアルケニル部分は、上記「アルケニル」と同義である。例えば、ビニルオキシ、プロペニルオキシ、イソプロペニルオキシ、ブテニルオキシ、イソブテニルオキシ、プレニルオキシ、ブタジエニルオキシ、ペンテニルオキシ、イソペンテニルオキシ、ペンタジエニルオキシ、ヘキセニルオキシ、イソヘキセニルオキシ、ヘキサジエニルオキシ等が挙げられる。 The alkenyl part of “alkenyloxy” has the same meaning as the above “alkenyl”. For example, vinyloxy, propenyloxy, isopropenyloxy, butenyloxy, isobutenyloxy, prenyloxy, butadienyloxy, pentenyloxy, isopentenyloxy, pentadienyloxy, hexenyloxy, isohexenyloxy, hexadienyloxy, etc. Is mentioned.

　「アルケニルチオ」のアルケニル部分は、上記「アルケニル」と同義である。例えば、ビニルチオ、プロペニルチオ、イソプロペニルチオ、ブテニルチオ、イソブテニルチオ、プレニルチオ、ブタジエニルチオ、ペンテニルチオ、イソペンテニルチオ、ペンタジエニルチオ、ヘキセニルチオ、イソヘキセニルチオ、ヘキサジエニルチオ等が挙げられる。 The alkenyl part of “alkenylthio” has the same meaning as the above “alkenyl”. Examples thereof include vinylthio, propenylthio, isopropenylthio, butenylthio, isobutenylthio, prenylthio, butadienylthio, pentenylthio, isopentenylthio, pentadienylthio, hexenylthio, isohexenylthio, hexadienylthio and the like.

「アルケニルオキシカルボニル」のアルケニルオキシ部分は、上記「アルケニルオキシ」と同義である。例えば、ビニルオキシカルボニル、プロペニルオキシカルボニル、イソプロペニルオキシカルボニル、ブテニルオキシカルボニル、イソブテニルオキシカルボニル、プレニルオキシカルボニル、ブタジエニルオキシカルボニル、ペンテニルオキシカルボニル、イソペンテニルオキシカルボニル、ペンタジエニルオキシカルボニル、ヘキセニルオキシカルボニル、イソヘキセニルオキシカルボニル、ヘキサジエニルオキシカルボニル等が挙げられる。 The alkenyloxy part of “alkenyloxycarbonyl” has the same meaning as the above “alkenyloxy”. For example, vinyloxycarbonyl, propenyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, isobutenyloxycarbonyl, prenyloxycarbonyl, butadienyloxycarbonyl, pentenyloxycarbonyl, isopentenyloxycarbonyl, pentadienyloxycarbonyl Hexenyloxycarbonyl, isohexenyloxycarbonyl, hexadienyloxycarbonyl and the like.

　「ハロアルケニル」、「アルケニルスルフィニル」、「アルケニルスルホニル」、「アルケニルスルホニルオキシ」、「アルケニルスルファモイル」等のアルケニル部分は、上記「アルケニル」と同義である。 The alkenyl moiety such as “haloalkenyl”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkenylsulfonyloxy”, “alkenylsulfamoyl” has the same meaning as the above “alkenyl”.

　「アルキニル」とは、任意の位置に１以上の三重結合を有する炭素数２～６、好ましくは炭素数２～３の直鎖または分枝状のアルキニルを包含する。これらは任意の位置に１以上の三重結合を有しており、さらに二重結合を有していてもよい。例えば、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル、１－ペンチニル、２－ペンチニル、種々のペンチニル異性体等が挙げられる。 “Alkynyl” includes linear or branched alkynyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more triple bonds at any position. These have one or more triple bonds at arbitrary positions, and may further have a double bond. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, various pentynyl isomers, and the like.

　「アルキニルオキシ」のアルキニル部分は、上記「アルキニル」と同義である。例えば、エチニルオキシ、プロピニルオキシ、ブチニルオキシ、ペンチニルオキシ等が挙げられる。好ましくは、Ｃ２～Ｃ６アルキニルオキシが挙げられる
The alkynyl part of “alkynyloxy” has the same meaning as the above “alkynyl”. For example, ethynyloxy, propynyloxy, butynyloxy, pentynyloxy and the like can be mentioned. Preferably, C2-C6 alkynyloxy is used.

　「アルキニルチオ」とは、アルキニル部分が上記「アルキニル」と同義である。例えば、エチニルチオ、プロピニルチオ、ブチニルチオ、ペンチニルチオ等が挙げられる。好ましくは、Ｃ２～Ｃ６アルキニルチオが挙げられる。 “Alkynylthio” has the same meaning as the above “alkynyl” in the alkynyl moiety. For example, ethynylthio, propynylthio, butynylthio, pentynylthio and the like can be mentioned. Preferably, C2-C6 alkynylthio is used.

「アルキニルオキシカルボニル」のアルキニルオキシ部分は、上記「アルキニルオキシ」と同義である。例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル、ブチニルオキシカルボニル、ペンチニルオキシカルボニル等が挙げられる。好ましくは、Ｃ２～Ｃ６アルキニルオキシカルボニルが挙げられる The alkynyloxy moiety of “alkynyloxycarbonyl” has the same meaning as the above “alkynyloxy”. Examples include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, and the like. Preferably, C2-C6 alkynyloxycarbonyl is used.

「アルキニルスルフィニル」、「アルキニルスルホニル」、「アルキニルスルホニルオキシ」、「アルキニルスルファモイル」等のアルキニル部分は、上記「アルキニキル」と同義である。 Alkynyl moieties such as “alkynylsulfinyl”, “alkynylsulfonyl”, “alkynylsulfonyloxy”, “alkynylsulfamoyl” and the like are synonymous with the above “alkynyl”.

　「アシル」とは、Ｒ－Ｃ（＝Ｏ）－（例えば、Ｒは上記「アルキル」、「アルケニル」もしくは「アルキニル」、または後述の「シクロアルキル」、「シクロアルケニル」、「アリール」、「ヘテロアリール」もしくは「非芳香族複素環式基」である。）で示される基を包含する。 “Acyl” is R—C (═O) — (for example, R is “alkyl”, “alkenyl” or “alkynyl”, or “cycloalkyl”, “cycloalkenyl”, “aryl”, “ A heteroaryl ”or a“ non-aromatic heterocyclic group ”).

　「アシルアミノ」および「アシルイミノ」の「アシル」部分は、上記「アシル」と同義である。 The “acyl” part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.

　「非置換スルファモイル」とは、－Ｓ（＝Ｏ）２－ＮＨ２で示される基を意味する。
　「置換基群Ａから選択される置換基で置換されたスルファモイル」とは、－Ｓ（＝Ｏ）２－ＮＲＸＲＹで示される基を意味する。ＲＸおよびＲＹの少なくとも一方は、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される基を包含する。
　具体的には、「置換基群Ａから選択される置換基で置換されたスルファモイル」は、非置換のアルキル、置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基および置換もしくは非置換のアリール）から選択される置換基で１以上置換されたアルキル、置換基群Ｂ（置換基群Ｂ：ヒドロキシ、置換もしくは非置換のアルキル、ハロゲンおよびカルバモイル）から選択される置換基で１以上置換されたアリール、非置換のアリール、置換基群Ｂから選択される置換基で１以上置換されたヘテロアリール、非置換のへテロアリール、置換基群Ｄ（置換基群Ｄ：ヒドロキシ、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル）から選択される置換基で１以上置換されたシクロアルキル、、非置換のシクロアルキル、置換基群Ｄから選択される置換基で１以上置換されたシクロアルケニル、非置換のシクロアルケニル、置換基群Ｅ（置換基群Ｅ：ヒドロキシ、アルキル、ハロゲン、オキソおよびカルバモイル）から選択される置換基で１以上置換された非芳香族複素環式基、非置換の非芳香族複素環式基、から選択される置換基で少なくとも１つ置換されたスルファモイルを包含する。 “Unsubstituted sulfamoyl” means a group represented by —S (═O) 2 —NH 2 .
“Sulphamoyl substituted with a substituent selected from Substituent Group A” means a group represented by —S (═O) 2 —NR X R Y. At least one of R X and R Y is a substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted Or a group selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
Specifically, “sulfamoyl substituted with a substituent selected from Substituent Group A” includes unsubstituted alkyl, Substituent Group C (Substituent Group C: hydroxy, halogen, substituted or unsubstituted alkoxy, Alkyl substituted with one or more substituents selected from substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted aryl) Selected from substituent group B (substituent group B: hydroxy, substituted or unsubstituted alkyl, halogen and carbamoyl), one or more substituted aryls, unsubstituted aryl, substituent group B Heteroaryl substituted with one or more substituents, unsubstituted heteroaryl, substituent group D (substituent group D: hydroxy, halogen , Cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl), one or more substituted cycloalkyl, unsubstituted cycloalkyl, substituent A substituent selected from cycloalkenyl, unsubstituted cycloalkenyl, substituent group E (substituent group E: hydroxy, alkyl, halogen, oxo and carbamoyl) substituted with one or more substituents selected from group D It includes sulfamoyl substituted with at least one substituent selected from one or more substituted non-aromatic heterocyclic groups and unsubstituted non-aromatic heterocyclic groups.

　「非置換アミノスルホニルアミノ」とは、－ＮＨ－Ｓ（＝Ｏ）２－ＮＨ２で示される基を意味する。
　「置換アミノスルホニルアミノ」とは、－ＮＲｚ－Ｓ（＝Ｏ）２－ＮＲＸＲＹで示される基を意味し、ＲＸ、ＲＹおよびＲｚの少なくとも１つは、下記に示す「置換アミノ」の置換基と同意義である。
　具体的には、「置換アミノスルホニルアミノ」における、ＲＸおよびＲＹの少なくとも一方は、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される基を包含する。Ｒｚは、下記に示す「置換アミノ」の置換基と同意義である。 “Unsubstituted aminosulfonylamino” means a group represented by —NH—S (═O) 2 —NH 2 .
“Substituted aminosulfonylamino” means a group represented by —NR z —S (═O) 2 —NR X R Y , and at least one of R X , R Y and R z is represented by “ The meaning is the same as the substituent of “substituted amino”.
Specifically, in “substituted aminosulfonylamino”, at least one of R X and R Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or non-substituted Substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Group. R z has the same meaning as the substituent of “substituted amino” shown below.

　「シクロアルカン」とは、炭素数が３～１０の単環式または多環式飽和炭素環を包含する。単環式シクロアルカンとしては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン等が挙げられる。多環式シクロアルカンとしては、ノルボルナン、テトラヒドロナフタレン等が挙げられる。 “Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms. Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.

　「シクロアルキル」とは、上記「シクロアルカン」から導かれる１価の基を包含する。単環式シクロアルキルとしては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。多環式シクロアルキルとしては、ノルボルニル、テトラヒドロナフタレン－５－イル、テトラヒドロナフタレン－６－イル、アダマンチル等が挙げられる。 “Cycloalkyl” includes a monovalent group derived from the above “cycloalkane”. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Examples of polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, adamantyl and the like.

　「シクロアルカンジイル」とは、上記「シクロアルカン」から導かれる２価の基を包含する。単環式シクロアルカンジイルとしては、例えば、シクロプロパンジイル、シクロブタンジイル、シクロペンタンジイル、シクロヘキサンジイル、シクロヘプタンジイル、シクロオクタンジイル、シクロノナンジイル、シクロデカンジイル等が挙げられる。多環式シクロアルカンジイルとしては、ノルボルナンジイル、アダマンタンジイル等が挙げられる。 “Cycloalkanediyl” includes a divalent group derived from the above “cycloalkane”. Examples of the monocyclic cycloalkanediyl include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, cyclooctanediyl, cyclononanediyl, cyclodecandidiyl and the like. Examples of polycyclic cycloalkanediyl include norbornanediyl, adamantanediyl and the like.

　「シクロアルキルオキシ」のシクロアルキル部分は、上記「シクロアルキル」と同義である。例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ、シクロノニルオキシ、シクロデシルオキシ等が挙げられる。多環式シクロアルキルオキシとしては、ノルボルニルオキシ、テトラヒドロナフタレン－５－イルオキシ、テトラヒドロナフタレン－６－イルオキシ、アダマンタンオキシ等が挙げられる。 The cycloalkyl part of “cycloalkyloxy” has the same meaning as the above “cycloalkyl”. For example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, cyclodecyloxy and the like can be mentioned. Examples of polycyclic cycloalkyloxy include norbornyloxy, tetrahydronaphthalen-5-yloxy, tetrahydronaphthalen-6-yloxy, adamantaneoxy and the like.

　「シクロアルキルオキシカルボニル」のシクロアルキルオキシ部分は、上記「シクロアルキルオキシ」と同義である。例えば、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル、シクロペンチルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロヘプチルオキシカルボニル、シクロオクチルオキシカルボニル、シクロノニルオキシカルボニル、シクロデシルオキシカルボニル等が挙げられる。多環式シクロアルキルオキシカルボニルとしては、ノルボルニルオキシカルボニル、テトラヒドロナフタレン－５－イルオキシカルボニル、テトラヒドロナフタレン－６－イルオキシカルボニル等が挙げられる。 The cycloalkyloxy part of “cycloalkyloxycarbonyl” has the same meaning as the above “cycloalkyloxy”. Examples include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, cyclooctyloxycarbonyl, cyclononyloxycarbonyl, cyclodecyloxycarbonyl, and the like. Examples of the polycyclic cycloalkyloxycarbonyl include norbornyloxycarbonyl, tetrahydronaphthalen-5-yloxycarbonyl, tetrahydronaphthalen-6-yloxycarbonyl and the like.

　「シクロアルケン」とは、少なくとも１つの炭素－炭素二重結合を含む炭素数３～１０の非芳香族単環または多環式環を包含する。単環式シクロアルケンとしては、シクロペンテン、シクロヘキセン等が挙げられる。多環式シクロアルケンとしてはノルボルネン、インデン等が挙げられる。 “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene. Examples of the polycyclic cycloalkene include norbornene and indene.

　「シクロアルケニル」とは、上記「シクロアルケン」から導かれる１価の基を包含する。単環式シクロアルケニルとしては、シクロペンテニル、シクロヘキセニル等が挙げられる。多環式シクロアルケニルとしてはノルボルネニル、インデン－１－イル、インデン－２－イル、インデン－３－イル等が挙げられる。 “Cycloalkenyl” includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.

　「シクロアルケンジイル」とは、上記「シクロアルケン」から導かれる２価の基を包含する。単環式シクロアルケンジイルとしては、シクロペンテンジイル、シクロヘキセンジイル等が挙げられる。多環式シクロアルケンジイルとしてはノルボルネンジイル等が挙げられる。 “Cycloalkenediyl” includes a divalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenediyl include cyclopentenediyl, cyclohexenediyl and the like. Examples of polycyclic cycloalkenediyl include norbornene diyl.

　「シクロアルケニルオキシ」のシクロアルケニル部分は、上記「シクロアルケニル」と同義である。例えば、単環式シクロアルケニルオキシとしては、シクロペンテニルオキシ、シクロヘキセニルオキシ等が挙げられる。多環式シクロアルケニルオキシとしてはノルボルネニルオキシ、インデニルオキシ等が挙げられる。 The cycloalkenyl part of “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”. For example, as monocyclic cycloalkenyloxy, cyclopentenyloxy, cyclohexenyloxy and the like can be mentioned. Examples of polycyclic cycloalkenyloxy include norbornenyloxy and indenyloxy.

　「シクロアルケニルオキシカルボニル」のシクロアルケニルオキシ部分は、上記「シクロアルケニルルオキシ」と同義である。例えば、単環式シクロアルケニルオキシカルボニルとしては、シクロペンテニルオキシカルボニル、シクロヘキセニルオキシカルボニル等が挙げられる。多環式シクロアルケニルオキシカルボニルとしてはノルボルネニルオキシカルボニル、インデニルオキシカルボニル等が挙げられる。 The cycloalkenyloxy moiety of “cycloalkenyloxycarbonyl” has the same meaning as the above “cycloalkenyloxy”. For example, examples of the monocyclic cycloalkenyloxycarbonyl include cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl, and the like. Examples of the polycyclic cycloalkenyloxycarbonyl include norbornenyloxycarbonyl, indenyloxycarbonyl and the like.

　「芳香族炭素環」とは、単環または縮合環の芳香族炭化水素環を包含する。例えば、ベンゼン環、ナフタレン環、アントラセン環、フェナントレン環等が挙げられる。 The “aromatic carbocycle” includes a monocyclic or condensed aromatic hydrocarbon ring. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned.

　「アリール」とは、上記「芳香族炭素環」から導かれる１価の基を意味する。例えば、フェニル、１－ナフチル、２－ナフチル、アントリル、フェナントリル等が挙げられる。 “Aryl” means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like.

　「アリールスルホニルオキシ」のアリール部分は、上記「アリール」と同義である。例えば、フェニルスルホニルオキシ、１－ナフチルスルホンオキシ等が挙げられる。 The aryl part of “arylsulfonyloxy” has the same meaning as the above “aryl”. For example, phenylsulfonyloxy, 1-naphthylsulfoneoxy and the like can be mentioned.

　「アリールオキシ」、「アリールオキシカルボニル」、「アリールアルキルアミノ」、「アリールスルフィニル」および「アリールアルキル」のアリール部分は、上記「アリール」と同義である。 The aryl part of “aryloxy”, “aryloxycarbonyl”, “arylalkylamino”, “arylsulfinyl” and “arylalkyl” has the same meaning as the above “aryl”.

　「芳香族炭素環ジイル」とは、上記「芳香族炭素環」から導かれる２価の基を包含する。例えば、１，２－フェニレン、１，３－フェニレン、１，４－フェニレン、１，２－ナフチレン等が挙げられる。 “Aromatic carbocyclic diyl” includes a divalent group derived from the above “aromatic carbocycle”. For example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like can be mentioned.

　「複素環」とは、環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員環、
それらが独立して２個以上縮合した環、または、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員環が、１以上の上記「芳香族炭素環」、上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環から誘導される、芳香族または非芳香族の縮合環を包含する。
　例えば、ピロリン、ピロリジン、ピペリジン、ピペラジン、モルホリン、チオモルホン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール等の、単環の非芳香族複素環；
　例えば、ピロール、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、テトラゾール、トリアジン、ピリダジン、ピリミジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の、単環の芳香族複素環；
　例えば、インドール、イソインドール、インダゾール、インドリジン、インドリン、イソインドリン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンゾピラン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾール、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の、縮合した複素環が挙げられる。 “Heterocycle” means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring,
A ring in which two or more of them are independently fused, or
A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”. An aromatic or non-aromatic fused ring derived from the above ring.
For example, monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc. ;
For example, pyrrole, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. Family heterocycles;
For example, indole, isoindole, indazole, indolizine, indoline, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyran, benzimidazole, benzisoxazole, benzoxazole, benzoxazidi Azole, benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazole, benzodioxane, tetrahydroquinoline, tetrahydrobenzothiophene, etc. And a condensed heterocyclic ring.

　「複素環基」とは、上記「複素環」から導かれる１価の基を包含する。
　例えば、ピロリニル、ピロリジノ、ピロリジニル、イミダゾリニル、イミダゾリジニル、ピラゾリニル、ピラゾリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、テトラヒドロピラニル、ジヒドロピリジル、ジヒドロピリダジニル、ジヒドロピラジニル、ジオキサニル、オキサチオラニル、チアニル、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等の、単環の非芳香族複素環式基；
　例えば、ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の、単環の芳香族複素環基；
　例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、インドリニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンゾピラニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル、ベンゾジオキサニル、テトラヒドロキノリン、テトラヒドロベンゾチエニル等の、縮合した複素環式基が挙げられる。 The “heterocyclic group” includes a monovalent group derived from the above “heterocycle”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl;
For example, pyrrolyl, pyrazinyl, pyrazolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. A ring group;
For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic groups such as linyl, benzodioxanyl, tetrahydroquinoline, tetrahydrobenzothienyl and the like.

　「芳香族複素環」とは、上記「複素環」のうち、芳香環であるものを包含する。
　環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の芳香環、
　それらが独立して２個以上縮合した芳香環、
　環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環を包含する。
　例えば、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、トリアジン、ピリダジン、ピリミジン、ピラジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の、単環の芳香族複素環；
　例えば、インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾリン等の、縮合した芳香族複素環が挙げられる。 The “aromatic heterocycle” includes the above “heterocycle” which is an aromatic ring.
A 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic ring in which two or more of them are independently fused,
An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. ring;
For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo Examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.

　「ヘテロアリール」とは、上記「芳香族複素環」から導かれる１価の基を包含する。環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の芳香環式基、
それらが独立して２個以上縮合した芳香環式基、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環式基を包含する。
　例えば、ピロリル、ピラジニル、ピラゾリル、インドリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の、単環のヘテロアリール、
　例えば、イソインドリル、インダゾリル、インドリジニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル等の、縮合したヘテロアリールが挙げられる。
　「ヘテロアリールオキシ」、「ヘテロアリールオキシカルボニル」、「ヘテロアリールアルキルアミノ」および「ヘテロアリールアルキル」のヘテロアリール部分は、上記「ヘテロアリール」と同義である。 “Heteroaryl” includes a monovalent group derived from the above “aromatic heterocycle”. A 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic cyclic group in which two or more of them are independently fused,
An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. Aryl,
For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.
The heteroaryl part of “heteroaryloxy”, “heteroaryloxycarbonyl”, “heteroarylalkylamino” and “heteroarylalkyl” has the same meaning as the above “heteroaryl”.

　「芳香族６員環」とは、上記「ベンゼン環」、および「芳香族複素環」のうち６員の芳香環であるものを包含する。
　例えば、ベンゼン環、ピリジン環、ピリダジン環、ピリミジン環、ピラジン、１，２，４－トリアジン、１，３，５－トリアジン、１，２，３－トリアジン、１、２，３，４－テトラジン等が挙げられる。 The “aromatic 6-membered ring” includes the above-mentioned “benzene ring” and “aromatic heterocycle” which are 6-membered aromatic rings.
For example, benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazine, 1,2,3,4-tetrazine, etc. Is mentioned.

　「非芳香族複素環」とは、上記「複素環」のうち、非芳香環であるものを包含する。
　環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の非芳香族環、
それらが独立して２個以上縮合した非芳香族環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の芳香族環が、１以上の上記「シクロアルカン」または上記「シクロアルケン」と縮合した環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５～７員の非芳香族複素環が、１以上の上記「芳香族炭素環」または「非芳香族炭素環」と縮合した環を包含する。
　例えば、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、チオモルホリン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジヒドロピラジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾリン、テトラヒドロイソチアゾリン等の、単環の非芳香族複素環、
　例えば、インドリン、イソインドリン、ベンゾピラン、ベンゾジオキサン、テトラヒドロキノリン、ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オン、テトラヒドロベンゾチオフェン等の、縮合した非芳香族ヘテロ芳香環が挙げられる。
　Ｃ環の非芳香族複素環としては、トリアゾール、ピラゾール、イミダゾール、ピロール、チオフェンが挙げられる。 The “non-aromatic heterocycle” includes those that are non-aromatic rings among the above-mentioned “heterocycle”.
A 5- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
A non-aromatic ring in which two or more of them are independently fused,
A ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
A 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”. Includes fused rings.
For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydro Monocyclic non-aromatic heterocycles such as thiazoline, tetrahydroisothiazoline,
Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophene and the like.
Examples of the non-aromatic heterocyclic ring of C ring include triazole, pyrazole, imidazole, pyrrole, and thiophene.

　「非芳香族複素環式基」とは、上記「非芳香族複素環」から導かれる１価の基を包含する。
　例えば、ピロリニル、ピロリジノ、ピロリジニル、イミダゾリニル、イミダゾリジニル、ピラゾリニル、ピラゾリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、テトラヒドロピラニル、ジヒドロピリジル、ジヒドロピリダジニル、ジヒドロピラジニル、ジオキサニル、オキサチオラニル、チアニル、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等の、単環の非芳香族複素環式基、
ベンゾジオキサン、テトラヒドロキノリン、ベンゾ［ｄ］オキサゾール－２（３Ｈ）－オン、テトラヒドロベンゾチオフェン等の縮合した複素環基が挙げられる。 The “non-aromatic heterocyclic group” includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl,
Examples thereof include condensed heterocyclic groups such as benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, and tetrahydrobenzothiophene.

　「非芳香族含硫黄複素環式基」なる用語は、硫黄原子を少なくとも１つ環内に含み、さらに酸素原子および窒素原子から任意に選ばれる原子を環内に１個以上含んでいてもよい非芳香族の４～７員環またはそれらが２個以上縮合した環から誘導される基を包含する。例えば、チオモルホリニル、チオモルホリノ、チアニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等が挙げられる。 The term “non-aromatic sulfur-containing heterocyclic group” includes at least one sulfur atom in the ring, and may further include one or more atoms arbitrarily selected from an oxygen atom and a nitrogen atom in the ring. It includes a group derived from a non-aromatic 4- to 7-membered ring or a ring in which two or more thereof are condensed. Examples thereof include thiomorpholinyl, thiomorpholino, thianyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl and the like.

　「非芳香族複素環オキシ」、「非芳香族複素環オキシカルボニル」「非芳香族複素環アルキルアミノ」および「非芳香族複素環アルキル」の非芳香族複素環部分は、上記「非芳香族複素環」と同義である。 The non-aromatic heterocyclic moiety of “non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic alkylamino” and “non-aromatic heterocyclic alkyl” Synonymous with “heterocycle”.

　「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換アルキルオキシ」、「置換アルケニルオキシ」、「置換アルキニルオキシ」、「置換アルキルチオ」、「置換アルケニルチオ」、「置換アルキニルチオ」、「置換アルキルオキシカルボニル」、「置換アルケニルオキシカルボニル」、「置換アルキニルオキシカルボニル」、「置換アルキルカルバモイル」、「置換アルケニルカルバモイル」、「置換アルキニルカルバモイル」、「置換アルキルスルファモイル」、「置換アルケニルスルファモイル」、「置換アルキニルスルファモイル」「置換アルキルスルフィニル」、「置換アルケニルスルフィニル」、「置換アルキニルスルフィニル」、「置換アルキルスルホニル」、「置換アルケニルスルホニル」、「置換アルキニルスルホニル」、「置換アルキルスルホニルオキシ」、「置換アシル」、の置換基としては、以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるが、これに限定されない：
重水素、ヒドロキシ、カルボキシ、ハロゲン（F、Cl、Br、I）、ハロアルキルオキシ（例えば、CF3O）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、アルキルオキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、アルキルオキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アリールアルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、アルキルオキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、置換基群α（置換基群α：アルキル、ハロゲン、ヒドロキシ、アルキルオキシ、アシル、アシルオキシ、カルボキシ、アルキルオキシカルボニル、アミノ、アシルアミノ、アルキルアミノ、アルキルオキシカルボニルアミノ、アルキルチオ、カルバモイル、アルキルカルバモイル、スルファモイル、アルキルスルファモイル、シアノおよびニトロ）から選択される置換基で置換もしくは非置換のアリール（例えば、フェニル、メチルフェニル、エチルフェニル、メチルオキシフェニル、エチルオキシフェニル、フルオロフェニル、クロロフェニル、メチルオキシフェニル、エチルオキシフェニル、アミノフェニル、メチルアミノフェニル、ジメチルアミノフェニル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキル（例えば、ベンジル、フェニルエチル、メチルフェニルメチル、エチルフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、フルオロフェニルメチル、クロロフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、アミノフェニルメチル、メチルアミノフェニルメチル、ジメチルアミノフェニルメチル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキルオキシ（例えば、ベンジルオキシ、フェニルエチルオキシ、メチルフェニルメチルオキシ、エチルフェニルメチルオキシ、メチルオキシフェニルメチルオキシ、エチルオキシフェニルメチルオキシ、フルオロフェニルメチルオキシ、クロロフェニルメチルオキシ、メチルオキシフェニルメチルオキシ、エチルオキシフェニルメチルオキシ、アミノフェニルメチルオキシ、メチルアミノフェニルメチルオキシ、ジメチルアミノフェニルメチルオキシ等）、置換基群αから選択される置換基で置換もしくは非置換の非芳香族複素環式基（例えば、ピロリニル、ピペリジル、ピペラジノピロリジノ、ピロリジニル、モルホリニル、モルホリノ、メチルピロリニル、メチルピペリジル、メチルピペラジノピロリジノ、メチルピロリジニル、メチルモルホリニル、メチルモルホリノ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリール（例えば、フリル、チエニル、ピリジル、イソオキサゾリル、チアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル、メチルフリル、メチルチエニル、メチルピリジル、メチルイソオキサゾリル、メチルチアゾリル、メチルチアジアゾリル、メチルオキサゾリル、メチルオキサジアゾリル等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールアルキル（ピリジルメチル、ピリジルエチル、メチルピリジルメチル、メチルピリジルエチル等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、アルキルチオ（例えば、メチルチオ等）、アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、カルバモイル、アルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル等）、スルファモイル、アルキルスルファモイル、アシル（例えば、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミド、トリアルキルシリル（トリメチルシリル等）、およびオキソ。 “Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkynylthio”, "Substituted alkyloxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkynyloxycarbonyl", "substituted alkylcarbamoyl", "substituted alkenylcarbamoyl", "substituted alkynylcarbamoyl", "substituted alkylsulfamoyl", "substituted alkenyl" Sulfamoyl, substituted alkynylsulfamoyl, substituted alkylsulfinyl, substituted alkenylsulfinyl, substituted alkynylsulfinyl, substituted alkylsulfonyl, substituted alkenylsulfonyl, substituted alkynyl Examples of the substituents of “rusulfonyl”, “substituted alkylsulfonyloxy”, and “substituted acyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of: Not:
Deuterium, hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyloxy (eg CF 3 O), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg Methoxy, ethoxy, propoxy, butoxy, etc.), alkenyloxy (eg, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino ( For example, methylamino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, imino, hydro Simino, alkylimino (eg, methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino, ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, substituent group α (substituted) Group α: alkyl, halogen, hydroxy, alkyloxy, acyl, acyloxy, carboxy, alkyloxycarbonyl, amino, acylamino, alkylamino, alkyloxycarbonylamino, alkylthio, carbamoyl, alkylcarbamoyl, sulfamoyl, alkylsulfamoyl, cyano Substituted or unsubstituted aryl (eg, phenyl, methylphenyl, ethylphenyl, methyloxyphenyl, ethyloxyphenyl) with a substituent selected from Nyl, fluorophenyl, chlorophenyl, methyloxyphenyl, ethyloxyphenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, etc.), substituted or unsubstituted arylalkyl with a substituent selected from the substituent group α (for example, benzyl , Phenylethyl, methylphenylmethyl, ethylphenylmethyl, methyloxyphenylmethyl, ethyloxyphenylmethyl, fluorophenylmethyl, chlorophenylmethyl, methyloxyphenylmethyl, ethyloxyphenylmethyl, aminophenylmethyl, methylaminophenylmethyl, dimethylamino Phenylmethyl, etc.), substituted or unsubstituted arylalkyloxy (eg, benzyloxy, phenylethyloxy, methyl) with a substituent selected from the substituent group α Phenylmethyloxy, ethylphenylmethyloxy, methyloxyphenylmethyloxy, ethyloxyphenylmethyloxy, fluorophenylmethyloxy, chlorophenylmethyloxy, methyloxyphenylmethyloxy, ethyloxyphenylmethyloxy, aminophenylmethyloxy, methylaminophenyl Methyloxy, dimethylaminophenylmethyloxy, etc.), a non-aromatic heterocyclic group substituted or unsubstituted with a substituent selected from the substituent group α (for example, pyrrolinyl, piperidyl, piperazinopyrrolidino, pyrrolidinyl, morpholinyl) , Morpholino, methylpyrrolinyl, methylpiperidyl, methylpiperazinopyrrolidino, methylpyrrolidinyl, methylmorpholinyl, methylmorpholino, etc.), a substituent selected from the substituent group α Substituted or unsubstituted heteroaryl (eg, furyl, thienyl, pyridyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, methylfuryl, methylthienyl, methylpyridyl, methylisoxazolyl, methylthiazolyl, methylthiazolyl, methyl Oxazolyl, methyloxadiazolyl, etc.), a heteroarylalkyl substituted or unsubstituted with a substituent selected from the substituent group α (pyridylmethyl, pyridylethyl, methylpyridylmethyl, methylpyridylethyl, etc.), cyano, isocyano , Isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), carbamoyl, al Rucarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.), sulfamoyl, alkylsulfamoyl, acyl (eg, acetyl, etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, Azide, ureido, amidino, guanidino, phthalimide, trialkylsilyl (such as trimethylsilyl), and oxo.

　「置換アミノ」、「置換アミノスルホニルアミノ」の置換基としては、以下の群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれらに限定されない：
アルキル（例えば、メチル、エチル、イソプロピル、ｔｅｒｔ-ブチル等）、ハロアルキル（例えば、CF3、CH2CF3、CH2CCl3等）、ヒドロキシアルキル（例えば、ヒドロキシエチル、-C（CH3）2CH2OH等）、アルケニル（例えば、ビニル）、アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、アルキルオキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、ハロアルキルオキシ（例えば、CF3O）、アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、アルキルオキシカルボニル（ｔｅｒｔ-ブチルオキシカルボニル等）、アミノ、アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アリールアルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、アルキルオキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、置換基群αから選択される置換基で置換もしくは非置換のアリール（例えば、フェニルメチルフェニル、エチルフェニル、メチルオキシフェニル、エチルオキシフェニル、フルオロフェニル、クロロフェニル、メチルオキシフェニル、エチルオキシフェニル、アミノフェニル、メチルアミノフェニル、ジメチルアミノフェニル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキル（例えば、ベンジル、フェニルエチル、メチルフェニルメチル、エチルフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、フルオロフェニルメチル、クロロフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、アミノフェニルメチル、メチルアミノフェニルメチル、ジメチルアミノフェニルメチル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールオキシ（例えば、フェノキシ、メチルフェニルオキシ等）、置換基群αから選択される置換基で置換もしくは非置換の非芳香族複素環式基（例えば、ピロリニル、ピロリジノ、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、メチルピロリニル、メチルピロリジノ、メチルピペリジノ、メチルピペリジル、メチルピペラジノ、メチルピペラジニル、メチルモルホリニル、メチルモルホリノ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリール（例えば、ピリジル、チエニル、チアゾリル、フリル、メチルフリル、メチルチエニル、メチルピリジル、メチルイソオキサゾリル、メチルチアゾリル、メチルチアジアゾリル、メチルオキサゾリル、メチルオキサジアゾリル等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールアルキル（例えば、ピリジルメチル、チエニルメチル、チアゾリルメチル、フリルメチル、メチルピリジルメチル、メチルチエニルメチル、メチルチアゾリルメチル、メチルフリルメチル等）、置換基群αから選択される置換基で置換もしくは非置換の非芳香族複素環オキシ（ピペラジノオキシ、ピペリジノオキシ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールオキシ（ピリジルオキシ、メチルピペラジノオキシ、メチルピペリジノオキシ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールオキシ（ピリジルオキシ、メチルピリジルオキシ等）、ヒドロキシ、ハロゲン（F、Cl、Br、I）、シアノおよびアシル（例えば、アセチル等）。
　「置換もしくは非置換のアルキルスルホニルアミノ」、「置換もしくは非置換のアミノスルホニルアミノ」、「置換もしくは非置換のシクロアルキルスルホニルアミノ」、「置換もしくは非置換の非芳香族複素環スルホニルアミノ」、「置換もしくは非置換のアリールスルホニルアミノ」、または「置換もしくは非置換のヘテロアリールスルホニルアミノ」における「アミノ」も、上記「置換アミノ」で示される置換基で置換されていてもよい。 Substituents for “substituted amino” and “substituted aminosulfonylamino” include, but are not limited to, one or more of the same or different substituents selected from the following group:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.), haloalkyloxy (eg CF 3 O), alkenyloxy (eg vinyloxy, allyloxy etc.), alkyloxycarbonyl (tert-butyloxycarbonyl etc.), amino, alkylamino (eg methylamino, ethylamino, dimethyl) Amino), acylamino (eg, Tilamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, imino, hydroxyimino, alkylimino (eg, methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino) , Ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), substituted or unsubstituted aryl with a substituent selected from the substituent group α (eg, phenylmethylphenyl, ethylphenyl, methyloxyphenyl, ethyl) Oxyphenyl, fluorophenyl, chlorophenyl, methyloxyphenyl, ethyloxyphenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, etc.), a substituent selected from the substituent group α Substituted or unsubstituted arylalkyl (eg benzyl, phenylethyl, methylphenylmethyl, ethylphenylmethyl, methyloxyphenylmethyl, ethyloxyphenylmethyl, fluorophenylmethyl, chlorophenylmethyl, methyloxyphenylmethyl, ethyloxyphenyl) Methyl, aminophenylmethyl, methylaminophenylmethyl, dimethylaminophenylmethyl, etc.), substituted or unsubstituted aryloxy (for example, phenoxy, methylphenyloxy, etc.), substituent group a non-aromatic heterocyclic group substituted or unsubstituted with a substituent selected from α (for example, pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, methylpyrrole) Nyl, methylpyrrolidino, methylpiperidino, methylpiperidyl, methylpiperazino, methylpiperazinyl, methylmorpholinyl, methylmorpholino, etc.), substituted or unsubstituted heteroaryl (for example, pyridyl) , Thienyl, thiazolyl, furyl, methylfuryl, methylthienyl, methylpyridyl, methylisoxazolyl, methylthiazolyl, methylthiadiazolyl, methyloxazolyl, methyloxadiazolyl), a substituent selected from the substituent group α Substituted or unsubstituted heteroarylalkyl (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, methylpyridylmethyl, methylthienylmethyl, methylthiazolylmethyl, methylfurylmethyl, etc.), substituent group α Substituted or unsubstituted non-aromatic heterocyclic oxy (piperazinooxy, piperidinooxy, etc.), or substituted or unsubstituted heteroaryloxy (pyridyloxy, methylpiperazi) with a substituent selected from the substituent group α Nooxy, methylpiperidinooxy, etc.), substituted or unsubstituted heteroaryloxy (pyridyloxy, methylpyridyloxy, etc.), hydroxy, halogen (F, Cl, Br, etc.) selected from the substituent group α I), cyano and acyl (eg acetyl etc.).
“Substituted or unsubstituted alkylsulfonylamino”, “substituted or unsubstituted aminosulfonylamino”, “substituted or unsubstituted cycloalkylsulfonylamino”, “substituted or unsubstituted nonaromatic heterocyclic sulfonylamino”, “ “Amino” in “substituted or unsubstituted arylsulfonylamino” or “substituted or unsubstituted heteroarylsulfonylamino” may also be substituted with the substituent represented by the above “substituted amino”.

　「置換非芳香族炭素環基」、「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換非芳香族複素環式基」、「置換ヘテロアリール」、「置換シクロアルキルオキシ」、「置換シクロアルケニルオキシ」、「置換非芳香族複素環オキシ」、
「置換アリールオキシ」、「置換ヘテロアリールオキシ」、「置換アリールアルキル」、「置換ヘテロアリールアルキル」、「置換シクロアルキルカルバモイル」、「置換シクロアルケニルカルバモイル」、「置換非芳香族複素環カルバモイル」、「置換アリールカルバモイル」、「置換ヘテロアリールカルバモイル」、「置換シクロアルキルスルファモイル」、「置換シクロアルケニルスルファモイル」、「置換非芳香族複素環スルファモイル」、「置換アリールスルファモイル」、「置換ヘテロアリールスルファモイル」、「置換シクロアルキルオキシカルボニル」、「置換シクロアルケニルオキシカルボニル」、「置換非芳香族複素環オキシカルボニル」、「置換アリールオキシカルボニル」、「置換ヘテロアリールオキシカルボニル」、「置換シクロアルキルスルフィニル」、「置換シクロアルケニルスルフィニル」、「置換非芳香族複素環スルフィニル」、「置換アリールスルフィニル」、「置換ヘテロアリールスルフィニル」、「置換シクロアルキルスルホニル」、「置換シクロアルケニルスルホニル」、「置換非芳香族複素環スルホニル」、「置換アリールスルホニル」、「置換ヘテロアリールスルホニル」、「置換アリールスルホニルオキシ」、「置換非芳香族複素環式基」および「含窒素非芳香族複素環基」の置換基としては、以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない：
アルキル（例えば、メチル、エチル、イソプロピル、ｔｅｒｔ-ブチル等）、ハロアルキル（例えば、CF3、CH2CF3、CH2CCl3等）、ハロアルキルオキシ（例えば、CF3O、CHCF2O等）、アルケニル（例えば、ビニル）、アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、アルキルオキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、アルキルオキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキルアミノ（例えば、ベンジルアミノ、メチルフェニルメチルアミノ、エチルフェニルメチルアミノ、メチルオキシフェニルメチルアミノ、エチルオキシフェニルメチルアミノ、フルオロフェニルメチルアミノ、クロロフェニルメチルアミノ、メチルオキシフェニルメチルアミノ、エチルオキシフェニルメチルアミノ、アミノフェニルメチルアミノ、メチルアミノフェニルメチルアミノ、ジメチルアミノフェニルメチル、トリチルアミノ等）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、アルキルオキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、置換基群αから選択される置換基で置換もしくは非置換のアリール（例えば、フェニル、メチルフェニル、エチルフェニル、メチルオキシフェニル、エチルオキシフェニル、フルオロフェニル、クロロフェニル、メチルオキシフェニル、エチルオキシフェニル、アミノフェニル、メチルアミノフェニル、ジメチルアミノフェニル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキル（例えば、ベンジル、フェニルエチル、メチルフェニルメチル、エチルフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、フルオロフェニルメチル、クロロフェニルメチル、メチルオキシフェニルメチル、エチルオキシフェニルメチル、アミノフェニルメチル、メチルアミノフェニルメチル、ジメチルアミノフェニルメチル等）、置換基群αから選択される置換基で置換もしくは非置換のアリールオキシ（例えば、フェノキシ、メチルフェニルオキシ等）、置換基群αから選択される置換基で置換もしくは非置換のアリールアルキルオキシ（例えば、ベンジルオキシ、フェニルエチルオキシ、メチルフェニルメチルオキシ、エチルフェニルメチルオキシ、メチルオキシフェニルメチルオキシ、エチルオキシフェニルメチルオキシ、フルオロフェニルメチルオキシ、クロロフェニルメチルオキシ、メチルオキシフェニルメチルオキシ、エチルオキシフェニルメチルオキシ、アミノフェニルメチルオキシ、メチルアミノフェニルメチルオキシ、ジメチルアミノフェニルメチルオキシ等）、置換基群αから選択される置換基で置換もしくは非置換の非芳香族複素環式基（例えば、ピロリニル、ピロリジノ、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、メチルピロリニル、メチルピロリジノ、メチルピペリジノ、メチルピペリジル、メチルピペラジノ、メチルピペラジニル、メチルモルホリニル、メチルモルホリノ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリール（例えば、ピリジル、チエニル、チアゾリル、フリル、メチルピリジル、メチルチエニル、メチルチアゾリル、メチルフリル等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールアルキル（例えば、ピリジルメチル、チエニルメチル、チアゾリルメチル、フリルメチル、メチルピリジルメチル、メチルチエニルメチル、メチルチアゾリルメチル、メチルフリルメチル等）、置換基群αから選択される置換基で置換もしくは非置換の非芳香族複素環オキシ（ピペラジノオキシ、ピペリジノオキシ、メチルピペラジノオキシ、メチルピペリジノオキシ等）、置換基群αから選択される置換基で置換もしくは非置換のヘテロアリールオキシ（ピリジルオキシ、メチルピリジルオキシ等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、アルキルチオ（例えば、メチルチオ等）、アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、（例えば、カルバモイル、Ｎ－メチル－Ｎ－メトキシカルバモイル等）、置換もしくは非置換のアルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ヒドロキシエチルカルバモイル、トリフルオロメチルカルバモイル、トリフルオロエチルカルバモイル等）、スルファモイル、アルキルスルファモイル、ヒドロキシ、カルボキシ、ハロゲン（F、Cl、Br、I）、アシル（例えば、ホルミル、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミドおよびオキソ。
「置換アリール」および「置換ヘテロアリール」の置換基としては、ハロゲン、メチル、トリフルオロメチル、エチル、n-プロピル、イソプロピル、メキルオキシ、エチルオキシ、ｎ－プロピルオキシ、イソプロピルオキシ、トリフルオロメチルオキシハロゲン、ヒドロキシ、カルバモイル等が挙げられる。好ましくは、ハロゲン、メチル、イソプロピル、ヒドロキシ、カルバモイル等が挙げられる。 “Substituted non-aromatic carbocyclic group”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted non-aromatic heterocyclic group”, “substituted heteroaryl”, “substituted cycloalkyloxy” , “Substituted cycloalkenyloxy”, “substituted non-aromatic heterocyclic oxy”,
“Substituted aryloxy”, “substituted heteroaryloxy”, “substituted arylalkyl”, “substituted heteroarylalkyl”, “substituted cycloalkylcarbamoyl”, “substituted cycloalkenylcarbamoyl”, “substituted non-aromatic heterocyclic carbamoyl”, “Substituted arylcarbamoyl”, “substituted heteroarylcarbamoyl”, “substituted cycloalkylsulfamoyl”, “substituted cycloalkenylsulfamoyl”, “substituted non-aromatic heterocyclic sulfamoyl”, “substituted arylsulfamoyl”, “ “Substituted heteroarylsulfamoyl”, “substituted cycloalkyloxycarbonyl”, “substituted cycloalkenyloxycarbonyl”, “substituted non-aromatic heterocyclic oxycarbonyl”, “substituted aryloxycarbonyl”, “substituted heteroaryloxycarbonyl” , “Substituted cycloalkylsulfinyl”, “substituted cycloalkenylsulfinyl”, “substituted non-aromatic heterocyclic sulfinyl”, “substituted arylsulfinyl”, “substituted heteroarylsulfinyl”, “substituted cycloalkylsulfonyl”, “substituted cycloalkenylsulfonyl” , “Substituted non-aromatic heterocyclic sulfonyl”, “substituted arylsulfonyl”, “substituted heteroarylsulfonyl”, “substituted arylsulfonyloxy”, “substituted non-aromatic heterocyclic group” and “nitrogen-containing non-aromatic heterocyclic” Substituents for “ring groups” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), haloalkyloxy (eg, CF 3 O, CHCF 2 O, etc.), Alkenyl (eg vinyl), alkynyl (eg ethynyl), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg methoxy, ethoxy, propoxy, butoxy etc.), alkenyloxy ( For example, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (For example, Arylamino, substituted or unsubstituted with a substituent selected from the substituent group α (for example, benzylamino, methylphenylmethylamino, ethylphenylmethylamino, methyloxyphenylmethylamino, ethyloxy) Phenylmethylamino, fluorophenylmethylamino, chlorophenylmethylamino, methyloxyphenylmethylamino, ethyloxyphenylmethylamino, aminophenylmethylamino, methylaminophenylmethylamino, dimethylaminophenylmethyl, tritylamino, etc.), hydroxyamino, imino Hydroxyimino, alkylimino (for example, methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (for example, methoxyimino, ethoxyimino) Mino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, aryl substituted or unsubstituted with a substituent selected from substituent group α (eg, phenyl, methylphenyl, ethylphenyl, methyloxyphenyl, Ethyloxyphenyl, fluorophenyl, chlorophenyl, methyloxyphenyl, ethyloxyphenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, etc.), substituted or unsubstituted arylalkyl with a substituent selected from the substituent group α (for example, , Benzyl, phenylethyl, methylphenylmethyl, ethylphenylmethyl, methyloxyphenylmethyl, ethyloxyphenylmethyl, fluorophenylmethyl, chlorophenylmethyl, methyloxyphenylmethyl, ethyloxy Phenylmethyl, aminophenylmethyl, methylaminophenylmethyl, dimethylaminophenylmethyl, etc.), substituted or unsubstituted aryloxy (eg, phenoxy, methylphenyloxy, etc.), substituents selected from the substituent group α Arylalkyloxy substituted or unsubstituted with a substituent selected from group α (eg, benzyloxy, phenylethyloxy, methylphenylmethyloxy, ethylphenylmethyloxy, methyloxyphenylmethyloxy, ethyloxyphenylmethyloxy, fluoro Phenylmethyloxy, chlorophenylmethyloxy, methyloxyphenylmethyloxy, ethyloxyphenylmethyloxy, aminophenylmethyloxy, methylaminophenylmethyloxy, dimethylaminopheny A non-aromatic heterocyclic group substituted or unsubstituted with a substituent selected from the substituent group α (for example, pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, methylpyrrolinyl, A heteroaryl substituted or unsubstituted with a substituent selected from methylpyrrolidino, methylpiperidino, methylpiperidyl, methylpiperazino, methylpiperazinyl, methylmorpholinyl, methylmorpholino, etc.), substituent group α (eg pyridyl, thienyl , Thiazolyl, furyl, methylpyridyl, methylthienyl, methylthiazolyl, methylfuryl, etc.), substituted or unsubstituted heteroarylalkyl with a substituent selected from the substituent group α (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl) Furylmethyl, methylpyridylmethyl, methylthienylmethyl, methylthiazolylmethyl, methylfurylmethyl, etc.), substituted or unsubstituted non-aromatic heterocyclic oxy (piperazinooxy, piperidinooxy, Methylpiperazinooxy, methylpiperidinooxy, etc.), heteroaryloxy (pyridyloxy, methylpyridyloxy, etc.) substituted or unsubstituted with a substituent selected from the substituent group α, cyano, isocyano, isocyanato, thiocyanato , Isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A (eg, carbamoyl) N-methyl-N-methoxycarbamoyl), substituted or unsubstituted alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, hydroxyethylcarbamoyl, trifluoromethylcarbamoyl, trifluoroethylcarbamoyl, etc.), sulfamoyl, alkyl Sulfamoyl, hydroxy, carboxy, halogen (F, Cl, Br, I), acyl (eg, formyl, acetyl, etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azide Ureido, amidino, guanidino, phthalimide and oxo.
Substituents for “substituted aryl” and “substituted heteroaryl” include halogen, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, mekyloxy, ethyloxy, n-propyloxy, isopropyloxy, trifluoromethyloxyhalogen, Hydroxy, carbamoyl and the like can be mentioned. Preferably, halogen, methyl, isopropyl, hydroxy, carbamoyl and the like can be mentioned.

　本明細書中、式（Ｉ）における置換基Ｒ１０の結合手が、２つの環にまたがっている場合は、Ｒ１０がいずれの環に置換してもよいことを示す。また、本明細書中、置換基Ｒ１０の結合手が、１つの環のみに置換している場合は、Ｒ１０がその環に置換してもよいことを示す In the present specification, when the bond of the substituent R 10 in the formula (I) extends over two rings, it indicates that R 10 may be substituted on any ring. In the present specification, when the bond of the substituent R 10 is substituted on only one ring, it indicates that R 10 may be substituted on that ring.

　さらに、一般式（Ｉ）の化合物の一つ以上の水素、炭素または他の原子は、水素、炭素または他の原子の同位体で置換され得る。一般式（Ｉ）の化合物は、一般式（Ｉ）の化合物のすべての放射性標識体を包含する。一般式（Ｉ）の化合物のそのような「放射性標識化」、「放射性標識体」などは、それぞれが本発明に包含され、代謝薬物動態研究ならびに結合アッセイにおける研究および／または診断ツールとして有用である。本発明の一般式（Ｉ）の化合物に組み込まれ得る同位体の例としては、それぞれ２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、および３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、および塩素が包含される。本発明の放射性標識化合物は、当該技術分野で周知の方法で調製できる。例えば、一般式（Ｉ）のトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式Ｉの特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在または非存在下で、一般式（Ｉ）の化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含してもよい。他のトリチウム標識化合物を調製するための適切な方法としては、文書Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987年).を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 Furthermore, one or more hydrogen, carbon or other atoms of the compound of general formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms. The compound of general formula (I) includes all radiolabeled compounds of the compound of general formula (I). Such “radiolabeled”, “radiolabeled” and the like of compounds of general formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. is there. Examples of isotopes that can be incorporated into the compound of the general formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, and 35, respectively. Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine are included, such as S, 18 F, and 36 Cl. The radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, a tritium-labeled compound of general formula (I) can be prepared by introducing tritium into a specific compound of formula I, for example, by a catalytic dehalogenation reaction using tritium. This process comprises reacting a compound of general formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It may be included. For suitable methods for preparing other tritium labeled compounds, reference may be made to the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.

　上記一般式（Ｉ）で示される本発明化合物またはその塩は、公知の方法により、水和物または溶媒和物に変換されることもある。適当な溶媒和物としては、アセトン、２－ブタノール、２－プロパノール、エタノール、酢酸エチル、テトラヒドロフラン、ジエチルエーテル等との溶媒和物があげられる。例えば、非毒性かつ水溶性である、水和物または溶媒和物（例えば、エタノール等）が挙げられる。水和物を形成する時は、任意の数の水分子と配位していてもよい。
　本発明に係る化合物は製薬上許容される塩を包含する。例えば、アルカリ金属（リチウム、ナトリウムまたはカリウム等）、アルカリ土類金属（マグネシウムまたはカルシウム等）、アンモニウム、有機塩基およびアミノ酸との塩、または無機酸（塩酸、硫酸、硝酸、臭化水素酸、リン酸またはヨウ化水素酸等）、および有機酸（酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸またはエタンスルホン酸等）との塩が挙げられる。特に塩酸、リン酸、酒石酸またはメタンスルホン酸等が好ましい。これらの塩は、通常行われる方法によって形成させることができる。 The compound of the present invention represented by the above general formula (I) or a salt thereof may be converted into a hydrate or a solvate by a known method. Suitable solvates include solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether and the like. For example, non-toxic and water-soluble hydrates or solvates (for example, ethanol and the like) can be mentioned. When forming a hydrate, it may be coordinated with any number of water molecules.
The compounds according to the present invention include pharmaceutically acceptable salts. For example, alkali metals (such as lithium, sodium or potassium), alkaline earth metals (such as magnesium or calcium), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid) and organic acids (acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, and salts with p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). In particular, hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable. These salts can be formed by a commonly performed method.

　「調節剤」とは、作動剤、部分作動剤、逆作動剤および拮抗剤を包含する。
　「ヒスタミンＨ４調節剤」とは、ヒスタミンＨ４受容体の調節剤、すなわち、ヒスタミンＨ４受容体作動剤、ヒスタミンＨ４受容体部分作動剤、ヒスタミンＨ４受容体逆作動剤、ヒスタミンＨ４受容体拮抗剤を包含する。
“Modulators” include agonists, partial agonists, inverse agonists and antagonists.
“Histamine H4 modulator” includes histamine H4 receptor modulators, ie, histamine H4 receptor agonists, histamine H4 receptor partial agonists, histamine H4 receptor inverse agonists, histamine H4 receptor antagonists To do.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000038

であり、
Ｒ１ａが、
ａ）ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；

Ｂ２は、
Figure JPOXMLDOC01-appb-C000039
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000038
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxy Rubonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylo Ci, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);

B 2 is,
Figure JPOXMLDOC01-appb-C000039
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000040

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000041
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000040
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000041
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000042

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000043
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000042
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000043
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、

Figure JPOXMLDOC01-appb-C000045

（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):

And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000045
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000046

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000047
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000046
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000047
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000048

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000049
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000048
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000049
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000050

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000051
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000050
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000051
Wherein each R 10 independently represents a substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino or together oxo or thiooxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000052

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000053
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000052
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000053
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000054

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000055
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000054
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000055
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000056

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000057
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000056
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000057
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000058

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000059
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000058
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000059
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000060

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000061
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群C（置換基群C：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。

In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000060
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000061
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 is hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000062

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000063
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000062
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000063
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000064

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000065
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000064
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000065
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000066

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000067
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000066
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000067
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000068

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000069
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000068
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—, or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000069
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000070

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000071
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000070
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000071
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000072

であり、
Ｒ１ａが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシ；
ｎ１が、０～４の整数；
－Ｂ１が、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍが、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000073
（式中、Ｒ１０が、置換もしくは非置換のアルキル；
Ｒ１１が、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａまたはＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000072
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy;
n 1 is an integer from 0 to 4;
-B 1 is represented by the formula: -X- (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000073
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a or R 9b each independently represents hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000074

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000075
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000074
R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl , Substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl and substituted or unsubstituted heteroaryl), substituted or unsubstituted sulfamoyl, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from Substituent Group A, Substituent Group A Sulfonyl substituted with a substituent selected from Substituted, unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000075
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000076

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000077
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000076
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000077
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000078

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
－Ｂ２は、
Figure JPOXMLDOC01-appb-C000079
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000078
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
-B 2 is
Figure JPOXMLDOC01-appb-C000079
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000080

Ｒｘ２およびＲｘ３は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000081
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000080
R x2 and R x3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl , Substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl and substituted or unsubstituted heteroaryl), substituted or unsubstituted sulfamoyl, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from Substituent Group A, Substituent Group A Sulfonyl substituted with a substituent selected from Substituted, unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000081
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000082

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000083
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000082
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000083
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000084

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000085
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000084
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000085
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000086

Ｒｘ１、Ｒｘ２およびＲｘ３は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル（ただし、Ｒｘ３およびＲｘ４が、同時に２つ以上非置換スルファモイルである場合を除く）、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000087
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000086
R x1 , R x2 and R x3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or Unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy Carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Sulfamoyl substituted with a substituent selected from substituted aryl and substituted or unsubstituted heteroaryl), substituted or unsubstituted sulfamoyl (provided that R x3 and R x4 are two or more unsubstituted sulfamoyl at the same time) Or substituent group A) Sulfinyl substituted with a selected substituent, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted Or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000087
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000088

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000089
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000088
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000089
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000090

Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のシクロアルキルオキシ、または置換もしくは非置換の非芳香族複素環オキシ； 
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙが、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000091
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000090
R x3 and R x4 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted non-aromatic heterocyclic oxy;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000091
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000092

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000093
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000092
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000093
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000094

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）
で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000095
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000094
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is a substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from Sulfonyl substituted with a substituent
A group represented by:
B 2 is,
Figure JPOXMLDOC01-appb-C000095
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000096

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000097
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000096
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A;
) A group shown;
B 2 is,
Figure JPOXMLDOC01-appb-C000097
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000098

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換もしくは非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000099
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000098
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, substituted or unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aryloxy or substituted or unsubstituted heteroaryloxy;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000099
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000100

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000101
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000100
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000101
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000102

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキル、または置換もしくは非置換アシル；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000103
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000102
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000103
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000104

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000105
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000104
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or Sulfamoyl substituted with a substituent selected from (unsubstituted heteroaryl), sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonyloxy, Substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted Or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryl Oxy or substituted or unsubstituted heteroaryloxy;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000105
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000106

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000107
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000106
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000107
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000108

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
ｎ３は、０～２の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000109
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000108
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
n 3 is an integer from 0 to 2;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000109
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000110

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
ｎ４は、０または１の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000111
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000110
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Oxy, substituted or unsubstituted arylsulfo Nyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted Of heteroaryloxy;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 4 is an integer of 0 or 1;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000111
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000112

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ４は、０または１の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000113
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000112
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 4 is an integer of 0 or 1;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y represents substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000113
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000114

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ４は、０または１の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000115
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000114
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 4 is an integer of 0 or 1;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000115
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。

Figure JPOXMLDOC01-appb-C000116

であり、
Ｒ１ａが、
a) ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000117
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Figure JPOXMLDOC01-appb-C000116
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or non-substituted Substituted alkylsulfonyloxy, substituted or Unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, Or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) Two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000117
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000118

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000119
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000118
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000119
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000120

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000121
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000120
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000121
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。

Figure JPOXMLDOC01-appb-C000122

であり、
Ｒ１ａが、
a) ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000123
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Figure JPOXMLDOC01-appb-C000122
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or non-substituted Substituted alkylsulfonyloxy, substituted or Unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, Or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) Two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000123
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000124

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000125
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000124
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 , an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000125
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000126

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000127
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000126
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000127
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。

Figure JPOXMLDOC01-appb-C000128

であり、
Ｒ１ａが、
a) ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000129
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Figure JPOXMLDOC01-appb-C000128
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or non-substituted Substituted alkylsulfonyloxy, substituted or Unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, Or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) Two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000129
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000130

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000131
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000130
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000131
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000132

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000133
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000132
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000133
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。

Figure JPOXMLDOC01-appb-C000134

であり、
Ｒ１ａが、
a) ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｎ１は、０～４の整数；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000135
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノまたは一緒になってオキソもしくはチオキソ；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Figure JPOXMLDOC01-appb-C000134
And
R 1a is
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl Bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) Sulfamoyl substituted with a selected substituent, unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or non-substituted Substituted alkylsulfonyloxy, substituted or Unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, Or substituted or unsubstituted heteroaryloxy, or
It may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) Two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
n 1 is an integer from 0 to 4;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent);
B 2 is,
Figure JPOXMLDOC01-appb-C000135
Wherein each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or together oxo or thioxo;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4) or a compound represented by a substituted or unsubstituted amino-substituted alkylene), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000136

であり、
Ｒ１ｂが、
a)ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙが、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、非置換のスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニル）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000137
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000136
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 , an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituent group A (substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) selected from sulfamoyl, unsubstituted sulfamoyl or substituent group A substituted with a substituent selected from A sulfonyl substituted with a substituent selected from
B 2 is,
Figure JPOXMLDOC01-appb-C000137
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ）：

Figure JPOXMLDOC01-appb-C000138

であり、
Ｒ１ｂが、
a) ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基；
Ｒ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換アシル；
ｎ１は、０～４の整数；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘが、Ｎ（Ｒ７ｃ）；
Ｒ７ｃが、水素；
Ｒ８ａおよびＲ８ｂが、水素；
ｍは、１～５の整数：
Ｙは、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基）示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000139
（式中、Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される基）で示される化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I):
Figure JPOXMLDOC01-appb-C000138
And
R 1b is
a) halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group;
Each R 2b is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c );
R 7c is hydrogen;
R 8a and R 8b are hydrogen;
m is an integer from 1 to 5:
Y is substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted aryl Sulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen-containing non-aromatic heterocyclic group in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A) Group
B 2 is,
Figure JPOXMLDOC01-appb-C000139
Wherein R 10 are each independently substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
p is an integer of 0 to 4), or a pharmaceutically acceptable salt or solvate thereof.

　式（Ｉ）で示される本発明の化合物、その製薬上許容される塩またはそれらの溶媒和物としては、以下の一般式（Ｉ－Ａ）または（Ｉ－Ｂ）で示された各置換基の全ての選択肢の全ての考え得る組み合わせで示される化合物、その製薬上許容される塩またはそれらの溶媒和物が包含される。 Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include each substituent represented by the following general formula (IA) or (IB). Or a pharmaceutically acceptable salt or solvate thereof shown in all possible combinations of all options.

　以下の式（Ｉ－Ａ）または（Ｉ－Ｂ）において

Figure JPOXMLDOC01-appb-C000140

　例えば、Ｗ２として、Ｏ、Ｎ（Ｒ２ａ）、Ｓ、Ｓ（Ｏ）またはＳ（Ｏ）２、Ｒ２ａが、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルスルホニルまたは置換もしくは非置換のアシルが挙げられる。
　例えば、Ｗ２として、Ｎ（Ｒ２ａ）またはＳ、Ｒ２ａが、水素または置換もしくは非置換のアルキルが挙げられる。
　例えば、Ｗ２として、Ｎ（Ｒ２ａ）、Ｒ２ａが、水素または置換もしくは非置換のアルキルが挙げられる。
　例えば、Ｗ２として、Sが挙げられる。 In the following formula (IA) or (IB)
Figure JPOXMLDOC01-appb-C000140
For example, as W 2 , O, N (R 2a ), S, S (O) or S (O) 2 , R 2a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylsulfonyl or substituted or Examples include unsubstituted acyl.
For example, W 2 includes N (R 2a ) or S, R 2a is hydrogen or substituted or unsubstituted alkyl.
For example, as W 2 , N (R 2a ) and R 2a are hydrogen or substituted or unsubstituted alkyl.
For example, as W 2, it includes S is.

　例えば、Ｒ１ｂとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシが挙げられる。
　例えば、Ｒ１ｂとして、ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のシクロアルキル、または置換もしくは非置換の非芳香族複素環式基が挙げられる。 For example, as R 1b , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-substituted Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted An aryl and a substituted or unsubstituted heteroaryl), a sulfamoyl substituted with a substituent selected from substituent group A, a sulfinyl substituted with a substituent selected from substituent group A, and a substituent selected from substituent group A Substituted sulfonyl, substituted or unsubstituted al Rusulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy may be mentioned.
For example, R 1b includes halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclic group.

　例えば、ｎ２として、０～２の整数が挙げられる。
　例えば、ｎ２として、０でが挙げられる。
　例えば、Ｘとして、Ｎ（Ｒ７ｃ）またはＯ、Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシルが挙げられる。
　例えば、Ｘとして、Ｎ（Ｒ７ｃ）、Ｒ７ｃは、水素または置換もしくは非置換のアルキルが挙げられる。
　例えば、Ｘとして、ＮＨが挙げられる。
　例えば、ｍとして、１～３の整数が挙げられる。
　例えば、ｍとして、２が挙げられる。 For example, n2 is an integer of 0 to 2.
For example, n2 is 0.
For example, as X, N (R 7c ) or O, R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
For example, as X, N (R 7c ) and R 7c include hydrogen or substituted or unsubstituted alkyl.
For example, NH is exemplified as X.
For example, m is an integer of 1 to 3.
For example, 2 is mentioned as m.

　例えば、Ｙとして、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイルまたは置換基群Ａから選択される置換基で置換されたスルファモイルが挙げられる。
　例えば、Ｙとして、非置換スルファモイルまたは置換基群Ａから選択される置換基で置換されたスルファモイルが挙げられる。 For example, as Y, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Sulfinyl substituted with a substituent selected from Substituent Group A, Sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, substituted with a substituent selected from Substituent Group A Sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or Non-replacement Alkenylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen atom constituting the ring is selected from substituent group A And a nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent.
For example, as Y, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A Is mentioned.
For example, Y includes sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, or sulfamoyl substituted with a substituent selected from Substituent Group A.
For example, Y may be unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from substituent group A.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000141

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）
で示される基または置換もしくは非置換のアミノで置換されたアルキレンが挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000141
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer from 0 to 4)
Or an alkylene substituted with a substituted or unsubstituted amino.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000142

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000142
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000143

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000143
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000144

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000144
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000145

で示される基が挙げられる。
For example, a B 2,
Figure JPOXMLDOC01-appb-C000145
The group shown by these is mentioned.

　式（Ｉ）で示される本発明の化合物、その製薬上許容される塩またはそれらの溶媒和物としては、以下の一般式（Ｉ－Ｃ）で示された各置換基の全ての選択肢の全ての考え得る組み合わせで示される化合物、その製薬上許容される塩またはそれらの溶媒和物も包含される。
Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include all the options of each substituent represented by the following general formula (IC). Or a pharmaceutically acceptable salt thereof or a solvate thereof is also included.

　以下の式（Ｉ－Ｃ）において

Figure JPOXMLDOC01-appb-C000146

　例えば、Ｒ１ｃとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシが挙げられる。
　例えば、Ｒ１ｃとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシが挙げられる。
　例えば、Ｒ１ｃとして、ハロゲンまたはヒドロキシが挙げられる。
　例えば、Ｒ１ｃとしてが、ヒドロキシが挙げられる。
　例えば、Ｒ１ｃとして、ハロゲンが挙げられる。
　例えば、Ｒ１ｃとして、フッ素が挙げられる。 In the following formula (IC)
Figure JPOXMLDOC01-appb-C000146
For example, as R 1c , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy.
For example, R 1c includes halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, and hydroxy.
For example, R 1c includes halogen or hydroxy.
For example, R 1c includes hydroxy.
For example, R 1c includes halogen.
For example, fluorine is mentioned as R1c .

　例えば、Ｒ１ｄとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ヒドロキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のシクロアルキルオキシが挙げられる。
　例えば、Ｒ１ｄとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシまたはヒドロキシが挙げられる。
　例えば、Ｒ１ｄとして、Ｒ１ｃが結合する炭素原子に結合し、ハロゲンまたは置換もしくは非置換のアルキルが挙げられる。
　例えば、ｎ３がとして、０～３の整数が挙げられる。
　例えば、ｎ３がとして、０または１が挙げられる。
　例えば、Ｘとして、Ｎ（Ｒ７ｃ）またはＯ、Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシルが挙げられる。
　例えば、Ｘとして、Ｎ（Ｒ７ｃ）、Ｒ７ｃは、水素または置換もしくは非置換のアルキルが挙げられる。
　例えば、Ｘとして、ＮＨが挙げられる。
　例えば、ｍとして、１～３の整数が挙げられる。
　例えば、ｍとして、２が挙げられる。 For example, as R 1d , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyloxy.
For example, R 1d includes halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or hydroxy.
For example, R 1d is bonded to the carbon atom to which R 1c is bonded, and includes halogen or substituted or unsubstituted alkyl.
For example, n3 is an integer of 0 to 3.
For example, n3 is 0 or 1.
For example, as X, N (R 7c ) or O, R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
For example, as X, N (R 7c ) and R 7c include hydrogen or substituted or unsubstituted alkyl.
For example, NH is exemplified as X.
For example, m is an integer of 1 to 3.
For example, 2 is mentioned as m.

　例えば、Ｙとして、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイルまたは置換基群Ａから選択される置換基で置換されたスルホニルが挙げられる。 For example, as Y, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituent group A (Substituent group A: substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Substituted sulfinyl substituted with a substituent selected from a substituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl), substituted with a substituent selected from substituent group A Substituent selected from sulfonyl, unsubstituted sulfamoyl, substituent group A Substituted sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino Substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or a nitrogen atom constituting the ring And nitrogen-containing non-aromatic heterocyclic group substituted with sulfonyl substituted with a substituent selected from Substituent Group A.
For example, as Y, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A Is mentioned.
Examples of Y include unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, or sulfonyl substituted with a substituent selected from substituent group A.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000147

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）
で示される基または置換もしくは非置換のアミノで置換されたアルキレンが挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000147
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer from 0 to 4)
Or an alkylene substituted with a substituted or unsubstituted amino.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000148

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000148
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000149

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000149
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000150

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000150
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000151

で示される基が挙げられる。
For example, a B 2,
Figure JPOXMLDOC01-appb-C000151
The group shown by these is mentioned.

　式（Ｉ）で示される本発明の化合物、その製薬上許容される塩またはそれらの溶媒和物としては、以下の一般式（Ｉ－Ｄ）で示された各置換基の全ての選択肢の全ての考え得る組み合わせで示される化合物、その製薬上許容される塩またはそれらの溶媒和物も包含される。 Examples of the compound of the present invention represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof include all the options of each substituent represented by the following general formula (ID). Or a pharmaceutically acceptable salt thereof or a solvate thereof is also included.

　以下の式（Ｉ－Ｄ）において

Figure JPOXMLDOC01-appb-C000152
In the following formula (ID)
Figure JPOXMLDOC01-appb-C000152

　例えば、Ｒ１ａとして、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、置換もしくは非置換のカルバモイル、非置換スルファモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシが挙げられる。
　例えば、Ｒ１ａとして、ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキル、置換基群Ａから選択される置換基で置換されたスルホニルまたは置換もしくは非置換の非芳香族複素環式基が挙げられる。
　例えば、Ｒ１ａとして、１つのＲ１ａが、式（Ｉ－D）における環を構成する６位の窒素原子に結合し、ハロゲン、置換もしくは非置換のアルキル、シアノ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキル、置換基群Ａから選択される置換基で置換されたスルホニルまたは置換もしくは非置換の非芳香族複素環式基が挙げられる。
　例えば、Ｒ１ａとして、１つのＲ１ａが、式（Ｉ－D）における環を構成するの６位の窒素原子に結合し、置換もしくは非置換のアルキル、置換もしくは非置換のアシルまたは置換基群Ａから選択される置換基で置換されたスルホニルが挙げられる。 For example, as R 1a , halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-substituted Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted carbamoyl, unsubstituted sulfamoyl, substituent group A (substituent group A: substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted An aryl and a substituted or unsubstituted heteroaryl), a sulfamoyl substituted with a substituent selected from substituent group A, a sulfinyl substituted with a substituent selected from substituent group A, and a substituent selected from substituent group A Substituted sulfonyl, substituted or unsubstituted al Rusulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocycle Formula group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy may be mentioned.
For example, as R 1a , halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, sulfonyl substituted with a substituent selected from substituent group A, or substituted or An unsubstituted non-aromatic heterocyclic group is mentioned.
For example, as R 1a , one R 1a is bonded to the 6-position nitrogen atom constituting the ring in formula (ID), and is halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted acyl, And substituted or unsubstituted cycloalkyl, sulfonyl substituted with a substituent selected from Substituent Group A, or substituted or unsubstituted non-aromatic heterocyclic group.
For example, as R 1a , one R 1a is bonded to the 6-position nitrogen atom constituting the ring in Formula (ID), and is substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a group of substituents And sulfonyl substituted with a substituent selected from A.

　例えば、ｎ１として、１～４の整数が挙げられる。
　例えば、ｎ１として、１が挙げられる。
　例えば、Ｘがとして、Ｎ（Ｒ７ｃ）またはＯ、Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシルが挙げられる。
　例えば、Ｘがとして、Ｎ（Ｒ７ｃ）、Ｒ７ｃは、水素また置換もしくは非置換のアルキルが挙げられる。
　例えば、Ｘがとして、ＮＨが挙げられる。
　例えば、ｍとして、１～３の整数が挙げられる。
　例えば、ｍとして、２が挙げられる。 For example, n1 is an integer of 1 to 4.
For example, n1 is 1.
For example, as X, N (R 7c ) or O, R 7c includes hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
For example, as X, N (R 7c ) and R 7c may be hydrogen or substituted or unsubstituted alkyl.
For example, as X is NH.
For example, m is an integer of 1 to 3.
For example, 2 is mentioned as m.

　例えば、Ｙとして、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基が挙げられる。
　例えば、Ｙとして、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイルまたは置換基群Ａから選択される置換基で置換されたスルファモイルが挙げられる。
　例えば、Ｙとして、非置換スルファモイルまたは置換基群Ａから選択される置換基で置換されたスルファモイルが挙げられる。 For example, as Y, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Sulfinyl substituted with a substituent selected from Substituent Group A, Sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, substituted with a substituent selected from Substituent Group A Sulfamoyl, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or Non-replacement Alkenylsulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino or a nitrogen atom constituting the ring is selected from substituent group A And a nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent.
For example, as Y, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, Substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A Is mentioned.
For example, Y includes sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, or sulfamoyl substituted with a substituent selected from Substituent Group A.
For example, Y may be unsubstituted sulfamoyl or sulfamoyl substituted with a substituent selected from substituent group A.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000153

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素、置換もしくは非置換のシクロアルキル、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）
で示される基または置換もしくは非置換のアミノで置換されたアルキレンが挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000153
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 represents hydrogen, substituted or unsubstituted cycloalkyl, unsubstituted alkyl, or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituent selected from unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl) One or more substituted alkyls;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer from 0 to 4)
Or an alkylene substituted with a substituted or unsubstituted amino.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000154

（式中、Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000154
Wherein R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000155

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000155
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000156

（式中、Ｒ１０は、置換もしくは非置換のアルキル；
Ｒ１１は、水素、非置換のアルキルまたは置換基群Ｃ（置換基群Ｃ：ヒドロキシ、ハロゲン、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で１以上置換されたアルキル；
ｐは０～４の整数）
で示される基が挙げられる。 For example, a B 2,
Figure JPOXMLDOC01-appb-C000156
Wherein R 10 is substituted or unsubstituted alkyl;
R 11 represents hydrogen, unsubstituted alkyl or substituent group C (substituent group C: hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted Or alkyl substituted with one or more substituents selected from unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
p is an integer from 0 to 4)
The group shown by these is mentioned.

　例えば、Ｂ２として、

Figure JPOXMLDOC01-appb-C000157

で示される基が挙げられる。
For example, a B 2,
Figure JPOXMLDOC01-appb-C000157
The group shown by these is mentioned.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000158

［式中、Ｒａ１およびＲａ２は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、アシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
[式中、
－Ｘ－は、単結合、－Ｎ（Ｒ７）－、－Ｏ－または－Ｓ－；
Ｒ７は、水素、置換もしくは非置換のアルキルまたはアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000159
（式中、Ｒ１０、Ｒ１１、およびｐは上記と同意義）で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000158
Wherein R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted Is an unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A , Unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted Arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ is represented by the formula: —X— (CR 8a R 8b ) mY
[Where
—X— represents a single bond, —N (R 7 ) —, —O— or —S—;
R 7 is hydrogen, substituted or unsubstituted alkyl or acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A,
-B ''
Figure JPOXMLDOC01-appb-C000159
Wherein R 10 , R 11 , and p are as defined above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000160

［式中、Ｒａ１およびＲａ２は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、アシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）2－Ｙ
[式中、
－Ｘ－は、単結合、－Ｎ（Ｒ７）－、－Ｏ－または－Ｓ－；
Ｒ７は、水素、置換もしくは非置換のアルキルまたはアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、１～５の整数：
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000161
（式中、Ｒ１０、Ｒ１１、およびｐは上記と同意義）で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000160
Wherein R a1 and R a2 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted Is an unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A , Unsubstituted sulfamoyl, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted Arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ is represented by the formula: —X— (CR 8a R 8b ) 2 —Y
[Where
—X— represents a single bond, —N (R 7 ) —, —O— or —S—;
R 7 is hydrogen, substituted or unsubstituted alkyl or acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 1 to 5:
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A,
-B ''
Figure JPOXMLDOC01-appb-C000161
Wherein R 10 , R 11 , and p are as defined above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000162

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000163
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000164
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000162
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000163
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000164
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000165

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000166
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’あり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000167
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000165
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000166
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B 'and -B 2 is -B'';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000167
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000168

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000169
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000170
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000168
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000169
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B "and -B 2 is -B ';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000170
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000171

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000172
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000173
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000171
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000172
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000173
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000174

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000175
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’あり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000176
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000174
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000175
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B 'and -B 2 is -B'';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000176
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000177

［式中、Ｒａ１およびＲａ２が、それらが結合する炭素原子と一緒になって形成したＡ環が
Figure JPOXMLDOC01-appb-C000178
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｗ－は、－Ｏ－、－Ｎ（Ｒ２）－、－Ｓ－、－Ｓ（Ｏ）－または－Ｓ（Ｏ）２－；
Ｒ２は、水素、置換もしくは非置換のアルキルまたはアシル；
－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）ｍ－Ｙ；
ｍは、１～５の整数：
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000179
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000177
[Wherein the ring A formed by R a1 and R a2 together with the carbon atom to which they are bonded is
Figure JPOXMLDOC01-appb-C000178
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
—W— represents —O—, —N (R 2 ) —, —S—, —S (O) — or —S (O) 2 —;
R 2 is hydrogen, substituted or unsubstituted alkyl or acyl;
-B 1 is -B "and -B 2 is -B ';
—B ′ has the formula: —X— (CH 2 ) m —Y;
m is an integer from 1 to 5:
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000179
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000180

であり、
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’であるか、または－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）２－Ｙ；
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000181
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000180
And
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
-B 1 is -B 'and -B 2 is -B "or -B 1 is -B" and -B 2 is -B';
—B ′ has the formula: —X— (CH 2 ) 2 —Y;
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000181
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000182

であり、
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｂ１が－Ｂ’であり、－Ｂ２が－Ｂ’’あり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）２－Ｙ；
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000183
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000182
And
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
-B 1 is -B 'and -B 2 is -B'';
—B ′ has the formula: —X— (CH 2 ) 2 —Y;
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000183
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　本発明化合物において、一つの態様は以下の通りである。
　式（Ｉ’）：

Figure JPOXMLDOC01-appb-C000184

であり、
Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシ、ハロゲンまたはヒドロキシ；
ｎは、０～２の整数；
－Ｂ１が－Ｂ’’であり、－Ｂ２が－Ｂ’であり；
－Ｂ’は、式：－Ｘ－（ＣＨ２）２－Ｙ；
－Ｘ－は、－ＮＨ－；
Ｙは、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、；
－Ｂ’’が、
Figure JPOXMLDOC01-appb-C000185
Ｒ１０が、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、または置換もしくは非置換のアミノ；
Ｒ１１は、水素または置換もしくは非置換のアルキル；
ｐは０～４の整数）で示される環］で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。 In the compound of the present invention, one embodiment is as follows.
Formula (I ′):
Figure JPOXMLDOC01-appb-C000184
And
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, halogen or hydroxy;
n is an integer from 0 to 2;
-B 1 is -B "and -B 2 is -B ';
—B ′ has the formula: —X— (CH 2 ) 2 —Y;
—X— represents —NH—;
Y is unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A;
-B ''
Figure JPOXMLDOC01-appb-C000185
Each R 10 is independently substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino;
R 11 is hydrogen or substituted or unsubstituted alkyl;
or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is an integer of 0 to 4.

　上記一般式（Ｉ）で表される本発明化合物は、ヒスタミンＨ４受容体に対する調節作用を有し（作動剤、部分作動剤、逆作動剤および拮抗剤、特に拮抗剤）、ヒスタミンＨ４受容体が関与する疾患の治療剤として有用である。
　例えば、気管支喘息、アレルギー性鼻炎、慢性閉塞性肺疾患（ＣＯＰＤ）などの呼吸器系疾患；慢性関節リウマチ、アトピー性皮膚炎、アレルギー性結膜炎、乾癬、炎症性大腸炎、潰瘍性大腸炎、狼瘡、アテローム硬化症などの炎症性疾患；神経性疼痛および侵害性疼痛を含む疼痛緩和などに有効である。 The compound of the present invention represented by the above general formula (I) has a modulatory action on histamine H4 receptor (agonist, partial agonist, inverse agonist and antagonist, particularly antagonist), and histamine H4 receptor is It is useful as a therapeutic agent for diseases involved.
For example, respiratory diseases such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD); rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus Inflammatory diseases such as atherosclerosis; effective for pain relief including neuropathic pain and nociceptive pain.

　本発明の一般式（Ｉ）で表される化合物は、例えば、以下に示す合成ルートによって製造することができる。 The compound represented by the general formula (I) of the present invention can be produced, for example, by the following synthesis route.

　以下に本発明に含まれる化合物の一般的合成法を示すが、本合成法に限られるものではない。

Figure JPOXMLDOC01-appb-C000186

（式中、Ｒａ１およびＲａ２は上記（１）と同意義、Ｒ１４はハロゲン、置換もしくは非置換のアルキルオキシまたはシアノなどの脱離基、Ｒ１５は置換もしくは非置換のアルキルまたは置換もしくは非置換のアリール。）
　塩基存在下、一般式（ｉ）で示される化合物に対し、一般式（ｉｉ）で示される化合物を作用させることで、一般式（ｉｉｉ）で示される化合物を合成することができる。
　反応溶媒としてはＴＨＦ、ジエチルエーテル、ＤＭＦ、ＤＭＥ、ジオキサン、ヘキサン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウムまたは水素化カリウム等が挙げられ、化合物（ｉ）に対して、１～１０モル当量用いることができる。
　反応温度は－７８℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
The general synthesis method of the compound included in the present invention is shown below, but is not limited to this synthesis method.
Figure JPOXMLDOC01-appb-C000186
Wherein R a1 and R a2 are as defined above (1), R 14 is a leaving group such as halogen, substituted or unsubstituted alkyloxy or cyano, R 15 is substituted or unsubstituted alkyl or substituted or Unsubstituted aryl.)
The compound represented by the general formula (iii) can be synthesized by allowing the compound represented by the general formula (ii) to act on the compound represented by the general formula (i) in the presence of a base.
Examples of the reaction solvent include THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, hydrogen Examples thereof include sodium hydride and potassium hydride, and 1 to 10 molar equivalents can be used relative to compound (i).
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (iii) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000187

（式中の記号は、上記と同意義である。）
　塩基存在下、一般式（ｉｉｉ）で示される化合物と尿素を縮合させることで、一般式（ｉｖ）で示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド等が挙げられる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000187
(The symbols in the formula are as defined above.)
In the presence of a base, the compound represented by the general formula (iii) can be synthesized by condensing the compound represented by the general formula (iii) with urea.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The obtained compound represented by the general formula (iv) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000188

（式中、Ｚは置換アルキルまたは置換もしくは非置換の非芳香族複素環式基、その他の記号は上記と同意義である。）
　塩基存在下、一般式（ｉｉｉ）で示される化合物と一般式（ｖ）で示される化合物を縮合させることで、一般式（ｖｉ）で示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド等が挙げられ、一般式（ｉｉｉ）で示される化合物に対して１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｖｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000188
(In the formula, Z is substituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group, and other symbols are as defined above.)
By condensing the compound represented by the general formula (iii) and the compound represented by the general formula (v) in the presence of a base, the compound represented by the general formula (vi) can be synthesized.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (iii).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (vi) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000189

（式中、Ｑは臭素原子または塩素原子、その他の記号は上記と同意義である。）
　一般式（ｉｖ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｖｉｉ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリド等が挙げられ、化合物（ｉｖ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンを用いてもよい。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000189
(In the formula, Q is a bromine atom or a chlorine atom, and other symbols are as defined above.)
A compound represented by the general formula (vii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (iv).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride and the like, and 1 equivalent to a solvent amount can be used with respect to compound (iv). Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (vii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000190

（式中の記号は、上記と同意義である。）
　一般式（ｖｉ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｖｉｉｉ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリド等が挙げられ、化合物（ｖｉ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンを用いてもよい。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000190
(The symbols in the formula are as defined above.)
A compound represented by the general formula (viii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (vi).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride and the like, and 1 equivalent to a solvent amount can be used with respect to compound (vi). Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (viii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000191

（式中、Ｒ１６は置換アルキル、Ｚ’は置換もしくは非置換の非芳香族複素環式基、その他の記号は、上記と同意義である。）
　一般式（ｉｘ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘ）で示されるアミンを作用させることで、一般式（ｘｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｉｘ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000191
(Wherein R 16 is substituted alkyl, Z ′ is a substituted or unsubstituted non-aromatic heterocyclic group, and other symbols are as defined above.)
By reacting the compound represented by the general formula (ix) with the amine represented by the general formula (x) in the presence or absence of a base, the compound represented by the general formula (xi) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (ix).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xi) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000192

（式中の記号は、上記と同意義である。）
　一般式（ｖｉｉ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘ）で示されるアミンを作用させることで、一般式（ｘｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｖｉｉ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000192
(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (vii) with the amine represented by the general formula (x) in the presence or absence of a base, the compound represented by the general formula (xii) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (vii).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000193

（式中の記号は、上記と同意義である。）
　一般式（ｘｉｉ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘｉｉｉ）で示されるアミンを作用させることで、一般式（ｘｉｖ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジンナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｘｉｉ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000193
(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (xii) with the amine represented by the general formula (xiii) in the presence or absence of a base, the compound represented by the general formula (xiv) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used relative to compound (xii).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xiv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000194

（式中、Ｐ１はＢｏｃ、ベンジルオキシカルボニルまたはベンジル等の一般的なアミンの保護基、
Figure JPOXMLDOC01-appb-C000195
は非芳香族含窒素複素環基、その他の記号は上記と同意義である。）
　一般式（ｘｖ）で示される化合物に対して、公知の脱保護反応（参照：Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　Ｗｉｌｅｙ）を行うにより、一般式（ｘｖｉ）で示されるアミンが得られる。
　得られた一般式（ｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000194
Wherein P 1 is a common amine protecting group such as Boc, benzyloxycarbonyl or benzyl,
Figure JPOXMLDOC01-appb-C000195
Is a non-aromatic nitrogen-containing heterocyclic group, and other symbols are as defined above. )
An amine represented by the general formula (xvi) is obtained by subjecting the compound represented by the general formula (xv) to a known deprotection reaction (see: Green's Protective Groups in Organic Synthesis, Wiley).
The resulting compound represented by the general formula (xv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000196

（式中、Ｒ１８は水素または置換もしくは非置換アルキル、
Figure JPOXMLDOC01-appb-C000197
は非芳香族複素環基、その他の記号は、上記と同意義である。）
　一般式（ｘｖｉｉ）で示される化合物に対して、公知の脱保護反応（参照：Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　Ｗｉｌｅｙ）を行うにより、一般式（ｘｖｉｉｉ）で示されるアミンが得られる。
　得られた一般式（ｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000196
Wherein R 18 is hydrogen or substituted or unsubstituted alkyl,
Figure JPOXMLDOC01-appb-C000197
Is a non-aromatic heterocyclic group, and other symbols are as defined above. )
An amine represented by the general formula (xviii) is obtained by subjecting the compound represented by the general formula (xvii) to a known deprotection reaction (see: Green's Protective Groups in Organic Synthesis, Wiley).
The resulting compound represented by the general formula (xv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000198

（式の記号は、上記と同意義である。）
　一般式（ｘｉｘ）で示される化合物に対して、公知の脱保護反応（参照：Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　Ｗｉｌｅｙ）を行うにより、一般式（ｘｘ）で示されるアミンが得られる。
　得られた一般式（ｘｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000198
(The symbols in the formula are as defined above.)
By subjecting the compound represented by the general formula (xix) to a known deprotection reaction (see: Green's Protective Groups in Organic Synthesis, Wiley), an amine represented by the general formula (xx) is obtained.
The resulting compound represented by the general formula (xx) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000199

（式の記号は、上記と同意義である。）
　一般式（ｘｘｉ）で示される化合物に対して、公知の脱保護反応（参照：Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　Ｗｉｌｅｙ）を行うにより、一般式（ｘｘｉｉ）で示されるアミンが得られる。
　得られた一般式（ｘｘｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000199
(The symbols in the formula are as defined above.)
The compound represented by the general formula (xxi) is subjected to a known deprotection reaction (see Green's Protective Groups in Organic Synthesis, Wiley) to obtain the amine represented by the general formula (xxii).
The resulting compound represented by the general formula (xxii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000200

（式中、Ｒ１９は水素または置換もしくは非置換のアルキル、Ｒ２０は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、その他の記号は前記と同意義である。）
　一般式（ｘｘｉｉｉ）で示されるアミンに対して、塩基存在下、一般式（ｘｘｉｖ）で示される化合物を作用させることで、一般式（ｘｘｖ）で示される化合物が得られる。
　反応溶媒としてはＴＨＦ、アセトニトリル、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｘｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000200
Wherein R 19 is hydrogen or substituted or unsubstituted alkyl, R 20 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or (Unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.)
The compound represented by the general formula (xxv) is obtained by allowing the compound represented by the general formula (xxiv) to act on the amine represented by the general formula (xxiii) in the presence of a base.
Examples of the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (xxv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000201

（式中の記号は、前記と同意義である。）
　一般式（ｘｘｖｉ）で示されるアミンに対して、塩基存在下、一般式（ｘｘｉｖ）で示される化合物を作用させることで、一般式（ｘｘｖｉｉ）で示される化合物が得られる。
　反応溶媒としてはＴＨＦ、アセトニトリル、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｘｘｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000201
(The symbols in the formula are as defined above.)
A compound represented by the general formula (xxvii) is obtained by allowing a compound represented by the general formula (xxiv) to act on the amine represented by the general formula (xxvi) in the presence of a base.
Examples of the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (xxvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000202

（式中、ｔは０～２の整数、その他の記号は、上記と同意義である。）
　一般式（ｘｘｖｉｉｉ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｘｘｉｘ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリドなどが挙げられ、化合物（ｘｘｖｉｉｉ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンを用いてもよい。
　反応温度は－２０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｘｉｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000202
(In the formula, t is an integer of 0 to 2, and other symbols are as defined above.)
A compound represented by the general formula (xxix) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (xxviii).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, and the like, and 1 equivalent to a solvent amount can be used with respect to compound (xxviii). Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xxix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000203

（式中、Ｒ２１およびＲ２２は、それぞれ独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、その他の記号は前記と同意義である。）
　一般式（ｘｘｘ）で示される化合物に対して、塩基存在下、一般式（ｘｘｘｉ）で示されるアミンを作用させることで、一般式（ｘｘｘｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン等が挙げられ、化合物（ｘｘｘ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｘｘｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000203
Wherein R 21 and R 22 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted And cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other symbols are as defined above.)
By reacting the compound represented by the general formula (xxx) with the amine represented by the general formula (xxxi) in the presence of a base, the compound represented by the general formula (xxxii) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxx).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xxxii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000204

（式中、ｕは１～４の整数、その他の記号は前記と同意義である。）
　一般式（ｘｘｘｉｉｉ）で示される化合物に対して、酸を作用させることで、一般式（ｘｘｘｉｖ）で示される化合物が得られる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム等が挙げられ、単独または混合して用いることができる。
　酸としては、ヨウ化トリメチルシラン、三臭化ホウ素等が挙げられ、化合物（ｘｘｘｉｉｉ）に対して、１～３０モル当量用いることができる。
　反応温度は－７８℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｘｘｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000204
(In the formula, u is an integer of 1 to 4, and other symbols are as defined above.)
A compound represented by the general formula (xxxiv) is obtained by allowing an acid to act on the compound represented by the general formula (xxxiii).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
Examples of the acid include trimethylsilane iodide, boron tribromide, and the like. The acid can be used at 1 to 30 molar equivalents relative to the compound (xxxiii).
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000205

（式中、ｑは１～３の整数、ｒは１～３の整数、Ｒ２３は水素、置換もしくは非置換のアルキルオキシ、その他の記号は前記と同意義である。）
　一般式（ｘｘｘｖ）で示される化合物に対して、塩基存在下、１－クロロエチルクロロホルメートを作用させることで、一般式（ｘｘｖｉ）で示される化合物が得られる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン等が挙げられ、化合物（ｘｘｘｖ）に対して、１～１０モル当量用いることができる。
　反応温度は－７８℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｘｘｖｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000205
(Wherein q is an integer of 1 to 3, r is an integer of 1 to 3, R 23 is hydrogen, substituted or unsubstituted alkyloxy, and other symbols are as defined above.)
The compound represented by the general formula (xxxvi) is obtained by allowing 1-chloroethyl chloroformate to act on the compound represented by the general formula (xxxv) in the presence of a base.
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxxv).
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000206

（式中、Ｒ２４は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、その他の記号は前記と同意義である。）
　一般式（ｘｘｘｖｉ）で示される化合物に対して、塩基存在下、一般式（ｘｘｘｖｉｉ）で示される化合物を作用させることで、一般式（ｘｘｘｖｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、ＴＨＦ、ジエチルエーテル、ＤＭＦ、ＤＭＥ、ジオキサン、ヘキサン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、化合物（ｘｘｘｖｉ）に対して、１～２０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｘｘｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。

Figure JPOXMLDOC01-appb-C000206
Wherein R 24 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other symbols are as defined above.
The compound represented by the general formula (xxxviii) is obtained by allowing the compound represented by the general formula (xxxvii) to act on the compound represented by the general formula (xxxvi) in the presence of a base.
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, which can be used alone or in combination. .
Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like, and 1 to 20 molar equivalents are used with respect to the compound (xxxvi). it can.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000207

（式中、Ｚ２およびＺ３は臭素原子、塩素原子、トシレート、メシレート、アルキルスルホン、アリールスルホン等の脱離基、Ｒ３１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、Ｘ１、Ｘ２、Ｘ３およびＸ４は上記（１）と同意義である。）
　一般式（ｉｘｌ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘｌ）で示される化合物を作用させることで、一般式で示される化合物（ｘｌｉ）が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル、ピリジン等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｉｘｌ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｌｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000207
(Wherein Z 2 and Z 3 are a leaving group such as bromine atom, chlorine atom, tosylate, mesylate, alkylsulfone, arylsulfone, R 31 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, X 1 , X 2 , X 3 and X 4 are the same as defined in (1) above.)
By reacting the compound represented by the general formula (xl) with the compound represented by the general formula (ixl) in the presence or absence of a base, the compound (xli) represented by the general formula is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (ixl).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xli) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000208

（式中、Ｒ３２は水素、置換もしくは非置換アルキルまたはＲ３２とＺ４は一緒になって環を形成してもよい、Ｚ４は水素、置換もしくは非置換のアルキルまたはアシル、その他の記号は前記と同意義である。）
　一般式（ｘｌｉ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘｌｉｉ）で示される化合物を作用させることで、一般式（ｘｌｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル、ピリジン等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｘｌｉ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｌｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000208
Wherein R 32 is hydrogen, substituted or unsubstituted alkyl, or R 32 and Z 4 may be combined to form a ring, Z 4 is hydrogen, substituted or unsubstituted alkyl or acyl, or other symbols. Is as defined above.)
The compound represented by the general formula (xliii) is obtained by allowing the compound represented by the general formula (xlii) to act on the compound represented by the general formula (xli) in the presence or absence of a base.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (xli).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xliii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000209

（式中、Ｒ３３は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、Ｒ３４は水素、または２つのＲ３４が結合して－（ＣＲ６０ａＲ６０ｂ）ｔ－、ｔは１～３の整数、Ｒ６０ａおよびＲ６０ｂは、それぞれ独立して、水素またはアルキル。）
塩基存在下、一般式（ｘｌｉ）で示される化合物に対し、金属触媒および一般式（ｘｌｉｖ）で示されるボロン酸またはボロン酸エステルを作用させることで、一般式（ｘｌｖ）で、示される化合物を合成することができる。
反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、水、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ＤＭＦ，ＮＭＰ等が挙げられ、単独または混合して用いることができる。
金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウムなどが挙げられ、化合物（ｘｌｉ）に対して、０．００１～０．５モル当量用いることができる。また配位子としてトリフェニルホスフィン、トリブチルホスフィン、ｄｐｐｆ等の有機リン化合物を用いることもできる。
　塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム、炭酸セシウム等が挙げられ、化合物（ｘｌｉ）に対して、１～１０モル当量用いることができる。
　ボロン酸またはボロン酸エステル（ｘｌｉｖ）は、化合物（ｘｌｉ）に対して、１～１０モル当量用いることができる。
　反応温度は、２０℃～溶媒の還流温度が挙げられる。
　反応時間としては、０．５～４８時間が挙げられる。
得られた一般式（ｘｌｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000209
Wherein R 33 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 34 is hydrogen, or two R 34 are bonded to each other, and- (CR 60a R 60b ) t-, t is 1 to An integer of 3, R 60a and R 60b are each independently hydrogen or alkyl.)
By reacting a metal catalyst and a boronic acid or boronic acid ester represented by the general formula (xliv) with the compound represented by the general formula (xli) in the presence of a base, the compound represented by the general formula (xlv) Can be synthesized.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF, NMP and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. The compound can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound (xli). An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus Examples thereof include potassium oxyhydrogen, cesium carbonate, and the like, and can be used at 1 to 10 molar equivalents relative to the compound (xli).
Boronic acid or boronic acid ester (xliv) can be used at 1 to 10 molar equivalents relative to compound (xli).
With respect to the reaction temperature, it can be 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The obtained compound represented by the general formula (xlv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000210

（式中、Ｒ３５は水素、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ等、Ｒ３６およびＲ３７は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアミノ等、Ｒ３５およびＲ３６は一緒になって環を形成してもよい、その他の記号は前記と同意義である。）
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル、蟻酸等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）等が挙げられ、化合物（ｘｌｖｉ）に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は、１～５０気圧が挙げられる。
　反応温度は、０℃から溶媒の還流温度が挙げられる。
　反応時間としては、０．５～７２時間が挙げられる。
　得られた化合物（ｘｌｖｉｉ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000210
Wherein R 35 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, etc., R 36 and R 37 are each independently hydrogen, R 35 and R 36 may be combined to form a ring, such as substituted or unsubstituted alkyl, substituted or unsubstituted amino, etc., and other symbols are as defined above.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, formic acid and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (xlvi). Can do.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (xlvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000211

（式中、Ｒ３８は置換もしくは非置換のアルキレンまたは置換もしくは非置換のアルケニレンＲ３９は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、またはＺ４およびＲ３９が、一緒になって非芳香族複素環を形成してもよい；Ｐ１は、アミノ基の適切な保護基、その他の記号は前記と同意義である。）
　化合物（ｘｌｖｉｉｉ）を酸処理することにより、一般式（ｉｌ）で示されるアミン化合物を合成することができる。
　化合物（ｘｌｖｉｉｉ）に対して、トリフルオロ酢酸、塩酸、硫酸、蟻酸等を１モル当量～溶媒量用いることができる。
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ジオキサン、酢酸エチル、塩化メチレン、クロロホルム、水等が挙げられ、単独または混合して用いることができる。
　反応温度は、０℃～１００℃が挙げられる。　　　　
　反応時間としては、０．５～２４時間が挙げられる。
　得られた一般式（ｉｌ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000211
Wherein R 38 is substituted or unsubstituted alkylene or substituted or unsubstituted alkenylene R 39 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or Z 4 and R 39 May be combined to form a non-aromatic heterocycle; P 1 is a suitable protecting group for an amino group, and other symbols are as defined above.)
By subjecting compound (xlviii) to an acid treatment, an amine compound represented by general formula (il) can be synthesized.
For the compound (xlviii), trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid and the like can be used at 1 molar equivalent to a solvent amount.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to 100 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (il) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000212

（式中、Ｒ４０は（ＣＲ８ａＲ８ｂ）ｍ、ＣＲ８ａ、Ｒ８ｂおよびｍは上記（１）と同じ、Ｒ４１はＢｏｃ、ベンジルオキシカルボニル等のカルバメート基、Ｒ４２およびＲ４３は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、アシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、またはＲ４２およびＲ４３は一緒になって環状であってもよい、その他の記号は前記と同意義である。）
　一般式（ｌ）で示される化合物に対して、有機リン試薬と一般式（ｌｉｉ）で示されるジアゾカルボン酸エステルの存在下、一般式（ｌｉ）で示される化合物を作用させることで、一般式（ｌｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　有機リン試薬としては、トリフェニルホスフィン、トリブチルホスフィン等のアルキルまたはアリールホスフィンが挙げられ、化合物（ｌ）に対して、１～１０モル当量用いることができる。またジアゾカルボン酸エステルとしてはジエチルアゾジカルボキレート、ジイソプロピルカルボキシレートなどのジアゾカルボン酸アルキルエステルが挙げられる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｘｌｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000212
(Wherein R 40 is (CR 8a R 8b ) m, CR 8a , R 8b and m are the same as (1) above, R 41 is a carbamate group such as Boc and benzyloxycarbonyl, R 42 and R 43 are Each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 42 and R 43 may be cyclic together, and other symbols are as defined above. .)
By reacting the compound represented by the general formula (l) with the compound represented by the general formula (li) in the presence of the organophosphorus reagent and the diazocarboxylic acid ester represented by the general formula (lii), A compound represented by (liiii) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
Examples of the organophosphorus reagent include alkyl or aryl phosphines such as triphenylphosphine and tributylphosphine, and 1 to 10 molar equivalents can be used with respect to compound (l). Examples of diazocarboxylic acid esters include diazocarboxylic acid alkyl esters such as diethyl azodicarboxylate and diisopropylcarboxylate.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (xliii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000213

（式中、Ｒ４５は水素または置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、アシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、Ｒ４６は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、アシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールで環状であってもよい。Ｒ４７は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、アシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールで環状であってもよい。ａは０～３、ｂは０～３、Ｚ７は酸素、窒素、硫黄原子、その他の記号は前記と同意義である。）
　塩基存在下、一般式（ｌｉｖ）で示される化合物に対して、一般式（ｌｖ）で示される化合物を作用させることで、一般式（ｌｖｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジンナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｌｉｖ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｖｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000213
Wherein R 45 is hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or An unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 46 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It may be cyclic with acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, and R 47 is substituted or unsubstituted. Substituted alkyl, substituted or unsubstituted alkenyl, substituted or It may be cyclic with unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl. Is 0 to 3, b is 0 to 3, Z 7 is oxygen, nitrogen, sulfur atom, and other symbols are as defined above.)
In the presence of a base, the compound represented by the general formula (lv) is obtained by allowing the compound represented by the general formula (lv) to act on the compound represented by the general formula (lib).
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and can be used at 1 to 10 molar equivalents relative to the compound (lib).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lvi) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000214

（式中の記号は前記と同意義である。）
　化合物（ｌｖｉ）を酸処理することにより、一般式（ｌｖｉｉ）で示される化合物を合成することができる。
　化合物（ｌｖｉ）に対して、トリフルオロ酢酸、塩酸、硫酸、蟻酸等を１モル当量～溶媒量用いることができる。
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ジオキサン、酢酸エチル、塩化メチレン、クロロホルム、水等が挙げられ、単独または混合して用いることができる。
　反応温度は、０℃～１００℃が挙げられる。
　反応時間としては、０．５～２４時間が挙げられる。
　得られた一般式（ｌｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000214
(The symbols in the formula are as defined above.)
By treating the compound (lvi) with an acid, a compound represented by the general formula (lvii) can be synthesized.
For the compound (lvi), 1 molar equivalent to a solvent amount of trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid and the like can be used.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
Examples of the reaction temperature include 0 ° C. to 100 ° C.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000215

（式中、Ｒ４８はハロゲン、アルコキシ、シアノなど脱離基、Ｒ４９はアルキル、アリール基、Ｒｘ３およびＲｘ４は、上記（１）と同意義、）
　塩基存在下、一般式（ｌｖｉｉｉ）で示される化合物に対し、一般式（ｌｉｘ）で示される化合物を作用させることで、一般式（ｌｘ）でで示される化合物を合成することができる。
　反応溶媒としてはＴＨＦ、ジエチルエーテル、ＤＭＦ、ＤＭＥ、ジオキサン、ヘキサン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｌｖｉｉｉ）に対して、１～１０モル当量用いることができる。
　反応温度は－７８℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｌｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000215
(Wherein R 48 is a leaving group such as halogen, alkoxy, cyano, R 49 is an alkyl, aryl group, R x3 and R x4 have the same meanings as in (1) above)
The compound represented by the general formula (lx) can be synthesized by allowing the compound represented by the general formula (lix) to act on the compound represented by the general formula (lviii) in the presence of a base.
Examples of the reaction solvent include THF, diethyl ether, DMF, DME, dioxane, hexane, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Bases include sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, hydrogen Examples thereof include sodium hydride and potassium hydride, and 1 to 10 molar equivalents can be used with respect to compound (lviii).
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lx) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000216

（式中の記号は前記と同意義である。）
　塩基存在下、一般式（ｌｘ）で示される化合物と尿素を反応させることで、一般式（ｌｘｉ）で示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド等が挙げられる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｌｘｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000216
(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (lx) with urea in the presence of a base, the compound represented by the general formula (lxi) can be synthesized.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lxi) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).


（式中、Ｚ５は窒素、硫黄原子、Ｒ５０はアルキル、アリール基、その他の記号は、上記と同意義である。）
　塩基存在下、一般式（ｌｘ）で示される化合物と一般式（ｌｘｉｉ）で示される化合物を縮合させることで、一般式（ｌｘｉｉｉ）でで示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド等が挙げられ、一般式（ｌｘ）で示される化合物に対して１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｌｘｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
(In the formula, Z 5 is nitrogen, sulfur atom, R 50 is alkyl, aryl group, and other symbols are as defined above.)
By condensing the compound represented by the general formula (lx) and the compound represented by the general formula (lxii) in the presence of a base, the compound represented by the general formula (lxiii) can be synthesized.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
Examples of the base include sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (lx).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000218

（式中、Ｚ６は臭素、塩素原子、その他の記号は前記と同意義である。）
　一般式（ｌｘｉ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｌｘｉｖ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリド、二塩化フェニルリン酸等が挙げられ、化合物（ｌｘｉ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンを用いてもよい。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｘｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000218
(In the formula, Z 6 is bromine, chlorine atom, and other symbols are as defined above.)
A compound represented by the general formula (lxiv) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (lxi).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, phenyl dichloride diphosphoric acid, and the like. Can be used. Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000219

（式中、Ｇ１はハロゲン、ｃは０～３、ｄは０～３、他の記号は前記と同意義である。）
　化合物（ｌｘｖ）にハロゲン化試薬を作用させ、化合物（ｌｘｖｉ）を合成することができる。
　反応溶媒としては、塩化メチレン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
ハロゲン化試薬としては、ジエチルアミノ硫黄三フッ化物、モルホリノ硫黄三フッ化物、ビス（２－メトキシエチル）アミノ硫黄三フッ化物、２，２－ジフルオロ－１，３－ジメチルイミダゾリジン、五塩化リン、三塩化リン、六塩化タングステンなどが挙げられ、化合物（ｌｘｖ）に対して、１～１０モル当量用いることができる。
　反応温度は、－７８℃～溶媒の還流温度が挙げられる。
　反応時間としては、０．５～４８時間が挙げられる。
　得られた化合物（ｌｘｖｉ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000219
(In the formula, G 1 is halogen, c is 0 to 3, d is 0 to 3, and other symbols are as defined above.)
Compound (lxvi) can be synthesized by allowing a halogenating reagent to act on compound (lxv).
Examples of the reaction solvent include methylene chloride, chloroform, toluene and the like, and these can be used alone or in combination.
Examples of the halogenating reagent include diethylaminosulfur trifluoride, morpholinosulfur trifluoride, bis (2-methoxyethyl) aminosulfur trifluoride, 2,2-difluoro-1,3-dimethylimidazolidine, phosphorus pentachloride, Phosphorus chloride, tungsten hexachloride and the like can be mentioned, and 1 to 10 molar equivalents can be used with respect to compound (lxv).
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The obtained compound (lxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000220

（式中の記号は前記と同意義である。）
　一般式（ｌｘｖｉｉ）で示される化合物に対して、塩基の存在または非存在下、一般式（ｘｌｉｉ）で示される化合物を作用させることで、一般式（ｌｘｖｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル、ピリジン等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｌｘｖｉｉ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｘｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000220
(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (lxviii) with the compound represented by the general formula (xlii) in the presence or absence of a base, the compound represented by the general formula (lxviii) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisila Examples thereof include zido, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (lxvii).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000221

（式中、Ｘ５、Ｘ６、Ｘ７およびＸ８は、炭素原子または窒素原子、その他の記号は前記と同意義である。）
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル、トリフルオロ酢酸、塩酸、蟻酸等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）等が挙げられ、化合物（ｌｘｉｘ）に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は、１～５０気圧が挙げられる。
　反応温度は、０℃から溶媒の還流温度が挙げられる。
　反応時間としては、０．５～７２時間が挙げられる。
　得られた化合物（ｌｘｘ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000221
(Wherein, X 5 , X 6 , X 7 and X 8 are carbon atoms or nitrogen atoms, and other symbols are as defined above.)
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I) and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxix). Can do.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (lxx) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000222

（式中、Ｒ４８は置換ベンジル基、その他の記号は前記と同意義である。）
　塩基存在下、一般式（ｌｘｘｉ）で示される化合物に対して、一般式（ｌｘｘｉｉ）で示される化合物を作用させることで一般式（ｌｘｘｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジンナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ｎ－ブチルリチウム、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ナトリウムアミド、リチウムジイソプロピルアミド、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｌｘｘｉ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｘｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000222
(Wherein R 48 is a substituted benzyl group, and other symbols are as defined above.)
In the presence of a base, the compound represented by the general formula (lxxii) is obtained by allowing the compound represented by the general formula (lxxii) to act on the compound represented by the general formula (lxxii).
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Bases include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium pyridine pyridine, sodium ethoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide Potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, potassium hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound (lxxi).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000223

（式中の記号は前記と同意義である。）
　一般式（ｌｘｉｉｉ）で示される化合物に塩基を作用させることで、一般式（ｌｘｘｉｖ）で示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水等が挙げられ、単独または混合して用いることができる。
　塩基としてはナトリウムメトキシド、ナトリウムエトキシド、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム、炭酸セシウム等が挙げられ、一般式（ｌｘｘｉｉｉ）で示される化合物に対して１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～２４時間が挙げられる。
　得られた一般式（ｌｘｘｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000223
(The symbols in the formula are as defined above.)
A compound represented by the general formula (lxxiv) can be synthesized by allowing a base to act on the compound represented by the general formula (lxxiii).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
Bases include sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, hydrogen phosphate Examples thereof include sodium, potassium phosphate, potassium hydrogen phosphate, cesium carbonate and the like, and the compound can be used at 1 to 10 molar equivalents relative to the compound represented by the general formula (lxxiii).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000224

（式中、Ｒ４９およびＲ５０はそれぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、Ｚ８は臭素原子、塩素原子、トシレート、メシレート、アルキルスルホン、アリールスルホン等の脱離基、その他の記号は前記と同意義である。）
　塩基存在下、一般式（ｌｘｘｉｖ）で示される化合物に対して、一般式（ｌｘｘｖ）で示される化合物を作用させることで、一般式（ｌｘｘｖｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル、アセトン等が挙げられ、単独または混合して用いることができる。
　塩基としては、ナトリウムメトキシド、ナトリウムエトキシド、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム、炭酸セシウム等が挙げられ、一般式（ｌｘｘｉｖ）で示される化合物に対して１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｘｘｖｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000224
Wherein R 49 and R 50 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Z 8 is bromine atom, chlorine atom, tosylate, mesylate, alkylsulfone, arylsulfone Etc., and other symbols are as defined above.)
In the presence of a base, the compound represented by the general formula (lxxvi) is allowed to act on the compound represented by the general formula (lxxv) to obtain the compound represented by the general formula (lxxvi).
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, acetone and the like, and these can be used alone or in combination.
Bases include sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, phosphoric acid Sodium hydrogen, potassium phosphate, potassium hydrogen phosphate, cesium carbonate and the like can be mentioned, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (lxxiv).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000225

（式中の記号は前記と同意義である。）
　一般式（ｌｘｘｖｉ）で示される化合物を加熱するとで、一般式（ｌｘｘｖｉｉ）で示される化合物が得られる。
　反応溶媒としてはトルエン、水、ＤＭＦ、ＮＭＰ等が挙げられ、単独または混合して用いることができる。
　反応温度は室温～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｌｘｘｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000225
(The symbols in the formula are as defined above.)
When the compound represented by the general formula (lxxvi) is heated, the compound represented by the general formula (lxxvii) is obtained.
Examples of the reaction solvent include toluene, water, DMF, NMP and the like, and they can be used alone or in combination.
The reaction temperature may be from room temperature to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (lxxvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000226

（式中の記号は前記と同意義である。）
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル、トリフルオロ酢酸、塩酸、蟻酸等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）等が挙げられ、化合物（ｌｘｘｖｉｉ）に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は、１～５０気圧が挙げられる。
　反応温度は、０℃から溶媒の還流温度が挙げられる。
　反応時間としては、０．５～７２時間が挙げられる。
　得られた化合物（ｌｘｘｖｉｉｉ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000226
(The symbols in the formula are as defined above.)
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxxvii). Can do.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (lxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000227

（式中の記号は前記と同意義である。）
　化合物（ｌｘｘｖｉｉｉ）を酸処理することにより、一般式（ｌｘｘｉｘ）で示される化合物を合成することができる。
　化合物（ｌｘｘｖｉｉｉ）に対して、トリフルオロ酢酸、塩酸、硫酸等を１モル当量～溶媒量用いることができる。
　反応温度は、０℃～溶媒の還流温度が挙げられる。
　反応時間としては、０．５～２４時間が挙げられる。
　得られた一般式（ｌｘｘｉｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000227
(The symbols in the formula are as defined above.)
By treating the compound (lxxviii) with an acid, a compound represented by the general formula (lxxix) can be synthesized.
For the compound (lxxviii), 1 molar equivalent to a solvent amount of trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like can be used.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 24 hours.
The resulting compound represented by the general formula (lxxix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000228

（式中、Ｒ５１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、ｅは１～２整数、ｆは１～３の整数、その他の記号は前記と同意義である。）
　一般式（ｌｘｘｘ）で示されるアミンに対して、塩基存在下、一般式（ｌｘｘｘｉ）で示される化合物を作用させることで一般式（ｌｘｘｘｉｉ）で示される化合物が得られる。
　反応溶媒としてはＴＨＦ、アセトニトリル、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｌｘｘｘｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000228
Wherein R 51 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, e is an integer of 1 to 2, f is an integer of 1 to 3, and other symbols are as defined above.
A compound represented by the general formula (lxxxii) is obtained by allowing a compound represented by the general formula (lxxxi) to act on the amine represented by the general formula (lxxx) in the presence of a base.
Examples of the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (lxxxii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000229

（式中、Ｒ５２は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、その他の記号は前記と同意義である。）
　一般式（ｌｘｘｘｉｉ）で示されるアミンに対して、塩基存在下、一般式（ｌｘｘｘｉｉｉ）で示される化合物を作用させることで、一般式（ｉｘｘｘｉｖ）で示される化合物が得られる。
　反応溶媒としてはＴＨＦ、アセトニトリル、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｌｘｘｘｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000229
Wherein R 52 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic groups, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.
When the compound represented by the general formula (lxxxiii) is allowed to act on the amine represented by the general formula (lxxxii) in the presence of a base, the compound represented by the general formula (xxxiv) is obtained.
Examples of the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (lxxxiv) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000230

（式中の記号は前記と同意義である。）
　一般式（ｌｘｘｘｉｖ）で示される化合物に対して、アジ化ナトリウムを作用させることで、一般式（ｌｘｘｘｖ）で示されるアジドが得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル、ピリジン等が挙げられ、単独または混合して用いることができる。
　アジ化ナトリウムは化合物（ｌｘｘｘｉｖ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｌｘｘｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000230
(The symbols in the formula are as defined above.)
By reacting the compound represented by the general formula (lxxxiv) with sodium azide, the azide represented by the general formula (lxxxv) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile, pyridine and the like, and these can be used alone or in combination.
Sodium azide can be used at 1 to 10 molar equivalents relative to compound (lxxxiv).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (lxxxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000231

（式中の記号は前記と同意義である。）
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル、トリフルオロ酢酸、塩酸、蟻酸等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（Ｉ）等が挙げられ、化合物（ｌｘｘｘｖ）に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は、１～５０気圧が挙げられる。
　反応温度は、０℃から溶媒の還流温度が挙げられる。
　反応時間としては、０．５～７２時間が挙げられる。
　得られた化合物（ｌｘｘｘｖｉ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000231
(The symbols in the formula are as defined above.)
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, trifluoroacetic acid, hydrochloric acid, formic acid and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I) and the like, and 0.01 to 0.5 weight percent is used with respect to the compound (lxxxv). Can do.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained compound (lxxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000232

（式中、Ｒ５３は水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、またはＲ５２とＲ５３は一緒になって環を形成してもよい、Ｐ２はＢｏｃ、ベンジルオキシカルボニル、ベンジi等の一般的なアミンの保護基、その他の記号は前記と同意義である。）
　一般式（ｌｘｘｘｖｉｉ）で示される化合物に対して、公知の脱保護反応（参照：Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　Ｗｉｌｅｙ）を行うにより、一般式（ｌｘｘｘｖｉｉｉ）で示されるアミンが得られる。
　得られた一般式（ｌｘｘｘｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000232
Wherein R 53 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or R 52 and R 53 may be combined to form a ring, P 2 is Boc, benzyloxy Protecting groups for general amines such as carbonyl and benzi i, and other symbols are as defined above.)
An amine represented by the general formula (lxxxviii) is obtained by performing a known deprotection reaction (see Green's Protective Groups in Organic Synthesis, Wiley) on the compound represented by the general formula (lxxxvii).
The resulting compound represented by the general formula (lxxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000233

（式中、Ｒ５４は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、ｇは０～２、その記号は前記と同意義である。）
　一般式（ｌｘｘｘｖｉｉｉ）で示されるアミンに対して、塩基存在下、一般式（ｌｘｘｘｉｘ）で示される化合物を作用させることで一般式（ｘｃ）で示される化合物が得られる。
　反応溶媒としてはＴＨＦ、アセトニトリル、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｘｃ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000233
Wherein R 54 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted unsubstituted Aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, g is 0 to 2, and the symbols are as defined above.
A compound represented by the general formula (xc) is obtained by allowing a compound represented by the general formula (lxxxix) to act on the amine represented by the general formula (lxxxviii) in the presence of a base.
Examples of the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (xc) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000234

（式中、Ｒ５５は（ＣＲ８ａＲ８ｂ）ｍ、その記号は前記と同意義である。）
　一般式（ｘｃｉ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｘｃｉｉ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリド、塩化スルフリルなどが挙げられ、化合物（ｘｃｉ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンを用いてもよい。
　反応温度は－２０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｃｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000234
(In the formula, R 55 is (CR 8a R 8b ) m, and the symbols are as defined above.)
A compound represented by the general formula (xcii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (xci).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, sulfuryl chloride and the like, and 1 equivalent to a solvent amount is used with respect to the compound (xci). it can. Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xcii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000235

（式中、Ｒ５６およびＲ５７はそれぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール、その記号は前記と同意義である。）
　一般式（ｘｃｉｉ）で示される化合物に対して、塩基存在下、一般式（ｘｃｉｉｉ）で示されるアミンを作用させることで、一般式（ｘｃｉｖ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、水、ＤＭＦ、ＮＭＰ、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン等が挙げられ、化合物（ｘｃｉｖ）に対して、１～１０モル当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｘｃｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000235
Wherein R 56 and R 57 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, the symbols thereof are as defined above.
By reacting the compound represented by the general formula (xcii) with the amine represented by the general formula (xciii) in the presence of a base, the compound represented by the general formula (xciv) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, water, DMF, NMP, acetonitrile and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xciv).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xciv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

　以下に本発明に含まれる化合物の一般的合成法を示すが、本合成法に限られるものではない。

Figure JPOXMLDOC01-appb-C000236

（式中、Ｙは臭素、塩素、トシレート、メシレート、アルキルスルホニル、アリールスルホニルなどの脱離基、その他の記号は上記と同意義である。）
　一般式（ｘｃｖ）で示される化合物をハロゲン化剤により、一般式（ｘｃｖｉ）で示される化合物に変換することができる。
　ハロゲン化剤としてはN-クロロスクシニルイミド、N-ブロモスクシニルイミド、N-ヨードスクシニルイミド、塩素、臭素、ヨウ素等が挙げられ、一般式（ｘｃｖ）で示される化合物に対して、１～１０モル当量用いることができる。
　反応溶媒としては、塩化メチレン、クロロホルム等が挙げられ、単独または混合して用いることができる。
　反応温度は、－２０℃から溶媒の還流温度が挙げられる。
　反応時間としては、０．５～７２時間が挙げられる。
　得られたカルボン酸化合物（ｘｃｖｉ）は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
The general synthesis method of the compound included in the present invention is shown below, but is not limited to this synthesis method.
Figure JPOXMLDOC01-appb-C000236
(Wherein Y is a leaving group such as bromine, chlorine, tosylate, mesylate, alkylsulfonyl, arylsulfonyl, and other symbols are as defined above.)
A compound represented by the general formula (xcv) can be converted into a compound represented by the general formula (xcvi) with a halogenating agent.
Examples of the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine, iodine and the like. An equivalent amount can be used.
Examples of the reaction solvent include methylene chloride and chloroform, and these can be used alone or in combination.
With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The obtained carboxylic acid compound (xcvi) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000237

（式中の記号は上記と同意義である。）
　一般式（ｘｃｖｉｉ）で示される化合物を還元剤により、一般式（ｘｃｖｉｉｉ）で示されるアルコール化合物に変換することができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム等が挙げられ、一般式（ｘｃｖｉｉ）で示される化合物に対して、１～１０モル当量用いることができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、塩化メチレン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は－７８℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
得られた一般式（ｘｃｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000237
(The symbols in the formula are as defined above.)
The compound represented by the general formula (xcvii) can be converted into the alcohol compound represented by the general formula (xcviii) by a reducing agent.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like. The reducing agent can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by the general formula (xcvii).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (xcviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000238

（式中、Ｒ６１は水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール；Ｒ６２は水素、または置換もしくは非置換のベンジル、、その他の記号は上記と同意義である。）
　一般式（ｉｃ）で示される化合物に対して、ハロゲン化剤を作用させることで、一般式（ｃ）で示される化合物を合成することができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、トルエン、アセトニトリル等が挙げられ、単独または混合して用いる、または無溶媒でも行うことができる。
　ハロゲン化剤としては塩化チオニル、臭化チオニル、オキシ塩化リン、五塩化リン、三塩化リン、オキサリルクロリド、二塩化フェニルリン酸等が挙げられ、化合物（ｉｃ）に対して、１当量～溶媒量用いることができる。また添加剤としてジメチルホルムアミド、N,N-ジメチルアニリン、N,N-ジエチルアニリンを用いてもよい。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000238
Wherein R 61 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 62 represents hydrogen, or substituted or unsubstituted benzyl, and other symbols are as defined above.
The compound represented by the general formula (c) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (ic).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and the like. These can be used alone, in combination, or without solvent.
Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, phenyl dichloride phosphoric acid, and the like. Can be used. Further, dimethylformamide, N, N-dimethylaniline, N, N-diethylaniline may be used as an additive.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (c) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000239

（式中の記号は、上記と同意義である。）
　一般式（ｃ）で示される化合物に対して、過酸化物を作用させることで、一般式（ｃｉｉ）で示されるエポキシドを合成する事ができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、アセトン、水等が挙げられ、単独または混合して用いることができる。
　過酸化物としてはメタクロロ過安息香酸、過蟻酸、ジメチルジオキソラン、過酸化水素などが挙げられ、化合物（ｃ）に対して、１～２０当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000239
(The symbols in the formula are as defined above.)
The epoxide represented by the general formula (cii) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (c).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
Examples of the peroxide include metachloroperbenzoic acid, performic acid, dimethyldioxolane, hydrogen peroxide and the like, and 1 to 20 equivalents can be used with respect to the compound (c).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000240

（式中の記号は、上記と同意義である。）
　一般式（ｃｉｉ）で示される化合物を還元剤により、一般式（ｃｉｖ）で示されるアルコール化合物に変換することができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム等が挙げられ、一般式（ｃｉｉ）で示される化合物に対して、１～１０モル当量用いることができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、塩化メチレン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は－７８℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｉｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000240
(The symbols in the formula are as defined above.)
The compound represented by the general formula (cii) can be converted into the alcohol compound represented by the general formula (civ) by a reducing agent.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cii).
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be −78 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (civ) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000241

（式中、Ａｒ１は置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール；Ｒ６３は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアルキル非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール；Ｒ６４は水素、または２つのＲ６４が結合して－（ＣＲ６５ａＲ６５ｂ）ｔ－、Ｒ６５ａおよびＲ６５ｂはそれぞれ独立して、水素またはアルキル、ｔは１～３の整数、その他の記号は上記と同意義である。）
　塩基存在下、一般式（ｃｖ）で示される化合物に対し、金属触媒および一般式（ｃｖｉ）で示されるボロン酸またはボロン酸エステルを作用させることで一般式（ｃｖｉｉ）で示す化合物を合成することができる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、水、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ＤＭＦ，ＮＭＰ等が挙げられ、単独または混合して用いることができる。
金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウムなどが挙げられ、化合物（）に対して、０．００１～０．５モル当量用いることができる。また配位子としてトリフェニルフォスフィン、トリブチルフォスフィン、ｄｐｐｆ等の有機リン化合物を用いることもできる。
　塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム、炭酸セシウム等が挙げられ、化合物（）に対して、１～１０モル当量用いることができる。
　ボロン酸またはボロン酸エステル（ｃｖｉ）は、化合物（ｃｖ）に対して、１～１０モル当量用いることができる。
　反応温度は、２０℃～溶媒の還流温度が挙げられる。
　反応時間としては、０．５～４８時間が挙げられる。
　得られた一般式（ｃｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000241
Wherein Ar 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 63 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkyl non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 64 is hydrogen, or two R 64 is bonded to- (CR 65a R 65b ) t-, R 65a and R 65b are each independently hydrogen or alkyl, t is an integer of 1 to 3, and other symbols are as defined above. )
Synthesis of a compound represented by the general formula (cvii) by reacting a metal catalyst and a boronic acid or boronic acid ester represented by the general formula (cvi) on the compound represented by the general formula (cv) in the presence of a base. Can do.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF, NMP and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to the compound (). An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus Examples thereof include potassium oxyhydrogen, cesium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to the compound ().
Boronic acid or boronic acid ester (cvi) can be used in an amount of 1 to 10 molar equivalents relative to compound (cv).
With respect to the reaction temperature, it can be 20 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cvii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000242

（式中、Ｒ６６は置換もしくは非置換のベンジル、その他の記号は上記と同意義である。）
　金属触媒存在下、一般式（ｃｖｉｉｉ）で示される化合物を水素で還元することにより、一般式（ｃｉｘ）で示される化合物を合成することができる。
反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（I）等が挙げられ、一般式（ｃｖｉｉｉ）で示される化合物に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は１～５０気圧が挙げられる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｃｉｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000242
(Wherein R 66 is substituted or unsubstituted benzyl, and other symbols are as defined above.)
A compound represented by the general formula (cix) can be synthesized by reducing the compound represented by the general formula (cviii) with hydrogen in the presence of a metal catalyst.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like. 5 weight percent can be used.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (cix) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000243

（式中、Ｒ６７は置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、その他の記号は上記と同意義である。）
　塩基存在下、一般式（ｃｉｘ）で示される化合物をアシル化剤により、一般式（ｃｘｉ）で示されるアミド化合物に変換することができる。
　アシル化剤としては、無水酢酸などの酸無水物、アセチルクロリド等の酸塩化物等が挙げられ、一般式（ｃｉｘ）で示される化合物に対して、１～１０モル当量用いることができる。　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（）に対して、１～１０モル当量用いることができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、テトラヒドロフラン、ジエチルエーテル、ピリジン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000243
Wherein R 67 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, Other symbols are as defined above.)
In the presence of a base, a compound represented by the general formula (cix) can be converted to an amide compound represented by the general formula (cxi) by an acylating agent.
Examples of the acylating agent include acid anhydrides such as acetic anhydride and acid chlorides such as acetyl chloride. The acylating agent can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by the general formula (cix). Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride and the like. On the other hand, 1 to 10 molar equivalents can be used.
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The obtained compound represented by the general formula (cxi) can be isolated and purified by the known means (eg, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000244

（式中の記号は、上記と同意義である。）
　塩基存在下、一般式（ｃｉｘ）で示される化合物をスルホニル化剤により、一般式（ｃｘｉｉｉ）で示されるスルホンアミド化合物に変換することができる。
　スルホニル化剤としては、スルホン酸無水物、スルホン酸塩化物等が挙げられ、一般式（ｃｉｘ）で示される化合物に対して、１～１０モル当量用いることができる。　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｃｉｘ）に対して、１～１０モル当量用いることができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、テトラヒドロフラン、ジエチルエーテル、ピリジン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000244
(The symbols in the formula are as defined above.)
In the presence of a base, the compound represented by the general formula (cix) can be converted to a sulfonamide compound represented by the general formula (cxiii) with a sulfonylating agent.
Examples of the sulfonylating agent include sulfonic acid anhydrides and sulfonic acid chlorides, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cix). Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like (compix) 1 to 10 molar equivalents can be used.
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000245

（式中の記号は、上記と同意義である。）
　塩基存在下、一般式（ｃｉｘ）で示される化合物をアルキル化剤により、一般式（ｃｘｖ）で示される化合物に変換することができる。
　アルキル化剤としては、アルキルクロリド、アルキルブロミド、アルキルヨージド等が挙げられ、一般式（ｃｉｘ）で示される化合物に対して、１～１０モル当量用いることができる。　塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、、水素化ナトリウム、水素化カリウム等が挙げられ、化合物（ｃｉｘ）に対して、１～１０モル当量用いることができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、テトラヒドロフラン、ジエチルエーテル、ピリジン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000245
(The symbols in the formula are as defined above.)
In the presence of a base, the compound represented by the general formula (cix) can be converted to the compound represented by the general formula (cxv) with an alkylating agent.
Examples of the alkylating agent include alkyl chloride, alkyl bromide, alkyl iodide and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (cix). Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, and the like (compix) 1 to 10 molar equivalents can be used.
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The obtained compound represented by the general formula (cxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000246

（式中、Ｒ６８は置換もしくは非置換のベンジル、Ｒ６９およびＲ７０はそれぞれ独立して置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、またはＲ６９およびＲ７０は一緒になって環を形成していてもよい。）
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、テトラヒドロフラン、ジエチルエーテル、ピリジン、水等が挙げられ、単独または混合して用いることができる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｖｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000246
Wherein R 68 is substituted or unsubstituted benzyl, R 69 and R 70 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group , Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R 69 and R 70 may form a ring together.)
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, diethyl ether, pyridine, water and the like, and these can be used alone or in combination.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000247

（式中、ｎは１～３、その他の記号は上記と同意義である。）
　金属触媒存在下、一般式（ｃｘｉｘ）で示される化合物を水素で還元することにより、一般式（ｃｘｘ）で示される化合物を合成することができる。
　反応溶媒としてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフラン、ジエチルエーテル、トルエン、酢酸エチル等が挙げられ、単独または混合して用いることができる。
　金属触媒としては、パラジウム－炭素、水酸化パラジウム、酸化白金、クロロトリス（トリフェニルホスフィン）ロジウム（I）等が挙げられ、一般式（ｃｘｉｘ）で示される化合物に対して、０．０１～０．５重量パーセント用いることができる。
　水素気圧は１～５０気圧が挙げられる。
　反応温度は０℃から溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｃｘｘ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000247
(In the formula, n is 1 to 3, and other symbols are as defined above.)
The compound represented by the general formula (cxx) can be synthesized by reducing the compound represented by the general formula (cxix) with hydrogen in the presence of a metal catalyst.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium-carbon, palladium hydroxide, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and 0.01 to 0.000 with respect to the compound represented by the general formula (cxix). 5 weight percent can be used.
The hydrogen pressure is 1 to 50 atm.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (cxx) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000248

（式中、Ｒ７１は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、アシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール、その他の記号は上記と同意義である。）
　一般式（ｃｘｘｉ）で示される化合物に対して、有機リン試薬と一般式（ｃｘｘｉｉ）で示されるジアゾカルボン酸エステルの存在下、一般式（ｃｘｘ）で示される化合物を作用させることで一般式（ｃｘｘｉｉｉ）で示される化合物が得られる。
　反応溶媒としてはテトラヒドロフラン、ジオキサン、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。
　有機リン試薬としては、トリフェニルホスフィン、トリブチルホスフィン等のアルキルまたはアリールホスフィンが挙げられ、化合物（ｃｘｘｉ）に対して、１～１０モル当量用いることができる。またジアゾカルボン酸エステルとしてはジエチルアゾジカルボキレート、ジイソプロピルカルボキシレートなどのジアゾカルボン酸アルキルエステルが挙げられる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～７２時間が挙げられる。
　得られた一般式（ｃｘｘｉｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000248
Wherein R 71 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted And cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and other symbols are as defined above.)
By reacting the compound represented by the general formula (cxx) with the compound represented by the general formula (cxx) in the presence of the organophosphorus reagent and the diazocarboxylic acid ester represented by the general formula (cxxxii), cxxiii) is obtained.
Examples of the reaction solvent include tetrahydrofuran, dioxane, toluene, acetonitrile and the like, and these can be used alone or in combination.
Examples of the organophosphorus reagent include alkyl or aryl phosphines such as triphenylphosphine and tributylphosphine, and 1 to 10 molar equivalents can be used with respect to the compound (cxxi). Examples of diazocarboxylic acid esters include diazocarboxylic acid alkyl esters such as diethyl azodicarboxylate and diisopropylcarboxylate.
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 72 hours.
The resulting compound represented by the general formula (cxxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).

Figure JPOXMLDOC01-appb-C000249

（式中、ｍは１または２、その他の記号は上記と同意義である。）
　一般式（ｃｘｘｉｖ）で示される化合物に対して、過酸化物を作用させることで、一般式（ｃｘｘｖ）で示される化合物を合成する事ができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、アセトン、水等が挙げられ、単独または混合して用いることができる。
　過酸化物としてはメタクロロ過安息香酸、過蟻酸、ジメチルジオキソラン、過酸化水素などが挙げられ、化合物（ｃｘｘｉｖ）に対して、１～２０当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｘｖ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000249
(In the formula, m is 1 or 2, and other symbols are as defined above.)
The compound represented by the general formula (cxxv) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (cxxiv).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
Examples of peroxides include metachloroperbenzoic acid, formic acid, dimethyldioxolane, hydrogen peroxide, and the like, and 1 to 20 equivalents can be used with respect to compound (cxxiv).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cxxv) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

Figure JPOXMLDOC01-appb-C000250

（式中の記号は、上記と同意義である。）
　一般式（ｃｘｘｖｉ）で示される化合物に対して、過酸化物を作用させることで、一般式（ｃｘｘｖｉｉ）で示される化合物を合成する事ができる。
　反応溶媒としてはジクロロメタン、１，２－ジクロロエタン、クロロホルム、アセトン、水等が挙げられ、単独または混合して用いることができる。
　過酸化物としてはメタクロロ過安息香酸、過蟻酸、ジメチルジオキソラン、過酸化水素などが挙げられ、化合物（ｃｘｘｖｉ）に対して、１～１．５当量用いることができる。
　反応温度は０℃～溶媒の還流温度が挙げられる。
　反応時間としては０．５～４８時間が挙げられる。
　得られた一般式（ｃｘｘｖｉｉ）で示される化合物は、公知の手段（例えば、クロマトグラフィー、再結晶など）によって単離精製することができる。
Figure JPOXMLDOC01-appb-C000250
(The symbols in the formula are as defined above.)
The compound represented by the general formula (cxxvii) can be synthesized by allowing a peroxide to act on the compound represented by the general formula (cxxvi).
Examples of the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, acetone, water and the like, and these can be used alone or in combination.
Examples of the peroxide include metachloroperbenzoic acid, performic acid, dimethyldioxolane, hydrogen peroxide, and the like, and 1 to 1.5 equivalents can be used with respect to the compound (cxxvi).
With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
An example of the reaction time is 0.5 to 48 hours.
The resulting compound represented by the general formula (cxxvii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).

　本発明化合物の一つの態様は、以下の一般式（ＩＩ）において、以下の基を有するものである。

Figure JPOXMLDOC01-appb-C000251
One embodiment of the compound of the present invention has the following group in the following general formula (II).
Figure JPOXMLDOC01-appb-C000251

Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252

Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254

　AC、Ba、Bbの組み合わせが、以下の（AC、Ba、Bb）である化合物。
(AC,Ba, Bb)=(AC1,Ba1,Bb1),(AC1,Ba1,Bb2),(AC1,Ba1,Bb3),(AC1,Ba1,Bb4),(AC1,Ba1,Bb5),(AC1,Ba1,Bb6),(AC1,Ba2,Bb1),(AC1,Ba2,Bb2),(AC1,Ba2,Bb3),(AC1,Ba2,Bb4),(AC1,Ba2,Bb5),(AC1,Ba2,Bb6),(AC1,Ba3,Bb1),(AC1,Ba3,Bb2),(AC1,Ba3,Bb3),(AC1,Ba3,Bb4),(AC1,Ba3,Bb5),(AC1,Ba3,Bb6),(AC1,Ba4,Bb1),(AC1,Ba4,Bb2),(AC1,Ba4,Bb3),(AC1,Ba4,Bb4),(AC1,Ba4,Bb5),(AC1,Ba4,Bb6),(AC1,Ba5,Bb1),(AC1,Ba5,Bb2),(AC1,Ba5,Bb3),(AC1,Ba5,Bb4),(AC1,Ba5,Bb5),(AC1,Ba5,Bb6),(AC1,Ba6,Bb1),(AC1,Ba6,Bb2),(AC1,Ba6,Bb3),(AC1,Ba6,Bb4),(AC1,Ba6,Bb5),(AC1,Ba6,Bb6),(AC1,Ba7,Bb1),(AC1,Ba7,Bb2),(AC1,Ba7,Bb3),(AC1,Ba7,Bb4),(AC1,Ba7,Bb5),(AC1,Ba7,Bb6),(AC2,Ba1,Bb1),(AC2,Ba1,Bb2),(AC2,Ba1,Bb3),(AC2,Ba1,Bb4),(AC2,Ba1,Bb5),(AC2,Ba1,Bb6),(AC2,Ba2,Bb1),(AC2,Ba2,Bb2),(AC2,Ba2,Bb3),(AC2,Ba2,Bb4),(AC2,Ba2,Bb5),(AC2,Ba2,Bb6),(AC2,Ba3,Bb1),(AC2,Ba3,Bb2),(AC2,Ba3,Bb3),(AC2,Ba3,Bb4),(AC2,Ba3,Bb5),(AC2,Ba3,Bb6),(AC2,Ba4,Bb1),(AC2,Ba4,Bb2),(AC2,Ba4,Bb3),(AC2,Ba4,Bb4),(AC2,Ba4,Bb5),(AC2,Ba4,Bb6),(AC2,Ba5,Bb1),(AC2,Ba5,Bb2),(AC2,Ba5,Bb3),(AC2,Ba5,Bb4),(AC2,Ba5,Bb5),(AC2,Ba5,Bb6),(AC2,Ba6,Bb1),(AC2,Ba6,Bb2),(AC2,Ba6,Bb3),(AC2,Ba6,Bb4),(AC2,Ba6,Bb5),(AC2,Ba6,Bb6),(AC2,Ba7,Bb1),(AC2,Ba7,Bb2),(AC2,Ba7,Bb3),(AC2,Ba7,Bb4),(AC2,Ba7,Bb5),(AC2,Ba7,Bb6),(AC3,Ba1,Bb1),(AC3,Ba1,Bb2),(AC3,Ba1,Bb3),(AC3,Ba1,Bb4),(AC3,Ba1,Bb5),(AC3,Ba1,Bb6),(AC3,Ba2,Bb1),(AC3,Ba2,Bb2),(AC3,Ba2,Bb3),(AC3,Ba2,Bb4),(AC3,Ba2,Bb5),(AC3,Ba2,Bb6),(AC3,Ba3,Bb1),(AC3,Ba3,Bb2),(AC3,Ba3,Bb3),(AC3,Ba3,Bb4),(AC3,Ba3,Bb5),(AC3,Ba3,Bb6),(AC3,Ba4,Bb1),(AC3,Ba4,Bb2),(AC3,Ba4,Bb3),(AC3,Ba4,Bb4),(AC3,Ba4,Bb5),(AC3,Ba4,Bb6),(AC3,Ba5,Bb1),(AC3,Ba5,Bb2),(AC3,Ba5,Bb3),(AC3,Ba5,Bb4),(AC3,Ba5,Bb5),(AC3,Ba5,Bb6),(AC3,Ba6,Bb1),(AC3,Ba6,Bb2),(AC3,Ba6,Bb3),(AC3,Ba6,Bb4),(AC3,Ba6,Bb5),(AC3,Ba6,Bb6),(AC3,Ba7,Bb1),(AC3,Ba7,Bb2),(AC3,Ba7,Bb3),(AC3,Ba7,Bb4),(AC3,Ba7,Bb5),(AC3,Ba7,Bb6),(AC4,Ba1,Bb1),(AC4,Ba1,Bb2),(AC4,Ba1,Bb3),(AC4,Ba1,Bb4),(AC4,Ba1,Bb5),(AC4,Ba1,Bb6),(AC4,Ba2,Bb1),(AC4,Ba2,Bb2),(AC4,Ba2,Bb3),(AC4,Ba2,Bb4),(AC4,Ba2,Bb5),(AC4,Ba2,Bb6),(AC4,Ba3,Bb1),(AC4,Ba3,Bb2),(AC4,Ba3,Bb3),(AC4,Ba3,Bb4),(AC4,Ba3,Bb5),(AC4,Ba3,Bb6),(AC4,Ba4,Bb1),(AC4,Ba4,Bb2),(AC4,Ba4,Bb3),(AC4,Ba4,Bb4),(AC4,Ba4,Bb5),(AC4,Ba4,Bb6),(AC4,Ba5,Bb1),(AC4,Ba5,Bb2),(AC4,Ba5,Bb3),(AC4,Ba5,Bb4),(AC4,Ba5,Bb5),(AC4,Ba5,Bb6),(AC4,Ba6,Bb1),(AC4,Ba6,Bb2),(AC4,Ba6,Bb3),(AC4,Ba6,Bb4),(AC4,Ba6,Bb5),(AC4,Ba6,Bb6),(AC4,Ba7,Bb1),(AC4,Ba7,Bb2),(AC4,Ba7,Bb3),(AC4,Ba7,Bb4),(AC4,Ba7,Bb5),(AC4,Ba7,Bb6),(AC5,Ba1,Bb1),(AC5,Ba1,Bb2),(AC5,Ba1,Bb3),(AC5,Ba1,Bb4),(AC5,Ba1,Bb5),(AC5,Ba1,Bb6),(AC5,Ba2,Bb1),(AC5,Ba2,Bb2),(AC5,Ba2,Bb3),(AC5,Ba2,Bb4),(AC5,Ba2,Bb5),(AC5,Ba2,Bb6),(AC5,Ba3,Bb1),(AC5,Ba3,Bb2),(AC5,Ba3,Bb3),(AC5,Ba3,Bb4),(AC5,Ba3,Bb5),(AC5,Ba3,Bb6),(AC5,Ba4,Bb1),(AC5,Ba4,Bb2),(AC5,Ba4,Bb3),(AC5,Ba4,Bb4),(AC5,Ba4,Bb5),(AC5,Ba4,Bb6),(AC5,Ba5,Bb1),(AC5,Ba5,Bb2),(AC5,Ba5,Bb3),(AC5,Ba5,Bb4),(AC5,Ba5,Bb5),(AC5,Ba5,Bb6),(AC5,Ba6,Bb1),(AC5,Ba6,Bb2),(AC5,Ba6,Bb3),(AC5,Ba6,Bb4),(AC5,Ba6,Bb5),(AC5,Ba6,Bb6),(AC5,Ba7,Bb1),(AC5,Ba7,Bb2),(AC5,Ba7,Bb3),(AC5,Ba7,Bb4),(AC5,Ba7,Bb5),(AC5,Ba7,Bb6),(AC6,Ba1,Bb1),(AC6,Ba1,Bb2),(AC6,Ba1,Bb3),(AC6,Ba1,Bb4),(AC6,Ba1,Bb5),(AC6,Ba1,Bb6),(AC6,Ba2,Bb1),(AC6,Ba2,Bb2),(AC6,Ba2,Bb3),(AC6,Ba2,Bb4),(AC6,Ba2,Bb5),(AC6,Ba2,Bb6),(AC6,Ba3,Bb1),(AC6,Ba3,Bb2),(AC6,Ba3,Bb3),(AC6,Ba3,Bb4),(AC6,Ba3,Bb5),(AC6,Ba3,Bb6),(AC6,Ba4,Bb1),(AC6,Ba4,Bb2),(AC6,Ba4,Bb3),(AC6,Ba4,Bb4),(AC6,Ba4,Bb5),(AC6,Ba4,Bb6),(AC6,Ba5,Bb1),(AC6,Ba5,Bb2),(AC6,Ba5,Bb3),(AC6,Ba5,Bb4),(AC6,Ba5,Bb5),(AC6,Ba5,Bb6),(AC6,Ba6,Bb1),(AC6,Ba6,Bb2),(AC6,Ba6,Bb3),(AC6,Ba6,Bb4),(AC6,Ba6,Bb5),(AC6,Ba6,Bb6),(AC6,Ba7,Bb1),(AC6,Ba7,Bb2),(AC6,Ba7,Bb3),(AC6,Ba7,Bb4),(AC6,Ba7,Bb5),(AC6,Ba7,Bb6),(AC7,Ba1,Bb1),(AC7,Ba1,Bb2),(AC7,Ba1,Bb3),(AC7,Ba1,Bb4),(AC7,Ba1,Bb5),(AC7,Ba1,Bb6),(AC7,Ba2,Bb1),(AC7,Ba2,Bb2),(AC7,Ba2,Bb3),(AC7,Ba2,Bb4),(AC7,Ba2,Bb5),(AC7,Ba2,Bb6),(AC7,Ba3,Bb1),(AC7,Ba3,Bb2),(AC7,Ba3,Bb3),(AC7,Ba3,Bb4),(AC7,Ba3,Bb5),(AC7,Ba3,Bb6),(AC7,Ba4,Bb1),(AC7,Ba4,Bb2),(AC7,Ba4,Bb3),(AC7,Ba4,Bb4),(AC7,Ba4,Bb5),(AC7,Ba4,Bb6),(AC7,Ba5,Bb1),(AC7,Ba5,Bb2),(AC7,Ba5,Bb3),(AC7,Ba5,Bb4),(AC7,Ba5,Bb5),(AC7,Ba5,Bb6),(AC7,Ba6,Bb1),(AC7,Ba6,Bb2),(AC7,Ba6,Bb3),(AC7,Ba6,Bb4),(AC7,Ba6,Bb5),(AC7,Ba6,Bb6),(AC7,Ba7,Bb1),(AC7,Ba7,Bb2),(AC7,Ba7,Bb3),(AC7,Ba7,Bb4),(AC7,Ba7,Bb5),(AC7,Ba7,Bb6),(AC8,Ba1,Bb1),(AC8,Ba1,Bb2),(AC8,Ba1,Bb3),(AC8,Ba1,Bb4),(AC8,Ba1,Bb5),(AC8,Ba1,Bb6),(AC8,Ba2,Bb1),(AC8,Ba2,Bb2),(AC8,Ba2,Bb3),(AC8,Ba2,Bb4),(AC8,Ba2,Bb5),(AC8,Ba2,Bb6),(AC8,Ba3,Bb1),(AC8,Ba3,Bb2),(AC8,Ba3,Bb3),(AC8,Ba3,Bb4),(AC8,Ba3,Bb5),(AC8,Ba3,Bb6),(AC8,Ba4,Bb1),(AC8,Ba4,Bb2),(AC8,Ba4,Bb3),(AC8,Ba4,Bb4),(AC8,Ba4,Bb5),(AC8,Ba4,Bb6),(AC8,Ba5,Bb1),(AC8,Ba5,Bb2),(AC8,Ba5,Bb3),(AC8,Ba5,Bb4),(AC8,Ba5,Bb5),(AC8,Ba5,Bb6),(AC8,Ba6,Bb1),(AC8,Ba6,Bb2),(AC8,Ba6,Bb3),(AC8,Ba6,Bb4),(AC8,Ba6,Bb5),(AC8,Ba6,Bb6),(AC8,Ba7,Bb1),(AC8,Ba7,Bb2),(AC8,Ba7,Bb3),(AC8,Ba7,Bb4),(AC8,Ba7,Bb5),(AC8,Ba7,Bb6),(AC9,Ba1,Bb1),(AC9,Ba1,Bb2),(AC9,Ba1,Bb3),(AC9,Ba1,Bb4),(AC9,Ba1,Bb5),(AC9,Ba1,Bb6),(AC9,Ba2,Bb1),(AC9,Ba2,Bb2),(AC9,Ba2,Bb3),(AC9,Ba2,Bb4),(AC9,Ba2,Bb5),(AC9,Ba2,Bb6),(AC9,Ba3,Bb1),(AC9,Ba3,Bb2),(AC9,Ba3,Bb3),(AC9,Ba3,Bb4),(AC9,Ba3,Bb5),(AC9,Ba3,Bb6),(AC9,Ba4,Bb1),(AC9,Ba4,Bb2),(AC9,Ba4,Bb3),(AC9,Ba4,Bb4),(AC9,Ba4,Bb5),(AC9,Ba4,Bb6),(AC9,Ba5,Bb1),(AC9,Ba5,Bb2),(AC9,Ba5,Bb3),(AC9,Ba5,Bb4),(AC9,Ba5,Bb5),(AC9,Ba5,Bb6),(AC9,Ba6,Bb1),(AC9,Ba6,Bb2),(AC9,Ba6,Bb3),(AC9,Ba6,Bb4),(AC9,Ba6,Bb5),(AC9,Ba6,Bb6),(AC9,Ba7,Bb1),(AC9,Ba7,Bb2),(AC9,Ba7,Bb3),(AC9,Ba7,Bb4),(AC9,Ba7,Bb5),(AC9,Ba7,Bb6),(AC10,Ba1,Bb1),(AC10,Ba1,Bb2),(AC10,Ba1,Bb3),(AC10,Ba1,Bb4),(AC10,Ba1,Bb5),(AC10,Ba1,Bb6),(AC10,Ba2,Bb1),(AC10,Ba2,Bb2),(AC10,Ba2,Bb3),(AC10,Ba2,Bb4),(AC10,Ba2,Bb5),(AC10,Ba2,Bb6),(AC10,Ba3,Bb1),(AC10,Ba3,Bb2),(AC10,Ba3,Bb3),(AC10,Ba3,Bb4),(AC10,Ba3,Bb5),(AC10,Ba3,Bb6),(AC10,Ba4,Bb1),(AC10,Ba4,Bb2),(AC10,Ba4,Bb3),(AC10,Ba4,Bb4),(AC10,Ba4,Bb5),(AC10,Ba4,Bb6),(AC10,Ba5,Bb1),(AC10,Ba5,Bb2),(AC10,Ba5,Bb3),(AC10,Ba5,Bb4),(AC10,Ba5,Bb5),(AC10,Ba5,Bb6),(AC10,Ba6,Bb1),(AC10,Ba6,Bb2),(AC10,Ba6,Bb3),(AC10,Ba6,Bb4),(AC10,Ba6,Bb5),(AC10,Ba6,Bb6),(AC10,Ba7,Bb1),(AC10,Ba7,Bb2),(AC10,Ba7,Bb3),(AC10,Ba7,Bb4),(AC10,Ba7,Bb5),(AC10,Ba7,Bb6),(AC11,Ba1,Bb1),(AC11,Ba1,Bb2),(AC11,Ba1,Bb3),(AC11,Ba1,Bb4),(AC11,Ba1,Bb5),(AC11,Ba1,Bb6),(AC11,Ba2,Bb1),(AC11,Ba2,Bb2),(AC11,Ba2,Bb3),(AC11,Ba2,Bb4),(AC11,Ba2,Bb5),(AC11,Ba2,Bb6),(AC11,Ba3,Bb1),(AC11,Ba3,Bb2),(AC11,Ba3,Bb3),(AC11,Ba3,Bb4),(AC11,Ba3,Bb5),(AC11,Ba3,Bb6),(AC11,Ba4,Bb1),(AC11,Ba4,Bb2),(AC11,Ba4,Bb3),(AC11,Ba4,Bb4),(AC11,Ba4,Bb5),(AC11,Ba4,Bb6),(AC11,Ba5,Bb1),(AC11,Ba5,Bb2),(AC11,Ba5,Bb3),(AC11,Ba5,Bb4),(AC11,Ba5,Bb5),(AC11,Ba5,Bb6),(AC11,Ba6,Bb1),(AC11,Ba6,Bb2),(AC11,Ba6,Bb3),(AC11,Ba6,Bb4),(AC11,Ba6,Bb5),(AC11,Ba6,Bb6),(AC11,Ba7,Bb1),(AC11,Ba7,Bb2),(AC11,Ba7,Bb3),(AC11,Ba7,Bb4),(AC11,Ba7,Bb5),(AC11,Ba7,Bb6),(AC12,Ba1,Bb1),(AC12,Ba1,Bb2),(AC12,Ba1,Bb3),(AC12,Ba1,Bb4),(AC12,Ba1,Bb5),(AC12,Ba1,Bb6),(AC12,Ba2,Bb1),(AC12,Ba2,Bb2),(AC12,Ba2,Bb3),(AC12,Ba2,Bb4),(AC12,Ba2,Bb5),(AC12,Ba2,Bb6),(AC12,Ba3,Bb1),(AC12,Ba3,Bb2),(AC12,Ba3,Bb3),(AC12,Ba3,Bb4),(AC12,Ba3,Bb5),(AC12,Ba3,Bb6),(AC12,Ba4,Bb1),(AC12,Ba4,Bb2),(AC12,Ba4,Bb3),(AC12,Ba4,Bb4),(AC12,Ba4,Bb5),(AC12,Ba4,Bb6),(AC12,Ba5,Bb1),(AC12,Ba5,Bb2),(AC12,Ba5,Bb3),(AC12,Ba5,Bb4),(AC12,Ba5,Bb5),(AC12,Ba5,Bb6),(AC12,Ba6,Bb1),(AC12,Ba6,Bb2),(AC12,Ba6,Bb3),(AC12,Ba6,Bb4),(AC12,Ba6,Bb5),(AC12,Ba6,Bb6),(AC12,Ba7,Bb1),(AC12,Ba7,Bb2),(AC12,Ba7,Bb3),(AC12,Ba7,Bb4),(AC12,Ba7,Bb5),(AC12,Ba7,Bb6),(AC13,Ba1,Bb1),(AC13,Ba1,Bb2),(AC13,Ba1,Bb3),(AC13,Ba1,Bb4),(AC13,Ba1,Bb5),(AC13,Ba1,Bb6),(AC13,Ba2,Bb1),(AC13,Ba2,Bb2),(AC13,Ba2,Bb3),(AC13,Ba2,Bb4),(AC13,Ba2,Bb5),(AC13,Ba2,Bb6),(AC13,Ba3,Bb1),(AC13,Ba3,Bb2),(AC13,Ba3,Bb3),(AC13,Ba3,Bb4),(AC13,Ba3,Bb5),(AC13,Ba3,Bb6),(AC13,Ba4,Bb1),(AC13,Ba4,Bb2),(AC13,Ba4,Bb3),(AC13,Ba4,Bb4),(AC13,Ba4,Bb5),(AC13,Ba4,Bb6),(AC13,Ba5,Bb1),(AC13,Ba5,Bb2),(AC13,Ba5,Bb3),(AC13,Ba5,Bb4),(AC13,Ba5,Bb5),(AC13,Ba5,Bb6),(AC13,Ba6,Bb1),(AC13,Ba6,Bb2),(AC13,Ba6,Bb3),(AC13,Ba6,Bb4),(AC13,Ba6,Bb5),(AC13,Ba6,Bb6),(AC13,Ba7,Bb1),(AC13,Ba7,Bb2),(AC13,Ba7,Bb3),(AC13,Ba7,Bb4),(AC13,Ba7,Bb5),(AC13,Ba7,Bb6),(AC14,Ba1,Bb1),(AC14,Ba1,Bb2),(AC14,Ba1,Bb3),(AC14,Ba1,Bb4),(AC14,Ba1,Bb5),(AC14,Ba1,Bb6),(AC14,Ba2,Bb1),(AC14,Ba2,Bb2),(AC14,Ba2,Bb3),(AC14,Ba2,Bb4),(AC14,Ba2,Bb5),(AC14,Ba2,Bb6),(AC14,Ba3,Bb1),(AC14,Ba3,Bb2),(AC14,Ba3,Bb3),(AC14,Ba3,Bb4),(AC14,Ba3,Bb5),(AC14,Ba3,Bb6),(AC14,Ba4,Bb1),(AC14,Ba4,Bb2),(AC14,Ba4,Bb3),(AC14,Ba4,Bb4),(AC14,Ba4,Bb5),(AC14,Ba4,Bb6),(AC14,Ba5,Bb1),(AC14,Ba5,Bb2),(AC14,Ba5,Bb3),(AC14,Ba5,Bb4),(AC14,Ba5,Bb5),(AC14,Ba5,Bb6),(AC14,Ba6,Bb1),(AC14,Ba6,Bb2),(AC14,Ba6,Bb3),(AC14,Ba6,Bb4),(AC14,Ba6,Bb5),(AC14,Ba6,Bb6),(AC14,Ba7,Bb1),(AC14,Ba7,Bb2),(AC14,Ba7,Bb3),(AC14,Ba7,Bb4),(AC14,Ba7,Bb5),(AC14,Ba7,Bb6),(AC15,Ba1,Bb1),(AC15,Ba1,Bb2),(AC15,Ba1,Bb3),(AC15,Ba1,Bb4),(AC15,Ba1,Bb5),(AC15,Ba1,Bb6),(AC15,Ba2,Bb1),(AC15,Ba2,Bb2),(AC15,Ba2,Bb3),(AC15,Ba2,Bb4),(AC15,Ba2,Bb5),(AC15,Ba2,Bb6),(AC15,Ba3,Bb1),(AC15,Ba3,Bb2),(AC15,Ba3,Bb3),(AC15,Ba3,Bb4),(AC15,Ba3,Bb5),(AC15,Ba3,Bb6),(AC15,Ba4,Bb1),(AC15,Ba4,Bb2),(AC15,Ba4,Bb3),(AC15,Ba4,Bb4),(AC15,Ba4,Bb5),(AC15,Ba4,Bb6),(AC15,Ba5,Bb1),(AC15,Ba5,Bb2),(AC15,Ba5,Bb3),(AC15,Ba5,Bb4),(AC15,Ba5,Bb5),(AC15,Ba5,Bb6),(AC15,Ba6,Bb1),(AC15,Ba6,Bb2),(AC15,Ba6,Bb3),(AC15,Ba6,Bb4),(AC15,Ba6,Bb5),(AC15,Ba6,Bb6),(AC15,Ba7,Bb1),(AC15,Ba7,Bb2),(AC15,Ba7,Bb3),(AC15,Ba7,Bb4),(AC15,Ba7,Bb5),(AC15,Ba7,Bb6),(AC16,Ba1,Bb1),(AC16,Ba1,Bb2),(AC16,Ba1,Bb3),(AC16,Ba1,Bb4),(AC16,Ba1,Bb5),(AC16,Ba1,Bb6),(AC16,Ba2,Bb1),(AC16,Ba2,Bb2),(AC16,Ba2,Bb3),(AC16,Ba2,Bb4),(AC16,Ba2,Bb5),(AC16,Ba2,Bb6),(AC16,Ba3,Bb1),(AC16,Ba3,Bb2),(AC16,Ba3,Bb3),(AC16,Ba3,Bb4),(AC16,Ba3,Bb5),(AC16,Ba3,Bb6),(AC16,Ba4,Bb1),(AC16,Ba4,Bb2),(AC16,Ba4,Bb3),(AC16,Ba4,Bb4),(AC16,Ba4,Bb5),(AC16,Ba4,Bb6),(AC16,Ba5,Bb1),(AC16,Ba5,Bb2),(AC16,Ba5,Bb3),(AC16,Ba5,Bb4),(AC16,Ba5,Bb5),(AC16,Ba5,Bb6),(AC16,Ba6,Bb1),(AC16,Ba6,Bb2),(AC16,Ba6,Bb3),(AC16,Ba6,Bb4),(AC16,Ba6,Bb5),(AC16,Ba6,Bb6),(AC16,Ba7,Bb1),(AC16,Ba7,Bb2),(AC16,Ba7,Bb3),(AC16,Ba7,Bb4),(AC16,Ba7,Bb5),(AC16,Ba7,Bb6),(AC17,Ba1,Bb1),(AC17,Ba1,Bb2),(AC17,Ba1,Bb3),(AC17,Ba1,Bb4),(AC17,Ba1,Bb5),(AC17,Ba1,Bb6),(AC17,Ba2,Bb1),(AC17,Ba2,Bb2),(AC17,Ba2,Bb3),(AC17,Ba2,Bb4),(AC17,Ba2,Bb5),(AC17,Ba2,Bb6),(AC17,Ba3,Bb1),(AC17,Ba3,Bb2),(AC17,Ba3,Bb3),(AC17,Ba3,Bb4),(AC17,Ba3,Bb5),(AC17,Ba3,Bb6),(AC17,Ba4,Bb1),(AC17,Ba4,Bb2),(AC17,Ba4,Bb3),(AC17,Ba4,Bb4),(AC17,Ba4,Bb5),(AC17,Ba4,Bb6),(AC17,Ba5,Bb1),(AC17,Ba5,Bb2),(AC17,Ba5,Bb3),(AC17,Ba5,Bb4),(AC17,Ba5,Bb5),(AC17,Ba5,Bb6),(AC17,Ba6,Bb1),(AC17,Ba6,Bb2),(AC17,Ba6,Bb3),(AC17,Ba6,Bb4),(AC17,Ba6,Bb5),(A
C17,Ba6,Bb6),(AC17,Ba7,Bb1),(AC17,Ba7,Bb2),(AC17,Ba7,Bb3),(AC17,Ba7,Bb4),(AC17,Ba7,Bb5),(AC17,Ba7,Bb6),(AC18,Ba1,Bb1),(AC18,Ba1,Bb2),(AC18,Ba1,Bb3),(AC18,Ba1,Bb4),(AC18,Ba1,Bb5),(AC18,Ba1,Bb6),(AC18,Ba2,Bb1),(AC18,Ba2,Bb2),(AC18,Ba2,Bb3),(AC18,Ba2,Bb4),(AC18,Ba2,Bb5),(AC18,Ba2,Bb6),(AC18,Ba3,Bb1),(AC18,Ba3,Bb2),(AC18,Ba3,Bb3),(AC18,Ba3,Bb4),(AC18,Ba3,Bb5),(AC18,Ba3,Bb6),(AC18,Ba4,Bb1),(AC18,Ba4,Bb2),(AC18,Ba4,Bb3),(AC18,Ba4,Bb4),(AC18,Ba4,Bb5),(AC18,Ba4,Bb6),(AC18,Ba5,Bb1),(AC18,Ba5,Bb2),(AC18,Ba5,Bb3),(AC18,Ba5,Bb4),(AC18,Ba5,Bb5),(AC18,Ba5,Bb6),(AC18,Ba6,Bb1),(AC18,Ba6,Bb2),(AC18,Ba6,Bb3),(AC18,Ba6,Bb4),(AC18,Ba6,Bb5),(AC18,Ba6,Bb6),(AC18,Ba7,Bb1),(AC18,Ba7,Bb2),(AC18,Ba7,Bb3),(AC18,Ba7,Bb4),(AC18,Ba7,Bb5),(AC18,Ba7,Bb6),(AC19,Ba1,Bb1),(AC19,Ba1,Bb2),(AC19,Ba1,Bb3),(AC19,Ba1,Bb4),(AC19,Ba1,Bb5),(AC19,Ba1,Bb6),(AC19,Ba2,Bb1),(AC19,Ba2,Bb2),(AC19,Ba2,Bb3),(AC19,Ba2,Bb4),(AC19,Ba2,Bb5),(AC19,Ba2,Bb6),(AC19,Ba3,Bb1),(AC19,Ba3,Bb2),(AC19,Ba3,Bb3),(AC19,Ba3,Bb4),(AC19,Ba3,Bb5),(AC19,Ba3,Bb6),(AC19,Ba4,Bb1),(AC19,Ba4,Bb2),(AC19,Ba4,Bb3),(AC19,Ba4,Bb4),(AC19,Ba4,Bb5),(AC19,Ba4,Bb6),(AC19,Ba5,Bb1),(AC19,Ba5,Bb2),(AC19,Ba5,Bb3),(AC19,Ba5,Bb4),(AC19,Ba5,Bb5),(AC19,Ba5,Bb6),(AC19,Ba6,Bb1),(AC19,Ba6,Bb2),(AC19,Ba6,Bb3),(AC19,Ba6,Bb4),(AC19,Ba6,Bb5),(AC19,Ba6,Bb6),(AC19,Ba7,Bb1),(AC19,Ba7,Bb2),(AC19,Ba7,Bb3),(AC19,Ba7,Bb4),(AC19,Ba7,Bb5),(AC19,Ba7,Bb6),(AC20,Ba1,Bb1),(AC20,Ba1,Bb2),(AC20,Ba1,Bb3),(AC20,Ba1,Bb4),(AC20,Ba1,Bb5),(AC20,Ba1,Bb6),(AC20,Ba2,Bb1),(AC20,Ba2,Bb2),(AC20,Ba2,Bb3),(AC20,Ba2,Bb4),(AC20,Ba2,Bb5),(AC20,Ba2,Bb6),(AC20,Ba3,Bb1),(AC20,Ba3,Bb2),(AC20,Ba3,Bb3),(AC20,Ba3,Bb4),(AC20,Ba3,Bb5),(AC20,Ba3,Bb6),(AC20,Ba4,Bb1),(AC20,Ba4,Bb2),(AC20,Ba4,Bb3),(AC20,Ba4,Bb4),(AC20,Ba4,Bb5),(AC20,Ba4,Bb6),(AC20,Ba5,Bb1),(AC20,Ba5,Bb2),(AC20,Ba5,Bb3),(AC20,Ba5,Bb4),(AC20,Ba5,Bb5),(AC20,Ba5,Bb6),(AC20,Ba6,Bb1),(AC20,Ba6,Bb2),(AC20,Ba6,Bb3),(AC20,Ba6,Bb4),(AC20,Ba6,Bb5),(AC20,Ba6,Bb6),(AC20,Ba7,Bb1),(AC20,Ba7,Bb2),(AC20,Ba7,Bb3),(AC20,Ba7,Bb4),(AC20,Ba7,Bb5),(AC20,Ba7,Bb6),(AC21,Ba1,Bb1),(AC21,Ba1,Bb2),(AC21,Ba1,Bb3),(AC21,Ba1,Bb4),(AC21,Ba1,Bb5),(AC21,Ba1,Bb6),(AC21,Ba2,Bb1),(AC21,Ba2,Bb2),(AC21,Ba2,Bb3),(AC21,Ba2,Bb4),(AC21,Ba2,Bb5),(AC21,Ba2,Bb6),(AC21,Ba3,Bb1),(AC21,Ba3,Bb2),(AC21,Ba3,Bb3),(AC21,Ba3,Bb4),(AC21,Ba3,Bb5),(AC21,Ba3,Bb6),(AC21,Ba4,Bb1),(AC21,Ba4,Bb2),(AC21,Ba4,Bb3),(AC21,Ba4,Bb4),(AC21,Ba4,Bb5),(AC21,Ba4,Bb6),(AC21,Ba5,Bb1),(AC21,Ba5,Bb2),(AC21,Ba5,Bb3),(AC21,Ba5,Bb4),(AC21,Ba5,Bb5),(AC21,Ba5,Bb6),(AC21,Ba6,Bb1),(AC21,Ba6,Bb2),(AC21,Ba6,Bb3),(AC21,Ba6,Bb4),(AC21,Ba6,Bb5),(AC21,Ba6,Bb6),(AC21,Ba7,Bb1),(AC21,Ba7,Bb2),(AC21,Ba7,Bb3),(AC21,Ba7,Bb4),(AC21,Ba7,Bb5),(AC21,Ba7,Bb6). 
The compound whose combination of AC, Ba, and Bb is the following (AC, Ba, Bb).
(AC, Ba, Bb) = (AC1, Ba1, Bb1), (AC1, Ba1, Bb2), (AC1, Ba1, Bb3), (AC1, Ba1, Bb4), (AC1, Ba1, Bb5), (AC1 , Ba1, Bb6), (AC1, Ba2, Bb1), (AC1, Ba2, Bb2), (AC1, Ba2, Bb3), (AC1, Ba2, Bb4), (AC1, Ba2, Bb5), (AC1, Ba2 , Bb6), (AC1, Ba3, Bb1), (AC1, Ba3, Bb2), (AC1, Ba3, Bb3), (AC1, Ba3, Bb4), (AC1, Ba3, Bb5), (AC1, Ba3, Bb6 ), (AC1, Ba4, Bb1), (AC1, Ba4, Bb2), (AC1, Ba4, Bb3), (AC1, Ba4, Bb4), (AC1, Ba4, Bb5), (AC1, Ba4, Bb6), (AC1, Ba5, Bb1), (AC1, Ba5, Bb2), (AC1, Ba5, Bb3), (AC1, Ba5, Bb4), (AC1, Ba5, Bb5), (AC1, Ba5, Bb6), (AC1 , Ba6, Bb1), (AC1, Ba6, Bb2), (AC1, Ba6, Bb3), (AC1, Ba6, Bb4), (AC1, Ba6, Bb5), (AC1, Ba6, Bb6), (AC1, Ba7 , Bb1), (AC1, Ba7, Bb2), (AC1, Ba7, Bb3), (AC1, Ba7, Bb4), (AC1, Ba7, Bb5), (AC1, Ba7, Bb6), (AC2, Ba1, Bb1 ), (AC2, Ba1, Bb2), (AC2, Ba1, Bb3), (AC2, Ba1, Bb4), (AC2, Ba1, Bb5), (AC2, Ba1, Bb6), (AC2, Ba2, Bb1), (AC2, Ba2, Bb2), (AC2, Ba2, Bb3), (AC2, Ba2, Bb4), (AC2, Ba2, Bb5), (AC2, Ba2, Bb6), (AC2, Ba3, Bb1), (AC2 , Ba3, Bb2), (AC2, Ba3, Bb3), (AC2, Ba3, Bb4), (AC2, Ba3, Bb5), (AC2, Ba3, Bb6), (AC2, Ba4, Bb1), (AC2, Ba4 , Bb2), (AC2, Ba4, Bb3), (AC2, Ba4, Bb4), (AC2, Ba4, Bb5), (AC2, Ba4, Bb6), (AC2, Ba5, Bb1), (AC2, Ba5, Bb2 ), (AC2, Ba5, Bb3), (AC2, Ba5, Bb4), (AC2, Ba5 , Bb5), (AC2, Ba5, Bb6), (AC2, Ba6, Bb1), (AC2, Ba6, Bb2), (AC2, Ba6, Bb3), (AC2, Ba6, Bb4), (AC2, Ba6, Bb5 ), (AC2, Ba6, Bb6), (AC2, Ba7, Bb1), (AC2, Ba7, Bb2), (AC2, Ba7, Bb3), (AC2, Ba7, Bb4), (AC2, Ba7, Bb5), (AC2, Ba7, Bb6), (AC3, Ba1, Bb1), (AC3, Ba1, Bb2), (AC3, Ba1, Bb3), (AC3, Ba1, Bb4), (AC3, Ba1, Bb5), (AC3 , Ba1, Bb6), (AC3, Ba2, Bb1), (AC3, Ba2, Bb2), (AC3, Ba2, Bb3), (AC3, Ba2, Bb4), (AC3, Ba2, Bb5), (AC3, Ba2 , Bb6), (AC3, Ba3, Bb1), (AC3, Ba3, Bb2), (AC3, Ba3, Bb3), (AC3, Ba3, Bb4), (AC3, Ba3, Bb5), (AC3, Ba3, Bb6 ), (AC3, Ba4, Bb1), (AC3, Ba4, Bb2), (AC3, Ba4, Bb3), (AC3, Ba4, Bb4), (AC3, Ba4, Bb5), (AC3, Ba4, Bb6), (AC3, Ba5, Bb1), (AC3, Ba5, Bb2), (AC3, Ba5, Bb3), (AC3, Ba5, Bb4), (AC3, Ba5, Bb5), (AC3, Ba5, Bb6), (AC3 , Ba6, Bb1), (AC3, Ba6, Bb2), (AC3, Ba6, Bb3), (AC3, Ba6, Bb4), (AC3, Ba6, Bb5), (AC3, Ba6, Bb6), (AC3, Ba7 , Bb1), (AC3, Ba7, Bb2), (AC3, Ba7, Bb3), (AC3, Ba7, Bb4), (AC3, Ba7, Bb5), (AC3, Ba7, Bb6), (AC4, Ba1, Bb1 ), (AC4, Ba1, Bb2), (AC4, Ba1, Bb3), (AC4, Ba1, Bb4), (AC4, Ba1, Bb5), (AC4, Ba1, Bb6), (AC4, Ba2, Bb1), (AC4, Ba2, Bb2), (AC4, Ba2, Bb3), (AC4, Ba2, Bb4), (AC4, Ba2, Bb5), (AC4, Ba2, Bb6), (AC4, Ba3, Bb1), (AC4 , Ba3, Bb2), (AC4, Ba3, Bb3), (AC4, Ba3, Bb4), (AC4, Ba3, Bb5), (AC4, Ba3, Bb6), (AC4, Ba4, Bb1), (AC4, Ba4, Bb2), (AC4, Ba4, Bb3), (AC4, Ba4, Bb4), (AC4 , Ba4, Bb5), (AC4, Ba4, Bb6), (AC4, Ba5, Bb1), (AC4, Ba5, Bb2), (AC4, Ba5, Bb3), (AC4, Ba5, Bb4), (AC4, Ba5 , Bb5), (AC4, Ba5, Bb6), (AC4, Ba6, Bb1), (AC4, Ba6, Bb2), (AC4, Ba6, Bb3), (AC4, Ba6, Bb4), (AC4, Ba6, Bb5 ), (AC4, Ba6, Bb6), (AC4, Ba7, Bb1), (AC4, Ba7, Bb2), (AC4, Ba7, Bb3), (AC4, Ba7, Bb4), (AC4, Ba7, Bb5), (AC4, Ba7, Bb6), (AC5, Ba1, Bb1), (AC5, Ba1, Bb2), (AC5, Ba1, Bb3), (AC5, Ba1, Bb4), (AC5, Ba1, Bb5), (AC5 , Ba1, Bb6), (AC5, Ba2, Bb1), (AC5, Ba2, Bb2), (AC5, Ba2, Bb3), (AC5, Ba2, Bb4), (AC5, Ba2, Bb5), (AC5, Ba2 , Bb6), (AC5, Ba3, Bb1), (AC5, Ba3, Bb2), (AC5, Ba3, Bb3), (AC5, Ba3, Bb4), (AC5, Ba3, Bb5), (AC5, Ba3, Bb6 ), (AC5, Ba4, Bb1), (AC5, Ba4, Bb2), (AC5, Ba4, Bb3), (AC5, Ba4, Bb4), (AC5, Ba4, Bb5), (AC5, Ba4, Bb6), (AC5, Ba5, Bb1), (AC5, Ba5, Bb2), (AC5, Ba5, Bb3), (AC5, Ba5, Bb4), (AC5, Ba5, Bb5), (AC5, Ba5, Bb6), (AC5 , Ba6, Bb1), (AC5, Ba6, Bb2), (AC5, Ba6, Bb3), (AC5, Ba6, Bb4), (AC5, Ba6, Bb5), (AC5, Ba6, Bb6), (AC5, Ba7 , Bb1), (AC5, Ba7, Bb2), (AC5, Ba7, Bb3), (AC5, Ba7, Bb4), (AC5, Ba7, Bb5), (AC5, Ba7, Bb6), (AC6, Ba1, Bb1 ), (AC6, Ba1, Bb2), (AC6, Ba1, Bb3), (AC6, B a1, Bb4), (AC6, Ba1, Bb5), (AC6, Ba1, Bb6), (AC6, Ba2, Bb1), (AC6, Ba2, Bb2), (AC6, Ba2, Bb3), (AC6, Ba2, (Bb4), (AC6, Ba2, Bb5), (AC6, Ba2, Bb6), (AC6, Ba3, Bb1), (AC6, Ba3, Bb2), (AC6, Ba3, Bb3), (AC6, Ba3, Bb4) , (AC6, Ba3, Bb5), (AC6, Ba3, Bb6), (AC6, Ba4, Bb1), (AC6, Ba4, Bb2), (AC6, Ba4, Bb3), (AC6, Ba4, Bb4), ( (AC6, Ba4, Bb5), (AC6, Ba4, Bb6), (AC6, Ba5, Bb1), (AC6, Ba5, Bb2), (AC6, Ba5, Bb3), (AC6, Ba5, Bb4), (AC6, (Ba5, Bb5), (AC6, Ba5, Bb6), (AC6, Ba6, Bb1), (AC6, Ba6, Bb2), (AC6, Ba6, Bb3), (AC6, Ba6, Bb4), (AC6, Ba6, (Bb5), (AC6, Ba6, Bb6), (AC6, Ba7, Bb1), (AC6, Ba7, Bb2), (AC6, Ba7, Bb3), (AC6, Ba7, Bb4), (AC6, Ba7, Bb5) , (AC6, Ba7, Bb6), (AC7, Ba1, Bb1), (AC7, Ba1, Bb2), (AC7, Ba1, Bb3), (AC7, Ba1, Bb4), (AC7, Ba1, Bb5), ( (AC7, Ba1, Bb6), (AC7, Ba2, Bb1), (AC7, Ba2, Bb2), (AC7, Ba2, Bb3), (AC7, Ba2, Bb4), (AC7, Ba2, Bb5), (AC7, (Ba2, Bb6), (AC7, Ba3, Bb1), (AC7, Ba3, Bb2), (AC7, Ba3, Bb3), (AC7, Ba3, Bb4), (AC7, Ba3, Bb5), (AC7, Ba3, (Bb6), (AC7, Ba4, Bb1), (AC7, Ba4, Bb2), (AC7, Ba4, Bb3), (AC7, Ba4, Bb4), (AC7, Ba4, Bb5), (AC7, Ba4, Bb6) , (AC7, Ba5, Bb1), (AC7, Ba5, Bb2), (AC7, Ba5, Bb3), (AC7, Ba5, Bb4), (AC7, Ba5, Bb5), (AC7, Ba5, Bb6), ( (AC7, Ba6, Bb1), (AC7, Ba6, Bb2), (AC7, Ba6, Bb3) ), (AC7, Ba6, Bb4), (AC7, Ba6, Bb5), (AC7, Ba6, Bb6), (AC7, Ba7, Bb1), (AC7, Ba7, Bb2), (AC7, Ba7, Bb3), (AC7, Ba7, Bb4), (AC7, Ba7, Bb5), (AC7, Ba7, Bb6), (AC8, Ba1, Bb1), (AC8, Ba1, Bb2), (AC8, Ba1, Bb3), (AC8 , Ba1, Bb4), (AC8, Ba1, Bb5), (AC8, Ba1, Bb6), (AC8, Ba2, Bb1), (AC8, Ba2, Bb2), (AC8, Ba2, Bb3), (AC8, Ba2 , Bb4), (AC8, Ba2, Bb5), (AC8, Ba2, Bb6), (AC8, Ba3, Bb1), (AC8, Ba3, Bb2), (AC8, Ba3, Bb3), (AC8, Ba3, Bb4 ), (AC8, Ba3, Bb5), (AC8, Ba3, Bb6), (AC8, Ba4, Bb1), (AC8, Ba4, Bb2), (AC8, Ba4, Bb3), (AC8, Ba4, Bb4), (AC8, Ba4, Bb5), (AC8, Ba4, Bb6), (AC8, Ba5, Bb1), (AC8, Ba5, Bb2), (AC8, Ba5, Bb3), (AC8, Ba5, Bb4), (AC8 , Ba5, Bb5), (AC8, Ba5, Bb6), (AC8, Ba6, Bb1), (AC8, Ba6, Bb2), (AC8, Ba6, Bb3), (AC8, Ba6, Bb4), (AC8, Ba6) , Bb5), (AC8, Ba6, Bb6), (AC8, Ba7, Bb1), (AC8, Ba7, Bb2), (AC8, Ba7, Bb3), (AC8, Ba7, Bb4), (AC8, Ba7, Bb5 ), (AC8, Ba7, Bb6), (AC9, Ba1, Bb1), (AC9, Ba1, Bb2), (AC9, Ba1, Bb3), (AC9, Ba1, Bb4), (AC9, Ba1, Bb5), (AC9, Ba1, Bb6), (AC9, Ba2, Bb1), (AC9, Ba2, Bb2), (AC9, Ba2, Bb3), (AC9, Ba2, Bb4), (AC9, Ba2, Bb5), (AC9 , Ba2, Bb6), (AC9, Ba3, Bb1), (AC9, Ba3, Bb2), (AC9, Ba3, Bb3), (AC9, Ba3, Bb4), (AC9, Ba3, Bb5), (AC9, Ba3 , Bb6), (AC9, Ba4, Bb1), (AC9, Ba4, Bb2), (AC9 , Ba4, Bb3), (AC9, Ba4, Bb4), (AC9, Ba4, Bb5), (AC9, Ba4, Bb6), (AC9, Ba5, Bb1), (AC9, Ba5, Bb2), (AC9, Ba5 , Bb3), (AC9, Ba5, Bb4), (AC9, Ba5, Bb5), (AC9, Ba5, Bb6), (AC9, Ba6, Bb1), (AC9, Ba6, Bb2), (AC9, Ba6, Bb3 ), (AC9, Ba6, Bb4), (AC9, Ba6, Bb5), (AC9, Ba6, Bb6), (AC9, Ba7, Bb1), (AC9, Ba7, Bb2), (AC9, Ba7, Bb3), (AC9, Ba7, Bb4), (AC9, Ba7, Bb5), (AC9, Ba7, Bb6), (AC10, Ba1, Bb1), (AC10, Ba1, Bb2), (AC10, Ba1, Bb3), (AC10 , Ba1, Bb4), (AC10, Ba1, Bb5), (AC10, Ba1, Bb6), (AC10, Ba2, Bb1), (AC10, Ba2, Bb2), (AC10, Ba2, Bb3), (AC10, Ba2 , Bb4), (AC10, Ba2, Bb5), (AC10, Ba2, Bb6), (AC10, Ba3, Bb1), (AC10, Ba3, Bb2), (AC10, Ba3, Bb3), (AC10, Ba3, Bb4 ), (AC10, Ba3, Bb5), (AC10, Ba3, Bb6), (AC10, Ba4, Bb1), (AC10, Ba4, Bb2), (AC10, Ba4, Bb3), (AC10, Ba4, Bb4), (AC10, Ba4, Bb5), (AC10, Ba4, Bb6), (AC10, Ba5, Bb1), (AC10, Ba5, Bb2), (AC10, Ba5, Bb3), (AC10, Ba5, Bb4), (AC10 , Ba5, Bb5), (AC10, Ba5, Bb6), (AC10, Ba6, Bb1), (AC10, Ba6, Bb2), (AC10, Ba6, Bb3), (AC10, Ba6, Bb4), (AC10, Ba6) , Bb5), (AC10, Ba6, Bb6), (AC10, Ba7, Bb1), (AC10, Ba7, Bb2), (AC10, Ba7, Bb3), (AC10, Ba7, Bb4), (AC10, Ba7, Bb5 ), (AC10, Ba7, Bb6), (AC11, Ba1, Bb1), (AC11, Ba1, Bb2), (AC11, Ba1, Bb3), (AC11, Ba1, Bb4), (AC11, (Ba1, Bb5), (AC11, Ba1, Bb6), (AC11, Ba2, Bb1), (AC11, Ba2, Bb2), (AC11, Ba2, Bb3), (AC11, Ba2, Bb4), (AC11, Ba2, (Bb5), (AC11, Ba2, Bb6), (AC11, Ba3, Bb1), (AC11, Ba3, Bb2), (AC11, Ba3, Bb3), (AC11, Ba3, Bb4), (AC11, Ba3, Bb5) , (AC11, Ba3, Bb6), (AC11, Ba4, Bb1), (AC11, Ba4, Bb2), (AC11, Ba4, Bb3), (AC11, Ba4, Bb4), (AC11, Ba4, Bb5), ( (AC11, Ba4, Bb6), (AC11, Ba5, Bb1), (AC11, Ba5, Bb2), (AC11, Ba5, Bb3), (AC11, Ba5, Bb4), (AC11, Ba5, Bb5), (AC11, (Ba5, Bb6), (AC11, Ba6, Bb1), (AC11, Ba6, Bb2), (AC11, Ba6, Bb3), (AC11, Ba6, Bb4), (AC11, Ba6, Bb5), (AC11, Ba6, (Bb6), (AC11, Ba7, Bb1), (AC11, Ba7, Bb2), (AC11, Ba7, Bb3), (AC11, Ba7, Bb4), (AC11, Ba7, Bb5), (AC11, Ba7, Bb6) , (AC12, Ba1, Bb1), (AC12, Ba1, Bb2), (AC12, Ba1, Bb3), (AC12, Ba1, Bb4), (AC12, Ba1, Bb5), (AC12, Ba1, Bb6), ( (AC12, Ba2, Bb1), (AC12, Ba2, Bb2), (AC12, Ba2, Bb3), (AC12, Ba2, Bb4), (AC12, Ba2, Bb5), (AC12, Ba2, Bb6), (AC12, (Ba3, Bb1), (AC12, Ba3, Bb2), (AC12, Ba3, Bb3), (AC12, Ba3, Bb4), (AC12, Ba3, Bb5), (AC12, Ba3, Bb6), (AC12, Ba4, (Bb1), (AC12, Ba4, Bb2), (AC12, Ba4, Bb3), (AC12, Ba4, Bb4), (AC12, Ba4, Bb5), (AC12, Ba4, Bb6), (AC12, Ba5, Bb1) , (AC12, Ba5, Bb2), (AC12, Ba5, Bb3), (AC12, Ba5, Bb4), (AC12, Ba5, Bb5), ( (AC12, Ba5, Bb6), (AC12, Ba6, Bb1), (AC12, Ba6, Bb2), (AC12, Ba6, Bb3), (AC12, Ba6, Bb4), (AC12, Ba6, Bb5), (AC12, (Ba6, Bb6), (AC12, Ba7, Bb1), (AC12, Ba7, Bb2), (AC12, Ba7, Bb3), (AC12, Ba7, Bb4), (AC12, Ba7, Bb5), (AC12, Ba7, (Bb6), (AC13, Ba1, Bb1), (AC13, Ba1, Bb2), (AC13, Ba1, Bb3), (AC13, Ba1, Bb4), (AC13, Ba1, Bb5), (AC13, Ba1, Bb6) , (AC13, Ba2, Bb1), (AC13, Ba2, Bb2), (AC13, Ba2, Bb3), (AC13, Ba2, Bb4), (AC13, Ba2, Bb5), (AC13, Ba2, Bb6), ( (AC13, Ba3, Bb1), (AC13, Ba3, Bb2), (AC13, Ba3, Bb3), (AC13, Ba3, Bb4), (AC13, Ba3, Bb5), (AC13, Ba3, Bb6), (AC13, (Ba4, Bb1), (AC13, Ba4, Bb2), (AC13, Ba4, Bb3), (AC13, Ba4, Bb4), (AC13, Ba4, Bb5), (AC13, Ba4, Bb6), (AC13, Ba5, (Bb1), (AC13, Ba5, Bb2), (AC13, Ba5, Bb3), (AC13, Ba5, Bb4), (AC13, Ba5, Bb5), (AC13, Ba5, Bb6), (AC13, Ba6, Bb1) , (AC13, Ba6, Bb2), (AC13, Ba6, Bb3), (AC13, Ba6, Bb4), (AC13, Ba6, Bb5), (AC13, Ba6, Bb6), (AC13, Ba7, Bb1), ( (AC13, Ba7, Bb2), (AC13, Ba7, Bb3), (AC13, Ba7, Bb4), (AC13, Ba7, Bb5), (AC13, Ba7, Bb6), (AC14, Ba1, Bb1), (AC14, (Ba1, Bb2), (AC14, Ba1, Bb3), (AC14, Ba1, Bb4), (AC14, Ba1, Bb5), (AC14, Ba1, Bb6), (AC14, Ba2, Bb1), (AC14, Ba2, Bb2), (AC14, Ba2, Bb3), (AC14, Ba2, Bb4), (AC14, Ba2, Bb5), (AC14, Ba2, B b6), (AC14, Ba3, Bb1), (AC14, Ba3, Bb2), (AC14, Ba3, Bb3), (AC14, Ba3, Bb4), (AC14, Ba3, Bb5), (AC14, Ba3, Bb6) , (AC14, Ba4, Bb1), (AC14, Ba4, Bb2), (AC14, Ba4, Bb3), (AC14, Ba4, Bb4), (AC14, Ba4, Bb5), (AC14, Ba4, Bb6), ( (AC14, Ba5, Bb1), (AC14, Ba5, Bb2), (AC14, Ba5, Bb3), (AC14, Ba5, Bb4), (AC14, Ba5, Bb5), (AC14, Ba5, Bb6), (AC14, (Ba6, Bb1), (AC14, Ba6, Bb2), (AC14, Ba6, Bb3), (AC14, Ba6, Bb4), (AC14, Ba6, Bb5), (AC14, Ba6, Bb6), (AC14, Ba7, (Bb1), (AC14, Ba7, Bb2), (AC14, Ba7, Bb3), (AC14, Ba7, Bb4), (AC14, Ba7, Bb5), (AC14, Ba7, Bb6), (AC15, Ba1, Bb1) , (AC15, Ba1, Bb2), (AC15, Ba1, Bb3), (AC15, Ba1, Bb4), (AC15, Ba1, Bb5), (AC15, Ba1, Bb6), (AC15, Ba2, Bb1), ( (AC15, Ba2, Bb2), (AC15, Ba2, Bb3), (AC15, Ba2, Bb4), (AC15, Ba2, Bb5), (AC15, Ba2, Bb6), (AC15, Ba3, Bb1), (AC15, (Ba3, Bb2), (AC15, Ba3, Bb3), (AC15, Ba3, Bb4), (AC15, Ba3, Bb5), (AC15, Ba3, Bb6), (AC15, Ba4, Bb1), (AC15, Ba4, (Bb2), (AC15, Ba4, Bb3), (AC15, Ba4, Bb4), (AC15, Ba4, Bb5), (AC15, Ba4, Bb6), (AC15, Ba5, Bb1), (AC15, Ba5, Bb2) , (AC15, Ba5, Bb3), (AC15, Ba5, Bb4), (AC15, Ba5, Bb5), (AC15, Ba5, Bb6), (AC15, Ba6, Bb1), (AC15, Ba6, Bb2), ( (AC15, Ba6, Bb3), (AC15, Ba6, Bb4), (AC15, Ba6, Bb5), (AC15, Ba6, Bb6), (AC15, (Ba7, Bb1), (AC15, Ba7, Bb2), (AC15, Ba7, Bb3), (AC15, Ba7, Bb4), (AC15, Ba7, Bb5), (AC15, Ba7, Bb6), (AC16, Ba1, (Bb1), (AC16, Ba1, Bb2), (AC16, Ba1, Bb3), (AC16, Ba1, Bb4), (AC16, Ba1, Bb5), (AC16, Ba1, Bb6), (AC16, Ba2, Bb1) , (AC16, Ba2, Bb2), (AC16, Ba2, Bb3), (AC16, Ba2, Bb4), (AC16, Ba2, Bb5), (AC16, Ba2, Bb6), (AC16, Ba3, Bb1), ( (AC16, Ba3, Bb2), (AC16, Ba3, Bb3), (AC16, Ba3, Bb4), (AC16, Ba3, Bb5), (AC16, Ba3, Bb6), (AC16, Ba4, Bb1), (AC16, (Ba4, Bb2), (AC16, Ba4, Bb3), (AC16, Ba4, Bb4), (AC16, Ba4, Bb5), (AC16, Ba4, Bb6), (AC16, Ba5, Bb1), (AC16, Ba5, (Bb2), (AC16, Ba5, Bb3), (AC16, Ba5, Bb4), (AC16, Ba5, Bb5), (AC16, Ba5, Bb6), (AC16, Ba6, Bb1), (AC16, Ba6, Bb2) , (AC16, Ba6, Bb3), (AC16, Ba6, Bb4), (AC16, Ba6, Bb5), (AC16, Ba6, Bb6), (AC16, Ba7, Bb1), (AC16, Ba7, Bb2), ( (AC16, Ba7, Bb3), (AC16, Ba7, Bb4), (AC16, Ba7, Bb5), (AC16, Ba7, Bb6), (AC17, Ba1, Bb1), (AC17, Ba1, Bb2), (AC17, (Ba1, Bb3), (AC17, Ba1, Bb4), (AC17, Ba1, Bb5), (AC17, Ba1, Bb6), (AC17, Ba2, Bb1), (AC17, Ba2, Bb2), (AC17, Ba2, (Bb3), (AC17, Ba2, Bb4), (AC17, Ba2, Bb5), (AC17, Ba2, Bb6), (AC17, Ba3, Bb1), (AC17, Ba3, Bb2), (AC17, Ba3, Bb3) , (AC17, Ba3, Bb4), (AC17, Ba3, Bb5), (AC17, Ba3, Bb6), (AC17, Ba4, Bb1), ( (AC17, Ba4, Bb2), (AC17, Ba4, Bb3), (AC17, Ba4, Bb4), (AC17, Ba4, Bb5), (AC17, Ba4, Bb6), (AC17, Ba5, Bb1), (AC17, (Ba5, Bb2), (AC17, Ba5, Bb3), (AC17, Ba5, Bb4), (AC17, Ba5, Bb5), (AC17, Ba5, Bb6), (AC17, Ba6, Bb1), (AC17, Ba6, (Bb2), (AC17, Ba6, Bb3), (AC17, Ba6, Bb4), (AC17, Ba6, Bb5), (A
C17, Ba6, Bb6), (AC17, Ba7, Bb1), (AC17, Ba7, Bb2), (AC17, Ba7, Bb3), (AC17, Ba7, Bb4), (AC17, Ba7, Bb5), (AC17, (Ba7, Bb6), (AC18, Ba1, Bb1), (AC18, Ba1, Bb2), (AC18, Ba1, Bb3), (AC18, Ba1, Bb4), (AC18, Ba1, Bb5), (AC18, Ba1, (Bb6), (AC18, Ba2, Bb1), (AC18, Ba2, Bb2), (AC18, Ba2, Bb3), (AC18, Ba2, Bb4), (AC18, Ba2, Bb5), (AC18, Ba2, Bb6) , (AC18, Ba3, Bb1), (AC18, Ba3, Bb2), (AC18, Ba3, Bb3), (AC18, Ba3, Bb4), (AC18, Ba3, Bb5), (AC18, Ba3, Bb6), ( (AC18, Ba4, Bb1), (AC18, Ba4, Bb2), (AC18, Ba4, Bb3), (AC18, Ba4, Bb4), (AC18, Ba4, Bb5), (AC18, Ba4, Bb6), (AC18, (Ba5, Bb1), (AC18, Ba5, Bb2), (AC18, Ba5, Bb3), (AC18, Ba5, Bb4), (AC18, Ba5, Bb5), (AC18, Ba5, Bb6), (AC18, Ba6, (Bb1), (AC18, Ba6, Bb2), (AC18, Ba6, Bb3), (AC18, Ba6, Bb4), (AC18, Ba6, Bb5), (AC18, Ba6, Bb6), (AC18, Ba7, Bb1) , (AC18, Ba7, Bb2), (AC18, Ba7, Bb3), (AC18, Ba7, Bb4), (AC18, Ba7, Bb5), (AC18, Ba7, Bb6), (AC19, Ba1, Bb1), ( (AC19, Ba1, Bb2), (AC19, Ba1, Bb3), (AC19, Ba1, Bb4), (AC19, Ba1, Bb5), (AC19, Ba1, Bb6), (AC19, Ba2, Bb1), (AC19, (Ba2, Bb2), (AC19, Ba2, Bb3), (AC19, Ba2, Bb4), (AC19, Ba2, Bb5), (AC19, Ba2, Bb6), (AC19, Ba3, Bb1), (AC19, Ba3, (Bb2), (AC19, Ba3, Bb3), (AC19, Ba3, Bb4), (AC19, Ba3, Bb5), (AC19, Ba3, Bb 6), (AC19, Ba4, Bb1), (AC19, Ba4, Bb2), (AC19, Ba4, Bb3), (AC19, Ba4, Bb4), (AC19, Ba4, Bb5), (AC19, Ba4, Bb6) , (AC19, Ba5, Bb1), (AC19, Ba5, Bb2), (AC19, Ba5, Bb3), (AC19, Ba5, Bb4), (AC19, Ba5, Bb5), (AC19, Ba5, Bb6), ( (AC19, Ba6, Bb1), (AC19, Ba6, Bb2), (AC19, Ba6, Bb3), (AC19, Ba6, Bb4), (AC19, Ba6, Bb5), (AC19, Ba6, Bb6), (AC19, (Ba7, Bb1), (AC19, Ba7, Bb2), (AC19, Ba7, Bb3), (AC19, Ba7, Bb4), (AC19, Ba7, Bb5), (AC19, Ba7, Bb6), (AC20, Ba1, (Bb1), (AC20, Ba1, Bb2), (AC20, Ba1, Bb3), (AC20, Ba1, Bb4), (AC20, Ba1, Bb5), (AC20, Ba1, Bb6), (AC20, Ba2, Bb1) , (AC20, Ba2, Bb2), (AC20, Ba2, Bb3), (AC20, Ba2, Bb4), (AC20, Ba2, Bb5), (AC20, Ba2, Bb6), (AC20, Ba3, Bb1), ( (AC20, Ba3, Bb2), (AC20, Ba3, Bb3), (AC20, Ba3, Bb4), (AC20, Ba3, Bb5), (AC20, Ba3, Bb6), (AC20, Ba4, Bb1), (AC20, (Ba4, Bb2), (AC20, Ba4, Bb3), (AC20, Ba4, Bb4), (AC20, Ba4, Bb5), (AC20, Ba4, Bb6), (AC20, Ba5, Bb1), (AC20, Ba5, (Bb2), (AC20, Ba5, Bb3), (AC20, Ba5, Bb4), (AC20, Ba5, Bb5), (AC20, Ba5, Bb6), (AC20, Ba6, Bb1), (AC20, Ba6, Bb2) , (AC20, Ba6, Bb3), (AC20, Ba6, Bb4), (AC20, Ba6, Bb5), (AC20, Ba6, Bb6), (AC20, Ba7, Bb1), (AC20, Ba7, Bb2), ( (AC20, Ba7, Bb3), (AC20, Ba7, Bb4), (AC20, Ba7, Bb5), (AC20, Ba7, Bb6), (AC21, B a1, Bb1), (AC21, Ba1, Bb2), (AC21, Ba1, Bb3), (AC21, Ba1, Bb4), (AC21, Ba1, Bb5), (AC21, Ba1, Bb6), (AC21, Ba2, (Bb1), (AC21, Ba2, Bb2), (AC21, Ba2, Bb3), (AC21, Ba2, Bb4), (AC21, Ba2, Bb5), (AC21, Ba2, Bb6), (AC21, Ba3, Bb1) , (AC21, Ba3, Bb2), (AC21, Ba3, Bb3), (AC21, Ba3, Bb4), (AC21, Ba3, Bb5), (AC21, Ba3, Bb6), (AC21, Ba4, Bb1), ( (AC21, Ba4, Bb2), (AC21, Ba4, Bb3), (AC21, Ba4, Bb4), (AC21, Ba4, Bb5), (AC21, Ba4, Bb6), (AC21, Ba5, Bb1), (AC21, (Ba5, Bb2), (AC21, Ba5, Bb3), (AC21, Ba5, Bb4), (AC21, Ba5, Bb5), (AC21, Ba5, Bb6), (AC21, Ba6, Bb1), (AC21, Ba6, (Bb2), (AC21, Ba6, Bb3), (AC21, Ba6, Bb4), (AC21, Ba6, Bb5), (AC21, Ba6, Bb6), (AC21, Ba7, Bb1), (AC21, Ba7, Bb2) , (AC21, Ba7, Bb3), (AC21, Ba7, Bb4), (AC21, Ba7, Bb5), (AC21, Ba7, Bb6).

　本発明化合物の一つの態様は、以下の一般式（ＩＩＩ）において、以下の基を有するものである。

Figure JPOXMLDOC01-appb-C000255

　AC、Ba、Bbの組み合わせが、以下の（AC、Ba、Bb）である化合物。
(AC,Ba, Bb)= (AC1,Ba1,Bb1),(AC1,Ba1,Bb2),(AC1,Ba1,Bb3),(AC1,Ba1,Bb4),(AC1,Ba1,Bb5),(AC1,Ba1,Bb6),(AC1,Ba2,Bb1),(AC1,Ba2,Bb2),(AC1,Ba2,Bb3),(AC1,Ba2,Bb4),(AC1,Ba2,Bb5),(AC1,Ba2,Bb6),(AC1,Ba3,Bb1),(AC1,Ba3,Bb2),(AC1,Ba3,Bb3),(AC1,Ba3,Bb4),(AC1,Ba3,Bb5),(AC1,Ba3,Bb6),(AC1,Ba4,Bb1),(AC1,Ba4,Bb2),(AC1,Ba4,Bb3),(AC1,Ba4,Bb4),(AC1,Ba4,Bb5),(AC1,Ba4,Bb6),(AC1,Ba5,Bb1),(AC1,Ba5,Bb2),(AC1,Ba5,Bb3),(AC1,Ba5,Bb4),(AC1,Ba5,Bb5),(AC1,Ba5,Bb6),(AC1,Ba6,Bb1),(AC1,Ba6,Bb2),(AC1,Ba6,Bb3),(AC1,Ba6,Bb4),(AC1,Ba6,Bb5),(AC1,Ba6,Bb6),(AC1,Ba7,Bb1),(AC1,Ba7,Bb2),(AC1,Ba7,Bb3),(AC1,Ba7,Bb4),(AC1,Ba7,Bb5),(AC1,Ba7,Bb6),(AC2,Ba1,Bb1),(AC2,Ba1,Bb2),(AC2,Ba1,Bb3),(AC2,Ba1,Bb4),(AC2,Ba1,Bb5),(AC2,Ba1,Bb6),(AC2,Ba2,Bb1),(AC2,Ba2,Bb2),(AC2,Ba2,Bb3),(AC2,Ba2,Bb4),(AC2,Ba2,Bb5),(AC2,Ba2,Bb6),(AC2,Ba3,Bb1),(AC2,Ba3,Bb2),(AC2,Ba3,Bb3),(AC2,Ba3,Bb4),(AC2,Ba3,Bb5),(AC2,Ba3,Bb6),(AC2,Ba4,Bb1),(AC2,Ba4,Bb2),(AC2,Ba4,Bb3),(AC2,Ba4,Bb4),(AC2,Ba4,Bb5),(AC2,Ba4,Bb6),(AC2,Ba5,Bb1),(AC2,Ba5,Bb2),(AC2,Ba5,Bb3),(AC2,Ba5,Bb4),(AC2,Ba5,Bb5),(AC2,Ba5,Bb6),(AC2,Ba6,Bb1),(AC2,Ba6,Bb2),(AC2,Ba6,Bb3),(AC2,Ba6,Bb4),(AC2,Ba6,Bb5),(AC2,Ba6,Bb6),(AC2,Ba7,Bb1),(AC2,Ba7,Bb2),(AC2,Ba7,Bb3),(AC2,Ba7,Bb4),(AC2,Ba7,Bb5),(AC2,Ba7,Bb6),(AC3,Ba1,Bb1),(AC3,Ba1,Bb2),(AC3,Ba1,Bb3),(AC3,Ba1,Bb4),(AC3,Ba1,Bb5),(AC3,Ba1,Bb6),(AC3,Ba2,Bb1),(AC3,Ba2,Bb2),(AC3,Ba2,Bb3),(AC3,Ba2,Bb4),(AC3,Ba2,Bb5),(AC3,Ba2,Bb6),(AC3,Ba3,Bb1),(AC3,Ba3,Bb2),(AC3,Ba3,Bb3),(AC3,Ba3,Bb4),(AC3,Ba3,Bb5),(AC3,Ba3,Bb6),(AC3,Ba4,Bb1),(AC3,Ba4,Bb2),(AC3,Ba4,Bb3),(AC3,Ba4,Bb4),(AC3,Ba4,Bb5),(AC3,Ba4,Bb6),(AC3,Ba5,Bb1),(AC3,Ba5,Bb2),(AC3,Ba5,Bb3),(AC3,Ba5,Bb4),(AC3,Ba5,Bb5),(AC3,Ba5,Bb6),(AC3,Ba6,Bb1),(AC3,Ba6,Bb2),(AC3,Ba6,Bb3),(AC3,Ba6,Bb4),(AC3,Ba6,Bb5),(AC3,Ba6,Bb6),(AC3,Ba7,Bb1),(AC3,Ba7,Bb2),(AC3,Ba7,Bb3),(AC3,Ba7,Bb4),(AC3,Ba7,Bb5),(AC3,Ba7,Bb6),(AC4,Ba1,Bb1),(AC4,Ba1,Bb2),(AC4,Ba1,Bb3),(AC4,Ba1,Bb4),(AC4,Ba1,Bb5),(AC4,Ba1,Bb6),(AC4,Ba2,Bb1),(AC4,Ba2,Bb2),(AC4,Ba2,Bb3),(AC4,Ba2,Bb4),(AC4,Ba2,Bb5),(AC4,Ba2,Bb6),(AC4,Ba3,Bb1),(AC4,Ba3,Bb2),(AC4,Ba3,Bb3),(AC4,Ba3,Bb4),(AC4,Ba3,Bb5),(AC4,Ba3,Bb6),(AC4,Ba4,Bb1),(AC4,Ba4,Bb2),(AC4,Ba4,Bb3),(AC4,Ba4,Bb4),(AC4,Ba4,Bb5),(AC4,Ba4,Bb6),(AC4,Ba5,Bb1),(AC4,Ba5,Bb2),(AC4,Ba5,Bb3),(AC4,Ba5,Bb4),(AC4,Ba5,Bb5),(AC4,Ba5,Bb6),(AC4,Ba6,Bb1),(AC4,Ba6,Bb2),(AC4,Ba6,Bb3),(AC4,Ba6,Bb4),(AC4,Ba6,Bb5),(AC4,Ba6,Bb6),(AC4,Ba7,Bb1),(AC4,Ba7,Bb2),(AC4,Ba7,Bb3),(AC4,Ba7,Bb4),(AC4,Ba7,Bb5),(AC4,Ba7,Bb6),(AC5,Ba1,Bb1),(AC5,Ba1,Bb2),(AC5,Ba1,Bb3),(AC5,Ba1,Bb4),(AC5,Ba1,Bb5),(AC5,Ba1,Bb6),(AC5,Ba2,Bb1),(AC5,Ba2,Bb2),(AC5,Ba2,Bb3),(AC5,Ba2,Bb4),(AC5,Ba2,Bb5),(AC5,Ba2,Bb6),(AC5,Ba3,Bb1),(AC5,Ba3,Bb2),(AC5,Ba3,Bb3),(AC5,Ba3,Bb4),(AC5,Ba3,Bb5),(AC5,Ba3,Bb6),(AC5,Ba4,Bb1),(AC5,Ba4,Bb2),(AC5,Ba4,Bb3),(AC5,Ba4,Bb4),(AC5,Ba4,Bb5),(AC5,Ba4,Bb6),(AC5,Ba5,Bb1),(AC5,Ba5,Bb2),(AC5,Ba5,Bb3),(AC5,Ba5,Bb4),(AC5,Ba5,Bb5),(AC5,Ba5,Bb6),(AC5,Ba6,Bb1),(AC5,Ba6,Bb2),(AC5,Ba6,Bb3),(AC5,Ba6,Bb4),(AC5,Ba6,Bb5),(AC5,Ba6,Bb6),(AC5,Ba7,Bb1),(AC5,Ba7,Bb2),(AC5,Ba7,Bb3),(AC5,Ba7,Bb4),(AC5,Ba7,Bb5),(AC5,Ba7,Bb6),(AC6,Ba1,Bb1),(AC6,Ba1,Bb2),(AC6,Ba1,Bb3),(AC6,Ba1,Bb4),(AC6,Ba1,Bb5),(AC6,Ba1,Bb6),(AC6,Ba2,Bb1),(AC6,Ba2,Bb2),(AC6,Ba2,Bb3),(AC6,Ba2,Bb4),(AC6,Ba2,Bb5),(AC6,Ba2,Bb6),(AC6,Ba3,Bb1),(AC6,Ba3,Bb2),(AC6,Ba3,Bb3),(AC6,Ba3,Bb4),(AC6,Ba3,Bb5),(AC6,Ba3,Bb6),(AC6,Ba4,Bb1),(AC6,Ba4,Bb2),(AC6,Ba4,Bb3),(AC6,Ba4,Bb4),(AC6,Ba4,Bb5),(AC6,Ba4,Bb6),(AC6,Ba5,Bb1),(AC6,Ba5,Bb2),(AC6,Ba5,Bb3),(AC6,Ba5,Bb4),(AC6,Ba5,Bb5),(AC6,Ba5,Bb6),(AC6,Ba6,Bb1),(AC6,Ba6,Bb2),(AC6,Ba6,Bb3),(AC6,Ba6,Bb4),(AC6,Ba6,Bb5),(AC6,Ba6,Bb6),(AC6,Ba7,Bb1),(AC6,Ba7,Bb2),(AC6,Ba7,Bb3),(AC6,Ba7,Bb4),(AC6,Ba7,Bb5),(AC6,Ba7,Bb6),(AC7,Ba1,Bb1),(AC7,Ba1,Bb2),(AC7,Ba1,Bb3),(AC7,Ba1,Bb4),(AC7,Ba1,Bb5),(AC7,Ba1,Bb6),(AC7,Ba2,Bb1),(AC7,Ba2,Bb2),(AC7,Ba2,Bb3),(AC7,Ba2,Bb4),(AC7,Ba2,Bb5),(AC7,Ba2,Bb6),(AC7,Ba3,Bb1),(AC7,Ba3,Bb2),(AC7,Ba3,Bb3),(AC7,Ba3,Bb4),(AC7,Ba3,Bb5),(AC7,Ba3,Bb6),(AC7,Ba4,Bb1),(AC7,Ba4,Bb2),(AC7,Ba4,Bb3),(AC7,Ba4,Bb4),(AC7,Ba4,Bb5),(AC7,Ba4,Bb6),(AC7,Ba5,Bb1),(AC7,Ba5,Bb2),(AC7,Ba5,Bb3),(AC7,Ba5,Bb4),(AC7,Ba5,Bb5),(AC7,Ba5,Bb6),(AC7,Ba6,Bb1),(AC7,Ba6,Bb2),(AC7,Ba6,Bb3),(AC7,Ba6,Bb4),(AC7,Ba6,Bb5),(AC7,Ba6,Bb6),(AC7,Ba7,Bb1),(AC7,Ba7,Bb2),(AC7,Ba7,Bb3),(AC7,Ba7,Bb4),(AC7,Ba7,Bb5),(AC7,Ba7,Bb6),(AC8,Ba1,Bb1),(AC8,Ba1,Bb2),(AC8,Ba1,Bb3),(AC8,Ba1,Bb4),(AC8,Ba1,Bb5),(AC8,Ba1,Bb6),(AC8,Ba2,Bb1),(AC8,Ba2,Bb2),(AC8,Ba2,Bb3),(AC8,Ba2,Bb4),(AC8,Ba2,Bb5),(AC8,Ba2,Bb6),(AC8,Ba3,Bb1),(AC8,Ba3,Bb2),(AC8,Ba3,Bb3),(AC8,Ba3,Bb4),(AC8,Ba3,Bb5),(AC8,Ba3,Bb6),(AC8,Ba4,Bb1),(AC8,Ba4,Bb2),(AC8,Ba4,Bb3),(AC8,Ba4,Bb4),(AC8,Ba4,Bb5),(AC8,Ba4,Bb6),(AC8,Ba5,Bb1),(AC8,Ba5,Bb2),(AC8,Ba5,Bb3),(AC8,Ba5,Bb4),(AC8,Ba5,Bb5),(AC8,Ba5,Bb6),(AC8,Ba6,Bb1),(AC8,Ba6,Bb2),(AC8,Ba6,Bb3),(AC8,Ba6,Bb4),(AC8,Ba6,Bb5),(AC8,Ba6,Bb6),(AC8,Ba7,Bb1),(AC8,Ba7,Bb2),(AC8,Ba7,Bb3),(AC8,Ba7,Bb4),(AC8,Ba7,Bb5),(AC8,Ba7,Bb6),(AC9,Ba1,Bb1),(AC9,Ba1,Bb2),(AC9,Ba1,Bb3),(AC9,Ba1,Bb4),(AC9,Ba1,Bb5),(AC9,Ba1,Bb6),(AC9,Ba2,Bb1),(AC9,Ba2,Bb2),(AC9,Ba2,Bb3),(AC9,Ba2,Bb4),(AC9,Ba2,Bb5),(AC9,Ba2,Bb6),(AC9,Ba3,Bb1),(AC9,Ba3,Bb2),(AC9,Ba3,Bb3),(AC9,Ba3,Bb4),(AC9,Ba3,Bb5),(AC9,Ba3,Bb6),(AC9,Ba4,Bb1),(AC9,Ba4,Bb2),(AC9,Ba4,Bb3),(AC9,Ba4,Bb4),(AC9,Ba4,Bb5),(AC9,Ba4,Bb6),(AC9,Ba5,Bb1),(AC9,Ba5,Bb2),(AC9,Ba5,Bb3),(AC9,Ba5,Bb4),(AC9,Ba5,Bb5),(AC9,Ba5,Bb6),(AC9,Ba6,Bb1),(AC9,Ba6,Bb2),(AC9,Ba6,Bb3),(AC9,Ba6,Bb4),(AC9,Ba6,Bb5),(AC9,Ba6,Bb6),(AC9,Ba7,Bb1),(AC9,Ba7,Bb2),(AC9,Ba7,Bb3),(AC9,Ba7,Bb4),(AC9,Ba7,Bb5),(AC9,Ba7,Bb6),(AC10,Ba1,Bb1),(AC10,Ba1,Bb2),(AC10,Ba1,Bb3),(AC10,Ba1,Bb4),(AC10,Ba1,Bb5),(AC10,Ba1,Bb6),(AC10,Ba2,Bb1),(AC10,Ba2,Bb2),(AC10,Ba2,Bb3),(AC10,Ba2,Bb4),(AC10,Ba2,Bb5),(AC10,Ba2,Bb6),(AC10,Ba3,Bb1),(AC10,Ba3,Bb2),(AC10,Ba3,Bb3),(AC10,Ba3,Bb4),(AC10,Ba3,Bb5),(AC10,Ba3,Bb6),(AC10,Ba4,Bb1),(AC10,Ba4,Bb2),(AC10,Ba4,Bb3),(AC10,Ba4,Bb4),(AC10,Ba4,Bb5),(AC10,Ba4,Bb6),(AC10,Ba5,Bb1),(AC10,Ba5,Bb2),(AC10,Ba5,Bb3),(AC10,Ba5,Bb4),(AC10,Ba5,Bb5),(AC10,Ba5,Bb6),(AC10,Ba6,Bb1),(AC10,Ba6,Bb2),(AC10,Ba6,Bb3),(AC10,Ba6,Bb4),(AC10,Ba6,Bb5),(AC10,Ba6,Bb6),(AC10,Ba7,Bb1),(AC10,Ba7,Bb2),(AC10,Ba7,Bb3),(AC10,Ba7,Bb4),(AC10,Ba7,Bb5),(AC10,Ba7,Bb6),(AC11,Ba1,Bb1),(AC11,Ba1,Bb2),(AC11,Ba1,Bb3),(AC11,Ba1,Bb4),(AC11,Ba1,Bb5),(AC11,Ba1,Bb6),(AC11,Ba2,Bb1),(AC11,Ba2,Bb2),(AC11,Ba2,Bb3),(AC11,Ba2,Bb4),(AC11,Ba2,Bb5),(AC11,Ba2,Bb6),(AC11,Ba3,Bb1),(AC11,Ba3,Bb2),(AC11,Ba3,Bb3),(AC11,Ba3,Bb4),(AC11,Ba3,Bb5),(AC11,Ba3,Bb6),(AC11,Ba4,Bb1),(AC11,Ba4,Bb2),(AC11,Ba4,Bb3),(AC11,Ba4,Bb4),(AC11,Ba4,Bb5),(AC11,Ba4,Bb6),(AC11,Ba5,Bb1),(AC11,Ba5,Bb2),(AC11,Ba5,Bb3),(AC11,Ba5,Bb4),(AC11,Ba5,Bb5),(AC11,Ba5,Bb6),(AC11,Ba6,Bb1),(AC11,Ba6,Bb2),(AC11,Ba6,Bb3),(AC11,Ba6,Bb4),(AC11,Ba6,Bb5),(AC11,Ba6,Bb6),(AC11,Ba7,Bb1),(AC11,Ba7,Bb2),(AC11,Ba7,Bb3),(AC11,Ba7,Bb4),(AC11,Ba7,Bb5),(AC11,Ba7,Bb6),(AC12,Ba1,Bb1),(AC12,Ba1,Bb2),(AC12,Ba1,Bb3),(AC12,Ba1,Bb4),(AC12,Ba1,Bb5),(AC12,Ba1,Bb6),(AC12,Ba2,Bb1),(AC12,Ba2,Bb2),(AC12,Ba2,Bb3),(AC12,Ba2,Bb4),(AC12,Ba2,Bb5),(AC12,Ba2,Bb6),(AC12,Ba3,Bb1),(AC12,Ba3,Bb2),(AC12,Ba3,Bb3),(AC12,Ba3,Bb4),(AC12,Ba3,Bb5),(AC12,Ba3,Bb6),(AC12,Ba4,Bb1),(AC12,Ba4,Bb2),(AC12,Ba4,Bb3),(AC12,Ba4,Bb4),(AC12,Ba4,Bb5),(AC12,Ba4,Bb6),(AC12,Ba5,Bb1),(AC12,Ba5,Bb2),(AC12,Ba5,Bb3),(AC12,Ba5,Bb4),(AC12,Ba5,Bb5),(AC12,Ba5,Bb6),(AC12,Ba6,Bb1),(AC12,Ba6,Bb2),(AC12,Ba6,Bb3),(AC12,Ba6,Bb4),(AC12,Ba6,Bb5),(AC12,Ba6,Bb6),(AC12,Ba7,Bb1),(AC12,Ba7,Bb2),(AC12,Ba7,Bb3),(AC12,Ba7,Bb4),(AC12,Ba7,Bb5),(AC12,Ba7,Bb6),(AC13,Ba1,Bb1),(AC13,Ba1,Bb2),(AC13,Ba1,Bb3),(AC13,Ba1,Bb4),(AC13,Ba1,Bb5),(AC13,Ba1,Bb6),(AC13,Ba2,Bb1),(AC13,Ba2,Bb2),(AC13,Ba2,Bb3),(AC13,Ba2,Bb4),(AC13,Ba2,Bb5),(AC13,Ba2,Bb6),(AC13,Ba3,Bb1),(AC13,Ba3,Bb2),(AC13,Ba3,Bb3),(AC13,Ba3,Bb4),(AC13,Ba3,Bb5),(AC13,Ba3,Bb6),(AC13,Ba4,Bb1),(AC13,Ba4,Bb2),(AC13,Ba4,Bb3),(AC13,Ba4,Bb4),(AC13,Ba4,Bb5),(AC13,Ba4,Bb6),(AC13,Ba5,Bb1),(AC13,Ba5,Bb2),(AC13,Ba5,Bb3),(AC13,Ba5,Bb4),(AC13,Ba5,Bb5),(AC13,Ba5,Bb6),(AC13,Ba6,Bb1),(AC13,Ba6,Bb2),(AC13,Ba6,Bb3),(AC13,Ba6,Bb4),(AC13,Ba6,Bb5),(AC13,Ba6,Bb6),(AC13,Ba7,Bb1),(AC13,Ba7,Bb2),(AC13,Ba7,Bb3),(AC13,Ba7,Bb4),(AC13,Ba7,Bb5),(AC13,Ba7,Bb6),(AC14,Ba1,Bb1),(AC14,Ba1,Bb2),(AC14,Ba1,Bb3),(AC14,Ba1,Bb4),(AC14,Ba1,Bb5),(AC14,Ba1,Bb6),(AC14,Ba2,Bb1),(AC14,Ba2,Bb2),(AC14,Ba2,Bb3),(AC14,Ba2,Bb4),(AC14,Ba2,Bb5),(AC14,Ba2,Bb6),(AC14,Ba3,Bb1),(AC14,Ba3,Bb2),(AC14,Ba3,Bb3),(AC14,Ba3,Bb4),(AC14,Ba3,Bb5),(AC14,Ba3,Bb6),(AC14,Ba4,Bb1),(AC14,Ba4,Bb2),(AC14,Ba4,Bb3),(AC14,Ba4,Bb4),(AC14,Ba4,Bb5),(AC14,Ba4,Bb6),(AC14,Ba5,Bb1),(AC14,Ba5,Bb2),(AC14,Ba5,Bb3),(AC14,Ba5,Bb4),(AC14,Ba5,Bb5),(AC14,Ba5,Bb6),(AC14,Ba6,Bb1),(AC14,Ba6,Bb2),(AC14,Ba6,Bb3),(AC14,Ba6,Bb4),(AC14,Ba6,Bb5),(AC14,Ba6,Bb6),(AC14,Ba7,Bb1),(AC14,Ba7,Bb2),(AC14,Ba7,Bb3),(AC14,Ba7,Bb4),(AC14,Ba7,Bb5),(AC14,Ba7,Bb6),(AC15,Ba1,Bb1),(AC15,Ba1,Bb2),(AC15,Ba1,Bb3),(AC15,Ba1,Bb4),(AC15,Ba1,Bb5),(AC15,Ba1,Bb6),(AC15,Ba2,Bb1),(AC15,Ba2,Bb2),(AC15,Ba2,Bb3),(AC15,Ba2,Bb4),(AC15,Ba2,Bb5),(AC15,Ba2,Bb6),(AC15,Ba3,Bb1),(AC15,Ba3,Bb2),(AC15,Ba3,Bb3),(AC15,Ba3,Bb4),(AC15,Ba3,Bb5),(AC15,Ba3,Bb6),(AC15,Ba4,Bb1),(AC15,Ba4,Bb2),(AC15,Ba4,Bb3),(AC15,Ba4,Bb4),(AC15,Ba4,Bb5),(AC15,Ba4,Bb6),(AC15,Ba5,Bb1),(AC15,Ba5,Bb2),(AC15,Ba5,Bb3),(AC15,Ba5,Bb4),(AC15,Ba5,Bb5),(AC15,Ba5,Bb6),(AC15,Ba6,Bb1),(AC15,Ba6,Bb2),(AC15,Ba6,Bb3),(AC15,Ba6,Bb4),(AC15,Ba6,Bb5),(AC15,Ba6,Bb6),(AC15,Ba7,Bb1),(AC15,Ba7,Bb2),(AC15,Ba7,Bb3),(AC15,Ba7,Bb4),(AC15,Ba7,Bb5),(AC15,Ba7,Bb6),(AC16,Ba1,Bb1),(AC16,Ba1,Bb2),(AC16,Ba1,Bb3),(AC16,Ba1,Bb4),(AC16,Ba1,Bb5),(AC16,Ba1,Bb6),(AC16,Ba2,Bb1),(AC16,Ba2,Bb2),(AC16,Ba2,Bb3),(AC16,Ba2,Bb4),(AC16,Ba2,Bb5),(AC16,Ba2,Bb6),(AC16,Ba3,Bb1),(AC16,Ba3,Bb2),(AC16,Ba3,Bb3),(AC16,Ba3,Bb4),(AC16,Ba3,Bb5),(AC16,Ba3,Bb6),(AC16,Ba4,Bb1),(AC16,Ba4,Bb2),(AC16,Ba4,Bb3),(AC16,Ba4,Bb4),(AC16,Ba4,Bb5),(AC16,Ba4,Bb6),(AC16,Ba5,Bb1),(AC16,Ba5,Bb2),(AC16,Ba5,Bb3),(AC16,Ba5,Bb4),(AC16,Ba5,Bb5),(AC16,Ba5,Bb6),(AC16,Ba6,Bb1),(AC16,Ba6,Bb2),(AC16,Ba6,Bb3),(AC16,Ba6,Bb4),(AC16,Ba6,Bb5),(AC16,Ba6,Bb6),(AC16,Ba7,Bb1),(AC16,Ba7,Bb2),(AC16,Ba7,Bb3),(AC16,Ba7,Bb4),(AC16,Ba7,Bb5),(AC16,Ba7,Bb6),(AC17,Ba1,Bb1),(AC17,Ba1,Bb2),(AC17,Ba1,Bb3),(AC17,Ba1,Bb4),(AC17,Ba1,Bb5),(AC17,Ba1,Bb6),(AC17,Ba2,Bb1),(AC17,Ba2,Bb2),(AC17,Ba2,Bb3),(AC17,Ba2,Bb4),(AC17,Ba2,Bb5),(AC17,Ba2,Bb6),(AC17,Ba3,Bb1),(AC17,Ba3,Bb2),(AC17,Ba3,Bb3),(AC17,Ba3,Bb4),(AC17,Ba3,Bb5),(AC17,Ba3,Bb6),(AC17,Ba4,Bb1),(AC17,Ba4,Bb2),(AC17,Ba4,Bb3),(AC17,Ba4,Bb4),(AC17,Ba4,Bb5),(AC17,Ba4,Bb6),(AC17,Ba5,Bb1),(AC17,Ba5,Bb2),(AC17,Ba5,Bb3),(AC17,Ba5,Bb4),(AC17,Ba5,Bb5),(AC17,Ba5,Bb6),(AC17,Ba6,Bb1),(AC17,Ba6,Bb2),(AC17,Ba6,Bb3),(AC17,Ba6,Bb4),(AC17,Ba6,Bb5),(
AC17,Ba6,Bb6),(AC17,Ba7,Bb1),(AC17,Ba7,Bb2),(AC17,Ba7,Bb3),(AC17,Ba7,Bb4),(AC17,Ba7,Bb5),(AC17,Ba7,Bb6),(AC18,Ba1,Bb1),(AC18,Ba1,Bb2),(AC18,Ba1,Bb3),(AC18,Ba1,Bb4),(AC18,Ba1,Bb5),(AC18,Ba1,Bb6),(AC18,Ba2,Bb1),(AC18,Ba2,Bb2),(AC18,Ba2,Bb3),(AC18,Ba2,Bb4),(AC18,Ba2,Bb5),(AC18,Ba2,Bb6),(AC18,Ba3,Bb1),(AC18,Ba3,Bb2),(AC18,Ba3,Bb3),(AC18,Ba3,Bb4),(AC18,Ba3,Bb5),(AC18,Ba3,Bb6),(AC18,Ba4,Bb1),(AC18,Ba4,Bb2),(AC18,Ba4,Bb3),(AC18,Ba4,Bb4),(AC18,Ba4,Bb5),(AC18,Ba4,Bb6),(AC18,Ba5,Bb1),(AC18,Ba5,Bb2),(AC18,Ba5,Bb3),(AC18,Ba5,Bb4),(AC18,Ba5,Bb5),(AC18,Ba5,Bb6),(AC18,Ba6,Bb1),(AC18,Ba6,Bb2),(AC18,Ba6,Bb3),(AC18,Ba6,Bb4),(AC18,Ba6,Bb5),(AC18,Ba6,Bb6),(AC18,Ba7,Bb1),(AC18,Ba7,Bb2),(AC18,Ba7,Bb3),(AC18,Ba7,Bb4),(AC18,Ba7,Bb5),(AC18,Ba7,Bb6),(AC19,Ba1,Bb1),(AC19,Ba1,Bb2),(AC19,Ba1,Bb3),(AC19,Ba1,Bb4),(AC19,Ba1,Bb5),(AC19,Ba1,Bb6),(AC19,Ba2,Bb1),(AC19,Ba2,Bb2),(AC19,Ba2,Bb3),(AC19,Ba2,Bb4),(AC19,Ba2,Bb5),(AC19,Ba2,Bb6),(AC19,Ba3,Bb1),(AC19,Ba3,Bb2),(AC19,Ba3,Bb3),(AC19,Ba3,Bb4),(AC19,Ba3,Bb5),(AC19,Ba3,Bb6),(AC19,Ba4,Bb1),(AC19,Ba4,Bb2),(AC19,Ba4,Bb3),(AC19,Ba4,Bb4),(AC19,Ba4,Bb5),(AC19,Ba4,Bb6),(AC19,Ba5,Bb1),(AC19,Ba5,Bb2),(AC19,Ba5,Bb3),(AC19,Ba5,Bb4),(AC19,Ba5,Bb5),(AC19,Ba5,Bb6),(AC19,Ba6,Bb1),(AC19,Ba6,Bb2),(AC19,Ba6,Bb3),(AC19,Ba6,Bb4),(AC19,Ba6,Bb5),(AC19,Ba6,Bb6),(AC19,Ba7,Bb1),(AC19,Ba7,Bb2),(AC19,Ba7,Bb3),(AC19,Ba7,Bb4),(AC19,Ba7,Bb5),(AC19,Ba7,Bb6),(AC20,Ba1,Bb1),(AC20,Ba1,Bb2),(AC20,Ba1,Bb3),(AC20,Ba1,Bb4),(AC20,Ba1,Bb5),(AC20,Ba1,Bb6),(AC20,Ba2,Bb1),(AC20,Ba2,Bb2),(AC20,Ba2,Bb3),(AC20,Ba2,Bb4),(AC20,Ba2,Bb5),(AC20,Ba2,Bb6),(AC20,Ba3,Bb1),(AC20,Ba3,Bb2),(AC20,Ba3,Bb3),(AC20,Ba3,Bb4),(AC20,Ba3,Bb5),(AC20,Ba3,Bb6),(AC20,Ba4,Bb1),(AC20,Ba4,Bb2),(AC20,Ba4,Bb3),(AC20,Ba4,Bb4),(AC20,Ba4,Bb5),(AC20,Ba4,Bb6),(AC20,Ba5,Bb1),(AC20,Ba5,Bb2),(AC20,Ba5,Bb3),(AC20,Ba5,Bb4),(AC20,Ba5,Bb5),(AC20,Ba5,Bb6),(AC20,Ba6,Bb1),(AC20,Ba6,Bb2),(AC20,Ba6,Bb3),(AC20,Ba6,Bb4),(AC20,Ba6,Bb5),(AC20,Ba6,Bb6),(AC20,Ba7,Bb1),(AC20,Ba7,Bb2),(AC20,Ba7,Bb3),(AC20,Ba7,Bb4),(AC20,Ba7,Bb5),(AC20,Ba7,Bb6),(AC21,Ba1,Bb1),(AC21,Ba1,Bb2),(AC21,Ba1,Bb3),(AC21,Ba1,Bb4),(AC21,Ba1,Bb5),(AC21,Ba1,Bb6),(AC21,Ba2,Bb1),(AC21,Ba2,Bb2),(AC21,Ba2,Bb3),(AC21,Ba2,Bb4),(AC21,Ba2,Bb5),(AC21,Ba2,Bb6),(AC21,Ba3,Bb1),(AC21,Ba3,Bb2),(AC21,Ba3,Bb3),(AC21,Ba3,Bb4),(AC21,Ba3,Bb5),(AC21,Ba3,Bb6),(AC21,Ba4,Bb1),(AC21,Ba4,Bb2),(AC21,Ba4,Bb3),(AC21,Ba4,Bb4),(AC21,Ba4,Bb5),(AC21,Ba4,Bb6),(AC21,Ba5,Bb1),(AC21,Ba5,Bb2),(AC21,Ba5,Bb3),(AC21,Ba5,Bb4),(AC21,Ba5,Bb5),(AC21,Ba5,Bb6),(AC21,Ba6,Bb1),(AC21,Ba6,Bb2),(AC21,Ba6,Bb3),(AC21,Ba6,Bb4),(AC21,Ba6,Bb5),(AC21,Ba6,Bb6),(AC21,Ba7,Bb1),(AC21,Ba7,Bb2),(AC21,Ba7,Bb3),(AC21,Ba7,Bb4),(AC21,Ba7,Bb5),(AC21,Ba7,Bb6).
One embodiment of the compound of the present invention has the following group in the following general formula (III).
Figure JPOXMLDOC01-appb-C000255
The compound whose combination of AC, Ba, and Bb is the following (AC, Ba, Bb).
(AC, Ba, Bb) = (AC1, Ba1, Bb1), (AC1, Ba1, Bb2), (AC1, Ba1, Bb3), (AC1, Ba1, Bb4), (AC1, Ba1, Bb5), (AC1 , Ba1, Bb6), (AC1, Ba2, Bb1), (AC1, Ba2, Bb2), (AC1, Ba2, Bb3), (AC1, Ba2, Bb4), (AC1, Ba2, Bb5), (AC1, Ba2 , Bb6), (AC1, Ba3, Bb1), (AC1, Ba3, Bb2), (AC1, Ba3, Bb3), (AC1, Ba3, Bb4), (AC1, Ba3, Bb5), (AC1, Ba3, Bb6 ), (AC1, Ba4, Bb1), (AC1, Ba4, Bb2), (AC1, Ba4, Bb3), (AC1, Ba4, Bb4), (AC1, Ba4, Bb5), (AC1, Ba4, Bb6), (AC1, Ba5, Bb1), (AC1, Ba5, Bb2), (AC1, Ba5, Bb3), (AC1, Ba5, Bb4), (AC1, Ba5, Bb5), (AC1, Ba5, Bb6), (AC1 , Ba6, Bb1), (AC1, Ba6, Bb2), (AC1, Ba6, Bb3), (AC1, Ba6, Bb4), (AC1, Ba6, Bb5), (AC1, Ba6, Bb6), (AC1, Ba7 , Bb1), (AC1, Ba7, Bb2), (AC1, Ba7, Bb3), (AC1, Ba7, Bb4), (AC1, Ba7, Bb5), (AC1, Ba7, Bb6), (AC2, Ba1, Bb1 ), (AC2, Ba1, Bb2), (AC2, Ba1, Bb3), (AC2, Ba1, Bb4), (AC2, Ba1, Bb5), (AC2, Ba1, Bb6), (AC2, Ba2, Bb1), (AC2, Ba2, Bb2), (AC2, Ba2, Bb3), (AC2, Ba2, Bb4), (AC2, Ba2, Bb5), (AC2, Ba2, Bb6), (AC2, Ba3, Bb1), (AC2 , Ba3, Bb2), (AC2, Ba3, Bb3), (AC2, Ba3, Bb4), (AC2, Ba3, Bb5), (AC2, Ba3, Bb6), (AC2, Ba4, Bb1), (AC2, Ba4 , Bb2), (AC2, Ba4, Bb3), (AC2, Ba4, Bb4), (AC2, Ba4, Bb5), (AC2, Ba4, Bb6), (AC2, Ba5, Bb1), (AC2, Ba5, Bb2 ), (AC2, Ba5, Bb3), (AC2, Ba5, Bb4), (AC2, Ba 5, Bb5), (AC2, Ba5, Bb6), (AC2, Ba6, Bb1), (AC2, Ba6, Bb2), (AC2, Ba6, Bb3), (AC2, Ba6, Bb4), (AC2, Ba6, (Bb5), (AC2, Ba6, Bb6), (AC2, Ba7, Bb1), (AC2, Ba7, Bb2), (AC2, Ba7, Bb3), (AC2, Ba7, Bb4), (AC2, Ba7, Bb5) , (AC2, Ba7, Bb6), (AC3, Ba1, Bb1), (AC3, Ba1, Bb2), (AC3, Ba1, Bb3), (AC3, Ba1, Bb4), (AC3, Ba1, Bb5), ( (AC3, Ba1, Bb6), (AC3, Ba2, Bb1), (AC3, Ba2, Bb2), (AC3, Ba2, Bb3), (AC3, Ba2, Bb4), (AC3, Ba2, Bb5), (AC3, (Ba2, Bb6), (AC3, Ba3, Bb1), (AC3, Ba3, Bb2), (AC3, Ba3, Bb3), (AC3, Ba3, Bb4), (AC3, Ba3, Bb5), (AC3, Ba3, (Bb6), (AC3, Ba4, Bb1), (AC3, Ba4, Bb2), (AC3, Ba4, Bb3), (AC3, Ba4, Bb4), (AC3, Ba4, Bb5), (AC3, Ba4, Bb6) , (AC3, Ba5, Bb1), (AC3, Ba5, Bb2), (AC3, Ba5, Bb3), (AC3, Ba5, Bb4), (AC3, Ba5, Bb5), (AC3, Ba5, Bb6), ( (AC3, Ba6, Bb1), (AC3, Ba6, Bb2), (AC3, Ba6, Bb3), (AC3, Ba6, Bb4), (AC3, Ba6, Bb5), (AC3, Ba6, Bb6), (AC3, (Ba7, Bb1), (AC3, Ba7, Bb2), (AC3, Ba7, Bb3), (AC3, Ba7, Bb4), (AC3, Ba7, Bb5), (AC3, Ba7, Bb6), (AC4, Ba1, (Bb1), (AC4, Ba1, Bb2), (AC4, Ba1, Bb3), (AC4, Ba1, Bb4), (AC4, Ba1, Bb5), (AC4, Ba1, Bb6), (AC4, Ba2, Bb1) , (AC4, Ba2, Bb2), (AC4, Ba2, Bb3), (AC4, Ba2, Bb4), (AC4, Ba2, Bb5), (AC4, Ba2, Bb6), (AC4, Ba3, Bb1), ( (AC4, Ba3, Bb2), (AC4, Ba3, Bb3), (AC4, Ba3, Bb4) , (AC4, Ba3, Bb5), (AC4, Ba3, Bb6), (AC4, Ba4, Bb1), (AC4, Ba4, Bb2), (AC4, Ba4, Bb3), (AC4, Ba4, Bb4), ( (AC4, Ba4, Bb5), (AC4, Ba4, Bb6), (AC4, Ba5, Bb1), (AC4, Ba5, Bb2), (AC4, Ba5, Bb3), (AC4, Ba5, Bb4), (AC4, (Ba5, Bb5), (AC4, Ba5, Bb6), (AC4, Ba6, Bb1), (AC4, Ba6, Bb2), (AC4, Ba6, Bb3), (AC4, Ba6, Bb4), (AC4, Ba6, (Bb5), (AC4, Ba6, Bb6), (AC4, Ba7, Bb1), (AC4, Ba7, Bb2), (AC4, Ba7, Bb3), (AC4, Ba7, Bb4), (AC4, Ba7, Bb5) , (AC4, Ba7, Bb6), (AC5, Ba1, Bb1), (AC5, Ba1, Bb2), (AC5, Ba1, Bb3), (AC5, Ba1, Bb4), (AC5, Ba1, Bb5), ( (AC5, Ba1, Bb6), (AC5, Ba2, Bb1), (AC5, Ba2, Bb2), (AC5, Ba2, Bb3), (AC5, Ba2, Bb4), (AC5, Ba2, Bb5), (AC5, (Ba2, Bb6), (AC5, Ba3, Bb1), (AC5, Ba3, Bb2), (AC5, Ba3, Bb3), (AC5, Ba3, Bb4), (AC5, Ba3, Bb5), (AC5, Ba3, (Bb6), (AC5, Ba4, Bb1), (AC5, Ba4, Bb2), (AC5, Ba4, Bb3), (AC5, Ba4, Bb4), (AC5, Ba4, Bb5), (AC5, Ba4, Bb6) , (AC5, Ba5, Bb1), (AC5, Ba5, Bb2), (AC5, Ba5, Bb3), (AC5, Ba5, Bb4), (AC5, Ba5, Bb5), (AC5, Ba5, Bb6), ( (AC5, Ba6, Bb1), (AC5, Ba6, Bb2), (AC5, Ba6, Bb3), (AC5, Ba6, Bb4), (AC5, Ba6, Bb5), (AC5, Ba6, Bb6), (AC5, (Ba7, Bb1), (AC5, Ba7, Bb2), (AC5, Ba7, Bb3), (AC5, Ba7, Bb4), (AC5, Ba7, Bb5), (AC5, Ba7, Bb6), (AC6, Ba1, Bb1), (AC6, Ba1, Bb2), (AC6, Ba1, Bb3), (AC6, (Ba1, Bb4), (AC6, Ba1, Bb5), (AC6, Ba1, Bb6), (AC6, Ba2, Bb1), (AC6, Ba2, Bb2), (AC6, Ba2, Bb3), (AC6, Ba2, (Bb4), (AC6, Ba2, Bb5), (AC6, Ba2, Bb6), (AC6, Ba3, Bb1), (AC6, Ba3, Bb2), (AC6, Ba3, Bb3), (AC6, Ba3, Bb4) , (AC6, Ba3, Bb5), (AC6, Ba3, Bb6), (AC6, Ba4, Bb1), (AC6, Ba4, Bb2), (AC6, Ba4, Bb3), (AC6, Ba4, Bb4), ( (AC6, Ba4, Bb5), (AC6, Ba4, Bb6), (AC6, Ba5, Bb1), (AC6, Ba5, Bb2), (AC6, Ba5, Bb3), (AC6, Ba5, Bb4), (AC6, (Ba5, Bb5), (AC6, Ba5, Bb6), (AC6, Ba6, Bb1), (AC6, Ba6, Bb2), (AC6, Ba6, Bb3), (AC6, Ba6, Bb4), (AC6, Ba6, (Bb5), (AC6, Ba6, Bb6), (AC6, Ba7, Bb1), (AC6, Ba7, Bb2), (AC6, Ba7, Bb3), (AC6, Ba7, Bb4), (AC6, Ba7, Bb5) , (AC6, Ba7, Bb6), (AC7, Ba1, Bb1), (AC7, Ba1, Bb2), (AC7, Ba1, Bb3), (AC7, Ba1, Bb4), (AC7, Ba1, Bb5), ( (AC7, Ba1, Bb6), (AC7, Ba2, Bb1), (AC7, Ba2, Bb2), (AC7, Ba2, Bb3), (AC7, Ba2, Bb4), (AC7, Ba2, Bb5), (AC7, (Ba2, Bb6), (AC7, Ba3, Bb1), (AC7, Ba3, Bb2), (AC7, Ba3, Bb3), (AC7, Ba3, Bb4), (AC7, Ba3, Bb5), (AC7, Ba3, (Bb6), (AC7, Ba4, Bb1), (AC7, Ba4, Bb2), (AC7, Ba4, Bb3), (AC7, Ba4, Bb4), (AC7, Ba4, Bb5), (AC7, Ba4, Bb6) , (AC7, Ba5, Bb1), (AC7, Ba5, Bb2), (AC7, Ba5, Bb3), (AC7, Ba5, Bb4), (AC7, Ba5, Bb5), (AC7, Ba5, Bb6), ( (AC7, Ba6, Bb1), (AC7, Ba6, Bb2), (AC7, Ba6, Bb 3), (AC7, Ba6, Bb4), (AC7, Ba6, Bb5), (AC7, Ba6, Bb6), (AC7, Ba7, Bb1), (AC7, Ba7, Bb2), (AC7, Ba7, Bb3) , (AC7, Ba7, Bb4), (AC7, Ba7, Bb5), (AC7, Ba7, Bb6), (AC8, Ba1, Bb1), (AC8, Ba1, Bb2), (AC8, Ba1, Bb3), ( (AC8, Ba1, Bb4), (AC8, Ba1, Bb5), (AC8, Ba1, Bb6), (AC8, Ba2, Bb1), (AC8, Ba2, Bb2), (AC8, Ba2, Bb3), (AC8, (Ba2, Bb4), (AC8, Ba2, Bb5), (AC8, Ba2, Bb6), (AC8, Ba3, Bb1), (AC8, Ba3, Bb2), (AC8, Ba3, Bb3), (AC8, Ba3, (Bb4), (AC8, Ba3, Bb5), (AC8, Ba3, Bb6), (AC8, Ba4, Bb1), (AC8, Ba4, Bb2), (AC8, Ba4, Bb3), (AC8, Ba4, Bb4) , (AC8, Ba4, Bb5), (AC8, Ba4, Bb6), (AC8, Ba5, Bb1), (AC8, Ba5, Bb2), (AC8, Ba5, Bb3), (AC8, Ba5, Bb4), ( (AC8, Ba5, Bb5), (AC8, Ba5, Bb6), (AC8, Ba6, Bb1), (AC8, Ba6, Bb2), (AC8, Ba6, Bb3), (AC8, Ba6, Bb4), (AC8, (Ba6, Bb5), (AC8, Ba6, Bb6), (AC8, Ba7, Bb1), (AC8, Ba7, Bb2), (AC8, Ba7, Bb3), (AC8, Ba7, Bb4), (AC8, Ba7, (Bb5), (AC8, Ba7, Bb6), (AC9, Ba1, Bb1), (AC9, Ba1, Bb2), (AC9, Ba1, Bb3), (AC9, Ba1, Bb4), (AC9, Ba1, Bb5) , (AC9, Ba1, Bb6), (AC9, Ba2, Bb1), (AC9, Ba2, Bb2), (AC9, Ba2, Bb3), (AC9, Ba2, Bb4), (AC9, Ba2, Bb5), ( (AC9, Ba2, Bb6), (AC9, Ba3, Bb1), (AC9, Ba3, Bb2), (AC9, Ba3, Bb3), (AC9, Ba3, Bb4), (AC9, Ba3, Bb5), (AC9, (Ba3, Bb6), (AC9, Ba4, Bb1), (AC9, Ba4, Bb2), (AC 9, Ba4, Bb3), (AC9, Ba4, Bb4), (AC9, Ba4, Bb5), (AC9, Ba4, Bb6), (AC9, Ba5, Bb1), (AC9, Ba5, Bb2), (AC9, (Ba5, Bb3), (AC9, Ba5, Bb4), (AC9, Ba5, Bb5), (AC9, Ba5, Bb6), (AC9, Ba6, Bb1), (AC9, Ba6, Bb2), (AC9, Ba6, (Bb3), (AC9, Ba6, Bb4), (AC9, Ba6, Bb5), (AC9, Ba6, Bb6), (AC9, Ba7, Bb1), (AC9, Ba7, Bb2), (AC9, Ba7, Bb3) , (AC9, Ba7, Bb4), (AC9, Ba7, Bb5), (AC9, Ba7, Bb6), (AC10, Ba1, Bb1), (AC10, Ba1, Bb2), (AC10, Ba1, Bb3), ( (AC10, Ba1, Bb4), (AC10, Ba1, Bb5), (AC10, Ba1, Bb6), (AC10, Ba2, Bb1), (AC10, Ba2, Bb2), (AC10, Ba2, Bb3), (AC10, (Ba2, Bb4), (AC10, Ba2, Bb5), (AC10, Ba2, Bb6), (AC10, Ba3, Bb1), (AC10, Ba3, Bb2), (AC10, Ba3, Bb3), (AC10, Ba3, (Bb4), (AC10, Ba3, Bb5), (AC10, Ba3, Bb6), (AC10, Ba4, Bb1), (AC10, Ba4, Bb2), (AC10, Ba4, Bb3), (AC10, Ba4, Bb4) , (AC10, Ba4, Bb5), (AC10, Ba4, Bb6), (AC10, Ba5, Bb1), (AC10, Ba5, Bb2), (AC10, Ba5, Bb3), (AC10, Ba5, Bb4), ( (AC10, Ba5, Bb5), (AC10, Ba5, Bb6), (AC10, Ba6, Bb1), (AC10, Ba6, Bb2), (AC10, Ba6, Bb3), (AC10, Ba6, Bb4), (AC10, (Ba6, Bb5), (AC10, Ba6, Bb6), (AC10, Ba7, Bb1), (AC10, Ba7, Bb2), (AC10, Ba7, Bb3), (AC10, Ba7, Bb4), (AC10, Ba7, (Bb5), (AC10, Ba7, Bb6), (AC11, Ba1, Bb1), (AC11, Ba1, Bb2), (AC11, Ba1, Bb3), (AC11, Ba1, Bb4), (AC11 , Ba1, Bb5), (AC11, Ba1, Bb6), (AC11, Ba2, Bb1), (AC11, Ba2, Bb2), (AC11, Ba2, Bb3), (AC11, Ba2, Bb4), (AC11, Ba2 , Bb5), (AC11, Ba2, Bb6), (AC11, Ba3, Bb1), (AC11, Ba3, Bb2), (AC11, Ba3, Bb3), (AC11, Ba3, Bb4), (AC11, Ba3, Bb5 ), (AC11, Ba3, Bb6), (AC11, Ba4, Bb1), (AC11, Ba4, Bb2), (AC11, Ba4, Bb3), (AC11, Ba4, Bb4), (AC11, Ba4, Bb5), (AC11, Ba4, Bb6), (AC11, Ba5, Bb1), (AC11, Ba5, Bb2), (AC11, Ba5, Bb3), (AC11, Ba5, Bb4), (AC11, Ba5, Bb5), (AC11 , Ba5, Bb6), (AC11, Ba6, Bb1), (AC11, Ba6, Bb2), (AC11, Ba6, Bb3), (AC11, Ba6, Bb4), (AC11, Ba6, Bb5), (AC11, Ba6 , Bb6), (AC11, Ba7, Bb1), (AC11, Ba7, Bb2), (AC11, Ba7, Bb3), (AC11, Ba7, Bb4), (AC11, Ba7, Bb5), (AC11, Ba7, Bb6 ), (AC12, Ba1, Bb1), (AC12, Ba1, Bb2), (AC12, Ba1, Bb3), (AC12, Ba1, Bb4), (AC12, Ba1, Bb5), (AC12, Ba1, Bb6), (AC12, Ba2, Bb1), (AC12, Ba2, Bb2), (AC12, Ba2, Bb3), (AC12, Ba2, Bb4), (AC12, Ba2, Bb5), (AC12, Ba2, Bb6), (AC12 , Ba3, Bb1), (AC12, Ba3, Bb2), (AC12, Ba3, Bb3), (AC12, Ba3, Bb4), (AC12, Ba3, Bb5), (AC12, Ba3, Bb6), (AC12, Ba4 , Bb1), (AC12, Ba4, Bb2), (AC12, Ba4, Bb3), (AC12, Ba4, Bb4), (AC12, Ba4, Bb5), (AC12, Ba4, Bb6), (AC12, Ba5, Bb1 ), (AC12, Ba5, Bb2), (AC12, Ba5, Bb3), (AC12, Ba5, Bb4), (AC12, Ba5, Bb5), (AC12, Ba5, Bb6), (AC12, Ba6, Bb1), (AC12, Ba6, Bb2), (AC12, Ba6, Bb3), (AC12, Ba6, Bb4), (AC12, Ba6, Bb5), (AC12 , Ba6, Bb6), (AC12, Ba7, Bb1), (AC12, Ba7, Bb2), (AC12, Ba7, Bb3), (AC12, Ba7, Bb4), (AC12, Ba7, Bb5), (AC12, Ba7 , Bb6), (AC13, Ba1, Bb1), (AC13, Ba1, Bb2), (AC13, Ba1, Bb3), (AC13, Ba1, Bb4), (AC13, Ba1, Bb5), (AC13, Ba1, Bb6 ), (AC13, Ba2, Bb1), (AC13, Ba2, Bb2), (AC13, Ba2, Bb3), (AC13, Ba2, Bb4), (AC13, Ba2, Bb5), (AC13, Ba2, Bb6), (AC13, Ba3, Bb1), (AC13, Ba3, Bb2), (AC13, Ba3, Bb3), (AC13, Ba3, Bb4), (AC13, Ba3, Bb5), (AC13, Ba3, Bb6), (AC13 , Ba4, Bb1), (AC13, Ba4, Bb2), (AC13, Ba4, Bb3), (AC13, Ba4, Bb4), (AC13, Ba4, Bb5), (AC13, Ba4, Bb6), (AC13, Ba5 , Bb1), (AC13, Ba5, Bb2), (AC13, Ba5, Bb3), (AC13, Ba5, Bb4), (AC13, Ba5, Bb5), (AC13, Ba5, Bb6), (AC13, Ba6, Bb1 ), (AC13, Ba6, Bb2), (AC13, Ba6, Bb3), (AC13, Ba6, Bb4), (AC13, Ba6, Bb5), (AC13, Ba6, Bb6), (AC13, Ba7, Bb1), (AC13, Ba7, Bb2), (AC13, Ba7, Bb3), (AC13, Ba7, Bb4), (AC13, Ba7, Bb5), (AC13, Ba7, Bb6), (AC14, Ba1, Bb1), (AC14 , Ba1, Bb2), (AC14, Ba1, Bb3), (AC14, Ba1, Bb4), (AC14, Ba1, Bb5), (AC14, Ba1, Bb6), (AC14, Ba2, Bb1), (AC14, Ba2 , Bb2), (AC14, Ba2, Bb3), (AC14, Ba2, Bb4), (AC14, Ba2, Bb5), (AC14, Ba2, (Bb6), (AC14, Ba3, Bb1), (AC14, Ba3, Bb2), (AC14, Ba3, Bb3), (AC14, Ba3, Bb4), (AC14, Ba3, Bb5), (AC14, Ba3, Bb6) , (AC14, Ba4, Bb1), (AC14, Ba4, Bb2), (AC14, Ba4, Bb3), (AC14, Ba4, Bb4), (AC14, Ba4, Bb5), (AC14, Ba4, Bb6), ( (AC14, Ba5, Bb1), (AC14, Ba5, Bb2), (AC14, Ba5, Bb3), (AC14, Ba5, Bb4), (AC14, Ba5, Bb5), (AC14, Ba5, Bb6), (AC14, (Ba6, Bb1), (AC14, Ba6, Bb2), (AC14, Ba6, Bb3), (AC14, Ba6, Bb4), (AC14, Ba6, Bb5), (AC14, Ba6, Bb6), (AC14, Ba7, (Bb1), (AC14, Ba7, Bb2), (AC14, Ba7, Bb3), (AC14, Ba7, Bb4), (AC14, Ba7, Bb5), (AC14, Ba7, Bb6), (AC15, Ba1, Bb1) , (AC15, Ba1, Bb2), (AC15, Ba1, Bb3), (AC15, Ba1, Bb4), (AC15, Ba1, Bb5), (AC15, Ba1, Bb6), (AC15, Ba2, Bb1), ( (AC15, Ba2, Bb2), (AC15, Ba2, Bb3), (AC15, Ba2, Bb4), (AC15, Ba2, Bb5), (AC15, Ba2, Bb6), (AC15, Ba3, Bb1), (AC15, (Ba3, Bb2), (AC15, Ba3, Bb3), (AC15, Ba3, Bb4), (AC15, Ba3, Bb5), (AC15, Ba3, Bb6), (AC15, Ba4, Bb1), (AC15, Ba4, (Bb2), (AC15, Ba4, Bb3), (AC15, Ba4, Bb4), (AC15, Ba4, Bb5), (AC15, Ba4, Bb6), (AC15, Ba5, Bb1), (AC15, Ba5, Bb2) , (AC15, Ba5, Bb3), (AC15, Ba5, Bb4), (AC15, Ba5, Bb5), (AC15, Ba5, Bb6), (AC15, Ba6, Bb1), (AC15, Ba6, Bb2), ( (AC15, Ba6, Bb3), (AC15, Ba6, Bb4), (AC15, Ba6, Bb5), (AC15, Ba6, Bb6), (AC15 , Ba7, Bb1), (AC15, Ba7, Bb2), (AC15, Ba7, Bb3), (AC15, Ba7, Bb4), (AC15, Ba7, Bb5), (AC15, Ba7, Bb6), (AC16, Ba1 , Bb1), (AC16, Ba1, Bb2), (AC16, Ba1, Bb3), (AC16, Ba1, Bb4), (AC16, Ba1, Bb5), (AC16, Ba1, Bb6), (AC16, Ba2, Bb1 ), (AC16, Ba2, Bb2), (AC16, Ba2, Bb3), (AC16, Ba2, Bb4), (AC16, Ba2, Bb5), (AC16, Ba2, Bb6), (AC16, Ba3, Bb1), (AC16, Ba3, Bb2), (AC16, Ba3, Bb3), (AC16, Ba3, Bb4), (AC16, Ba3, Bb5), (AC16, Ba3, Bb6), (AC16, Ba4, Bb1), (AC16 , Ba4, Bb2), (AC16, Ba4, Bb3), (AC16, Ba4, Bb4), (AC16, Ba4, Bb5), (AC16, Ba4, Bb6), (AC16, Ba5, Bb1), (AC16, Ba5 , Bb2), (AC16, Ba5, Bb3), (AC16, Ba5, Bb4), (AC16, Ba5, Bb5), (AC16, Ba5, Bb6), (AC16, Ba6, Bb1), (AC16, Ba6, Bb2 ), (AC16, Ba6, Bb3), (AC16, Ba6, Bb4), (AC16, Ba6, Bb5), (AC16, Ba6, Bb6), (AC16, Ba7, Bb1), (AC16, Ba7, Bb2), (AC16, Ba7, Bb3), (AC16, Ba7, Bb4), (AC16, Ba7, Bb5), (AC16, Ba7, Bb6), (AC17, Ba1, Bb1), (AC17, Ba1, Bb2), (AC17 , Ba1, Bb3), (AC17, Ba1, Bb4), (AC17, Ba1, Bb5), (AC17, Ba1, Bb6), (AC17, Ba2, Bb1), (AC17, Ba2, Bb2), (AC17, Ba2 , Bb3), (AC17, Ba2, Bb4), (AC17, Ba2, Bb5), (AC17, Ba2, Bb6), (AC17, Ba3, Bb1), (AC17, Ba3, Bb2), (AC17, Ba3, Bb3 ), (AC17, Ba3, Bb4), (AC17, Ba3, Bb5), (AC17, Ba3, Bb6), (AC17, Ba4, Bb1), (AC17, Ba4, Bb2), (AC17, Ba4, Bb3), (AC17, Ba4, Bb4), (AC17, Ba4, Bb5), (AC17, Ba4, Bb6), (AC17, Ba5, Bb1), (AC17 , Ba5, Bb2), (AC17, Ba5, Bb3), (AC17, Ba5, Bb4), (AC17, Ba5, Bb5), (AC17, Ba5, Bb6), (AC17, Ba6, Bb1), (AC17, Ba6) , Bb2), (AC17, Ba6, Bb3), (AC17, Ba6, Bb4), (AC17, Ba6, Bb5), (
(AC17, Ba6, Bb6), (AC17, Ba7, Bb1), (AC17, Ba7, Bb2), (AC17, Ba7, Bb3), (AC17, Ba7, Bb4), (AC17, Ba7, Bb5), (AC17, (Ba7, Bb6), (AC18, Ba1, Bb1), (AC18, Ba1, Bb2), (AC18, Ba1, Bb3), (AC18, Ba1, Bb4), (AC18, Ba1, Bb5), (AC18, Ba1, (Bb6), (AC18, Ba2, Bb1), (AC18, Ba2, Bb2), (AC18, Ba2, Bb3), (AC18, Ba2, Bb4), (AC18, Ba2, Bb5), (AC18, Ba2, Bb6) , (AC18, Ba3, Bb1), (AC18, Ba3, Bb2), (AC18, Ba3, Bb3), (AC18, Ba3, Bb4), (AC18, Ba3, Bb5), (AC18, Ba3, Bb6), ( (AC18, Ba4, Bb1), (AC18, Ba4, Bb2), (AC18, Ba4, Bb3), (AC18, Ba4, Bb4), (AC18, Ba4, Bb5), (AC18, Ba4, Bb6), (AC18, (Ba5, Bb1), (AC18, Ba5, Bb2), (AC18, Ba5, Bb3), (AC18, Ba5, Bb4), (AC18, Ba5, Bb5), (AC18, Ba5, Bb6), (AC18, Ba6, (Bb1), (AC18, Ba6, Bb2), (AC18, Ba6, Bb3), (AC18, Ba6, Bb4), (AC18, Ba6, Bb5), (AC18, Ba6, Bb6), (AC18, Ba7, Bb1) , (AC18, Ba7, Bb2), (AC18, Ba7, Bb3), (AC18, Ba7, Bb4), (AC18, Ba7, Bb5), (AC18, Ba7, Bb6), (AC19, Ba1, Bb1), ( (AC19, Ba1, Bb2), (AC19, Ba1, Bb3), (AC19, Ba1, Bb4), (AC19, Ba1, Bb5), (AC19, Ba1, Bb6), (AC19, Ba2, Bb1), (AC19, (Ba2, Bb2), (AC19, Ba2, Bb3), (AC19, Ba2, Bb4), (AC19, Ba2, Bb5), (AC19, Ba2, Bb6), (AC19, Ba3, Bb1), (AC19, Ba3, (Bb2), (AC19, Ba3, Bb3), (AC19, Ba3, Bb4), (AC19, Ba3, Bb5), (AC19, Ba3, B b6), (AC19, Ba4, Bb1), (AC19, Ba4, Bb2), (AC19, Ba4, Bb3), (AC19, Ba4, Bb4), (AC19, Ba4, Bb5), (AC19, Ba4, Bb6) , (AC19, Ba5, Bb1), (AC19, Ba5, Bb2), (AC19, Ba5, Bb3), (AC19, Ba5, Bb4), (AC19, Ba5, Bb5), (AC19, Ba5, Bb6), ( (AC19, Ba6, Bb1), (AC19, Ba6, Bb2), (AC19, Ba6, Bb3), (AC19, Ba6, Bb4), (AC19, Ba6, Bb5), (AC19, Ba6, Bb6), (AC19, (Ba7, Bb1), (AC19, Ba7, Bb2), (AC19, Ba7, Bb3), (AC19, Ba7, Bb4), (AC19, Ba7, Bb5), (AC19, Ba7, Bb6), (AC20, Ba1, (Bb1), (AC20, Ba1, Bb2), (AC20, Ba1, Bb3), (AC20, Ba1, Bb4), (AC20, Ba1, Bb5), (AC20, Ba1, Bb6), (AC20, Ba2, Bb1) , (AC20, Ba2, Bb2), (AC20, Ba2, Bb3), (AC20, Ba2, Bb4), (AC20, Ba2, Bb5), (AC20, Ba2, Bb6), (AC20, Ba3, Bb1), ( (AC20, Ba3, Bb2), (AC20, Ba3, Bb3), (AC20, Ba3, Bb4), (AC20, Ba3, Bb5), (AC20, Ba3, Bb6), (AC20, Ba4, Bb1), (AC20, (Ba4, Bb2), (AC20, Ba4, Bb3), (AC20, Ba4, Bb4), (AC20, Ba4, Bb5), (AC20, Ba4, Bb6), (AC20, Ba5, Bb1), (AC20, Ba5, (Bb2), (AC20, Ba5, Bb3), (AC20, Ba5, Bb4), (AC20, Ba5, Bb5), (AC20, Ba5, Bb6), (AC20, Ba6, Bb1), (AC20, Ba6, Bb2) , (AC20, Ba6, Bb3), (AC20, Ba6, Bb4), (AC20, Ba6, Bb5), (AC20, Ba6, Bb6), (AC20, Ba7, Bb1), (AC20, Ba7, Bb2), ( (AC20, Ba7, Bb3), (AC20, Ba7, Bb4), (AC20, Ba7, Bb5), (AC20, Ba7, Bb6), (AC21, (Ba1, Bb1), (AC21, Ba1, Bb2), (AC21, Ba1, Bb3), (AC21, Ba1, Bb4), (AC21, Ba1, Bb5), (AC21, Ba1, Bb6), (AC21, Ba2, (Bb1), (AC21, Ba2, Bb2), (AC21, Ba2, Bb3), (AC21, Ba2, Bb4), (AC21, Ba2, Bb5), (AC21, Ba2, Bb6), (AC21, Ba3, Bb1) , (AC21, Ba3, Bb2), (AC21, Ba3, Bb3), (AC21, Ba3, Bb4), (AC21, Ba3, Bb5), (AC21, Ba3, Bb6), (AC21, Ba4, Bb1), ( (AC21, Ba4, Bb2), (AC21, Ba4, Bb3), (AC21, Ba4, Bb4), (AC21, Ba4, Bb5), (AC21, Ba4, Bb6), (AC21, Ba5, Bb1), (AC21, (Ba5, Bb2), (AC21, Ba5, Bb3), (AC21, Ba5, Bb4), (AC21, Ba5, Bb5), (AC21, Ba5, Bb6), (AC21, Ba6, Bb1), (AC21, Ba6, (Bb2), (AC21, Ba6, Bb3), (AC21, Ba6, Bb4), (AC21, Ba6, Bb5), (AC21, Ba6, Bb6), (AC21, Ba7, Bb1), (AC21, Ba7, Bb2) , (AC21, Ba7, Bb3), (AC21, Ba7, Bb4), (AC21, Ba7, Bb5), (AC21, Ba7, Bb6).

　本発明化合物の一つの態様は、以下の一般式（ＩＶ）および（Ｖ）において、以下の基を有するものである。

Figure JPOXMLDOC01-appb-C000256
One embodiment of the compound of the present invention has the following groups in the following general formulas (IV) and (V).
Figure JPOXMLDOC01-appb-C000256

Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000257

　AAC、BBa、BBbの組み合わせが、以下の（AAC、BBa、BBb）である化合物。
(AAC,Ba, Bb)= (AAC1,BBa1,BBb1),(AAC1,BBa1,BBb2),(AAC1,BBa1,BBb3),(AAC1,BBa2,BBb1),(AAC1,BBa2,BBb2),(AAC1,BBa2,BBb3),(AAC1,BBa3,BBb1),(AAC1,BBa3,BBb2),(AAC1,BBa3,BBb3),(AAC1,BBa4,BBb1),(AAC1,BBa4,BBb2),(AAC1,BBa4,BBb3),(AAC1,BBa5,BBb1),(AAC1,BBa5,BBb2),(AAC1,BBa5,BBb3),(AAC2,BBa1,BBb1),(AAC2,BBa1,BBb2),(AAC2,BBa1,BBb3),(AAC2,BBa2,BBb1),(AAC2,BBa2,BBb2),(AAC2,BBa2,BBb3),(AAC2,BBa3,BBb1),(AAC2,BBa3,BBb2),(AAC2,BBa3,BBb3),(AAC2,BBa4,BBb1),(AAC2,BBa4,BBb2),(AAC2,BBa4,BBb3),(AAC2,BBa5,BBb1),(AAC2,BBa5,BBb2),(AAC2,BBa5,BBb3),(AAC3,BBa1,BBb1),(AAC3,BBa1,BBb2),(AAC3,BBa1,BBb3),(AAC3,BBa2,BBb1),(AAC3,BBa2,BBb2),(AAC3,BBa2,BBb3),(AAC3,BBa3,BBb1),(AAC3,BBa3,BBb2),(AAC3,BBa3,BBb3),(AAC3,BBa4,BBb1),(AAC3,BBa4,BBb2),(AAC3,BBa4,BBb3),(AAC3,BBa5,BBb1),(AAC3,BBa5,BBb2),(AAC3,BBa5,BBb3),(AAC4,BBa1,BBb1),(AAC4,BBa1,BBb2),(AAC4,BBa1,BBb3),(AAC4,BBa2,BBb1),(AAC4,BBa2,BBb2),(AAC4,BBa2,BBb3),(AAC4,BBa3,BBb1),(AAC4,BBa3,BBb2),(AAC4,BBa3,BBb3),(AAC4,BBa4,BBb1),(AAC4,BBa4,BBb2),(AAC4,BBa4,BBb3),(AAC4,BBa5,BBb1),(AAC4,BBa5,BBb2),(AAC4,BBa5,BBb3),(AAC5,BBa1,BBb1),(AAC5,BBa1,BBb2),(AAC5,BBa1,BBb3),(AAC5,BBa2,BBb1),(AAC5,BBa2,BBb2),(AAC5,BBa2,BBb3),(AAC5,BBa3,BBb1),(AAC5,BBa3,BBb2),(AAC5,BBa3,BBb3),(AAC5,BBa4,BBb1),(AAC5,BBa4,BBb2),(AAC5,BBa4,BBb3),(AAC5,BBa5,BBb1),(AAC5,BBa5,BBb2),(AAC5,BBa5,BBb3),(AAC6,BBa1,BBb1),(AAC6,BBa1,BBb2),(AAC6,BBa1,BBb3),(AAC6,BBa2,BBb1),(AAC6,BBa2,BBb2),(AAC6,BBa2,BBb3),(AAC6,BBa3,BBb1),(AAC6,BBa3,BBb2),(AAC6,BBa3,BBb3),(AAC6,BBa4,BBb1),(AAC6,BBa4,BBb2),(AAC6,BBa4,BBb3),(AAC6,BBa5,BBb1),(AAC6,BBa5,BBb2),(AAC6,BBa5,BBb3),(AAC7,BBa1,BBb1),(AAC7,BBa1,BBb2),(AAC7,BBa1,BBb3),(AAC7,BBa2,BBb1),(AAC7,BBa2,BBb2),(AAC7,BBa2,BBb3),(AAC7,BBa3,BBb1),(AAC7,BBa3,BBb2),(AAC7,BBa3,BBb3),(AAC7,BBa4,BBb1),(AAC7,BBa4,BBb2),(AAC7,BBa4,BBb3),(AAC7,BBa5,BBb1),(AAC7,BBa5,BBb2),(AAC7,BBa5,BBb3),(AAC8,BBa1,BBb1),(AAC8,BBa1,BBb2),(AAC8,BBa1,BBb3),(AAC8,BBa2,BBb1),(AAC8,BBa2,BBb2),(AAC8,BBa2,BBb3),(AAC8,BBa3,BBb1),(AAC8,BBa3,BBb2),(AAC8,BBa3,BBb3),(AAC8,BBa4,BBb1),(AAC8,BBa4,BBb2),(AAC8,BBa4,BBb3),(AAC8,BBa5,BBb1),(AAC8,BBa5,BBb2),(AAC8,BBa5,BBb3)
The compound whose combination of AAC, BBa, and BBb is the following (AAC, BBa, BBb).
(AAC, Ba, Bb) = (AAC1, BBa1, BBb1), (AAC1, BBa1, BBb2), (AAC1, BBa1, BBb3), (AAC1, BBa2, BBb1), (AAC1, BBa2, BBb2), (AAC1 , BBa2, BBb3), (AAC1, BBa3, BBb1), (AAC1, BBa3, BBb2), (AAC1, BBa3, BBb3), (AAC1, BBa4, BBb1), (AAC1, BBa4, BBb2), (AAC1, BBa4 , BBb3), (AAC1, BBa5, BBb1), (AAC1, BBa5, BBb2), (AAC1, BBa5, BBb3), (AAC2, BBa1, BBb1), (AAC2, BBa1, BBb2), (AAC2, BBa1, BBb3 ), (AAC2, BBa2, BBb1), (AAC2, BBa2, BBb2), (AAC2, BBa2, BBb3), (AAC2, BBa3, BBb1), (AAC2, BBa3, BBb2), (AAC2, BBa3, BBb3), (AAC2, BBa4, BBb1), (AAC2, BBa4, BBb2), (AAC2, BBa4, BBb3), (AAC2, BBa5, BBb1), (AAC2, BBa5, BBb2), (AAC2, BBa5, BBb3), (AAC3 , BBa1, BBb1), (AAC3, BBa1, BBb2), (AAC3, BBa1, BBb3), (AAC3, BBa2, BBb1), (AAC3, BBa2, BBb2), (AAC3, BBa2, BBb3), (AAC3, BBa3 , BBb1), (AAC3, BBa3, BBb2), (AAC3, BBa3, BBb3), (AAC3, BBa4, BBb1), (AAC3, BBa4, BBb2), (AAC3, BBa4, BBb3), (AAC3, BBa5, BBb1 ), (AAC3, BBa5, BBb2), (AAC3, BBa5, BBb3), (AAC4, BBa1, BBb1), (AAC4, BBa1, BBb2), (AAC4, BBa1, BBb3), (AAC4, BBa2, BBb1), (AAC4, BBa2, BBb2), (AAC4, BBa2, BBb3), (AAC4, BBa3, BBb1), (AAC4, BBa3, BBb2), (AAC4, BBa3, BBb3), (AAC4, BBa4, BBb1), (AAC4 , BBa4, BBb2), (AAC4, BBa4, BBb3), (AAC4, BBa5, BBb1), (AAC4, BBa5, BBb2), (AAC4, BBa5, BBb3), (AAC5, BBa1, BBb1), (AAC5, BBa1, BBb2), (AAC5, BBa1, BBb3), (AAC5, BBa2, BBb1), (AAC5 , BBa2, BBb2), (AAC5, BBa2, BBb3), (AAC5, BBa3, BBb1), (AAC5, BBa3, BBb2), (AAC5, BBa3, BBb3), (AAC5, BBa4, BBb1), (AAC5, BBa4 , BBb2), (AAC5, BBa4, BBb3), (AAC5, BBa5, BBb1), (AAC5, BBa5, BBb2), (AAC5, BBa5, BBb3), (AAC6, BBa1, BBb1), (AAC6, BBa1, BBb2 ), (AAC6, BBa1, BBb3), (AAC6, BBa2, BBb1), (AAC6, BBa2, BBb2), (AAC6, BBa2, BBb3), (AAC6, BBa3, BBb1), (AAC6, BBa3, BBb2), (AAC6, BBa3, BBb3), (AAC6, BBa4, BBb1), (AAC6, BBa4, BBb2), (AAC6, BBa4, BBb3), (AAC6, BBa5, BBb1), (AAC6, BBa5, BBb2), (AAC6 , BBa5, BBb3), (AAC7, BBa1, BBb1), (AAC7, BBa1, BBb2), (AAC7, BBa1, BBb3), (AAC7, BBa2, BBb1), (AAC7, BBa2, BBb2), (AAC7, BBa2 , BBb3), (AAC7, BBa3, BBb1), (AAC7, BBa3, BBb2), (AAC7, BBa3, BBb3), (AAC7, BBa4, BBb1), (AAC7, BBa4, BBb2), (AAC7, BBa4, BBb3 ), (AAC7, BBa5, BBb1), (AAC7, BBa5, BBb2), (AAC7, BBa5, BBb3), (AAC8, BBa1, BBb1), (AAC8, BBa1, BBb2), (AAC8, BBa1, BBb3), (AAC8, BBa2, BBb1), (AAC8, BBa2, BBb2), (AAC8, BBa2, BBb3), (AAC8, BBa3, BBb1), (AAC8, BBa3, BBb2), (AAC8, BBa3, BBb3), (AAC8 , BBa4, BBb1), (AAC8, BBa4, BBb2), (AAC8, BBa4, BBb 3), (AAC8, BBa5, BBb1), (AAC8, BBa5, BBb2), (AAC8, BBa5, BBb3)

　上記一般式（Ｉ）で表される本発明化合物は、ヒスタミンＨ４受容体に対する調節作用を有し（作動剤、部分作動剤、逆作動剤および拮抗剤、特に拮抗剤）、ヒスタミンＨ４受容体が関与する疾患の治療剤として有用である。
　例えば、気管支喘息、アレルギー性鼻炎、慢性閉塞性肺疾患（ＣＯＰＤ）などの呼吸器系疾患；慢性関節リウマチ、アトピー性皮膚炎、アレルギー性結膜炎、乾癬、炎症性大腸炎、潰瘍性大腸炎、狼瘡、アテローム硬化症などの炎症性疾患；神経性疼痛および侵害性疼痛を含む疼痛緩和などに有効である。 The compound of the present invention represented by the above general formula (I) has a modulatory action on histamine H4 receptor (agonist, partial agonist, inverse agonist and antagonist, particularly antagonist), and histamine H4 receptor is It is useful as a therapeutic agent for diseases involved.
For example, respiratory diseases such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD); rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus Inflammatory diseases such as atherosclerosis; effective for pain relief including neuropathic pain and nociceptive pain.

　本発明の化合物は、ヒスタミン受容体、特にヒスタミンＨ４受容体に対して親和性が高く、サブタイプ選択性（ヒスタミンＨ１、Ｈ２、およびＨ３受容体に対する選択性、特にＨ３受容体に対する選択性）および他の受容体に対する選択性が高いため、副作用（たとえば運動機能への影響など）が軽減された医薬となり得る。また本発明の化合物は、安定性が高い、経口吸収性が高い、溶解度が高い、良好なバイオアベイラビリティーを示す、クリアランスが低い、半減期が長い、薬効持続性が高い、および／または肝酵素阻害活性が低い等の利点も有する。 The compounds of the present invention have a high affinity for histamine receptors, in particular histamine H4 receptors, subtype selectivity (selectivity for histamine H1, H2, and H3 receptors, in particular selectivity for H3 receptors) and Since it has high selectivity for other receptors, it can be a medicament with reduced side effects (for example, influence on motor function). In addition, the compound of the present invention has high stability, high oral absorption, high solubility, good bioavailability, low clearance, long half-life, high sustained efficacy, and / or liver enzyme There are also advantages such as low inhibitory activity.

　さらなる態様において、本発明は、有効量の本発明化合物と製薬的に許容し得る担体とを組み合わせて含有してなる医薬組成物を提供する。 In a further aspect, the present invention provides a pharmaceutical composition comprising a combination of an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.

　本発明化合物を医薬として用いる場合、例えば賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤、界面活性剤等、当分野において周知の製薬的に許容し得る担体を用い、常法に従って医薬組成物を製造することができる。 When the compound of the present invention is used as a pharmaceutical, for example, excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, surfactants, and the like, pharmaceutically acceptable carriers well known in the art Can be used to produce a pharmaceutical composition according to a conventional method.

　本発明に係る医薬組成物を、ヒトを含む哺乳動物の治療に投与する場合、投与単位剤形は治療目的と投与経路に応じて適宜選択することができる。具体的には錠剤、被覆錠剤、散剤、顆粒剤、カプセル剤、液剤、丸剤、懸濁剤、乳剤等の経口剤、および注射剤、坐剤、軟膏、貼付剤、エアゾール剤等の非経口剤が挙げられる。これら投与単位剤形は、当分野で周知の方法により製剤化される。 When the pharmaceutical composition according to the present invention is administered to the treatment of mammals including humans, the dosage unit dosage form can be appropriately selected depending on the therapeutic purpose and administration route. Specifically, oral preparations such as tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions, and parenterals such as injections, suppositories, ointments, patches, aerosols, etc. Agents. These dosage unit forms are formulated according to methods well known in the art.

　上記製剤中に含有されるべき本発明化合物の量は、剤形、投与経路、投与計画等によって適宜変更することができる。 The amount of the compound of the present invention to be contained in the above preparation can be appropriately changed depending on the dosage form, administration route, administration schedule and the like.

　本発明に係る医薬組成物の投与方法は、製剤の剤形、患者の年齢、性別、体重、症状の程度およびその他の条件等に応じて適宜決定され、経口、皮下、経皮、直腸、鼻内、口腔等の種々の経路から選択することができる。 The administration method of the pharmaceutical composition according to the present invention is appropriately determined according to the dosage form of the preparation, the age, sex, weight, symptom level and other conditions of the patient, and is oral, subcutaneous, transdermal, rectal, nasal It can be selected from various routes such as inner and oral cavity.

　本発明の医薬組成物に含有される本発明化合物の用量は、選択した投与経路、患者の年齢、性別、体重、疾患の状態、投与される本発明化合物の種類、その他の条件等に応じて適宜選択されるが、成人に経口投与する場合、通常０．０５～１０００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１００ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これら本発明の医薬組成物は１日に１回または複数回に分けて投与することができる。 The dose of the compound of the present invention contained in the pharmaceutical composition of the present invention depends on the selected route of administration, patient age, sex, weight, disease state, type of the compound administered, other conditions, etc. Although it is appropriately selected, in the case of oral administration to adults, it is usually 0.05 to 1000 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 100 mg / kg / day, preferably 0.01 to 1 mg / kg / day. These pharmaceutical compositions of the present invention can be administered once a day or divided into a plurality of times.

　以下に実施例を示し、本発明を具体的に説明するが、本発明はこれらに限定されるものではない。なお、各略号は本明細書中、以下に示す意味を有する。
Ｍｅ：メチル
Ｅｔ：エチル
Ｂｕ：ブチル
Ａｃ：アセチル
Ｂｏｃ２Ｏ：二炭酸－ジ－ｔｅｒｔ－ブチル
ＴＭＳ：テトラメチルシラン
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＳＯ：ジメチルスルホキシド
ＤＭＦ：ジメチルホルムアミド
ＮＭＰ：Ｎ－メチル－ピロリドン
ＴＨＦ：テトラヒドロフラン
ＤＭＡＰ：４－（ジメチルアミノ）ピリジン
ＬＨＭＤＳ：リチウムヘキナメチルジシラジド
ＴＦＡ：トリフルオロ酢酸
ＰｄＣｌ２（ｄｐｐｆ）ＣＨ２Ｃｌ２：［１，１’－ビス（ジフェニルフォスフィノ）－フェロセン］ジクロロパラジウム（ＩＩ），ジクロロメタンコンプレックス
ｒｔ：室温
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In addition, each abbreviation has the meaning shown below in this specification.
Me: methyl Et: ethyl Bu: butyl Ac: acetyl Boc 2 O: dicarbonate-di-tert-butyl TMS: tetramethylsilane DIEA: N, N-diisopropylethylamine DMSO: dimethyl sulfoxide DMF: dimethylformamide NMP: N-methyl - pyrrolidone THF: tetrahydrofuran DMAP: 4-(dimethylamino) pyridine LHMDS: lithium f Kina hexamethyldisilazide TFA: trifluoroacetic acid PdCl 2 (dppf) CH 2 Cl 2: [1,1'- bis (diphenylphosphino) -Ferrocene] dichloropalladium (II), dichloromethane complex rt: room temperature

化合物２（Ｉ－００２）の合成

Figure JPOXMLDOC01-appb-C000258

化合物１（１００　ｍｇ，　０．４９２　ｍｍｏｌ）をアセトニトリル（１．０　ｍＬ）に溶解し、タウリン（７４．０　ｍｇ，　０．５９１　ｍｍｏｌ）とＤＩＥＡ（０．３０１　ｍＬ，　１．７２４　ｍｍｏｌ）および水（０．１７７　ｍＬ）を加え、マイクロウェーブ照射下１３０℃で１５分間攪拌した。溶媒を減圧留去後、アセトニトリル（３．０　ｍＬ）を加えて３度共沸した。残渣をジクロロメタン（２．０　ｍＬ）に溶解し、氷浴下でオキサリルクロリド（０．１２９　ｍＬ，　１．４８　ｍｍｏｌ）とＤＭＦ（１．９２　μＬ，　０．０２５　ｍｍｏｌ）を加え、室温下で１０分間撹拌した。溶媒を減圧留去し、得られた残渣をジクロロメタン（１．０　ｍＬ）に溶解し、氷浴下にてベンジルアミン（７９　ｍｇ，　０．７３９　ｍｍｏｌ）とＤＩＥＡ（０．２１５　ｍＬ，　１．２３　ｍｍｏｌ）を加え、室温下で１０分間撹拌した。反応溶液にジクロロメタン（３．０　ｍＬ）および水（３．０　ｍＬ）を加えて撹拌した後、フェーズセパレーターを通して有機層を回収し、減圧留去した。得られた残渣をＮＭＰ（１．０　ｍＬ）に溶解し、Ｎ－メチルピペラジン（０．１１　ｍＬ，　０．９８５　ｍｍｏｌ）、ＤＩＥＡ（０．２１５ｍＬ，　１．２３　ｍｍｏｌ）を加え、マイクロウェーブ照射下１５０℃で６０分間攪拌した。反応溶液を分取用ＬＣ／ＭＳ（メソッドＥ）で精製し、化合物　２（７９．３　ｍｇ，　収率３６　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：１．６７　（ｓ，　４Ｈ），　２．１７　（ｓ，　５Ｈ），　２．２８　（ｓ，　４Ｈ），　２．４１　（ｓ，　２Ｈ），　３．２６　（ｓ，　２Ｈ），　３．６０　（ｓ，　４Ｈ），　３．６８　（ｓ，　２Ｈ），　４．１３　（ｓ，　２Ｈ），　６．４６　（ｓ，　１Ｈ），　７．２４－７．３８　（ｍ，　５Ｈ），　７．７０　（ｓ，　１Ｈ）
Synthesis of Compound 2 (I-002)

Figure JPOXMLDOC01-appb-C000258
Compound 1 (100 mg, 0.492 mmol) was dissolved in acetonitrile (1.0 mL), taurine (74.0 mg, 0.591 mmol), DIEA (0.301 mL, 1.724 mmol) and water. (0.177 mL) was added, and the mixture was stirred at 130 ° C. for 15 minutes under microwave irradiation. After the solvent was distilled off under reduced pressure, acetonitrile (3.0 mL) was added and azeotroped three times. The residue was dissolved in dichloromethane (2.0 mL), and oxalyl chloride (0.129 mL, 1.48 mmol) and DMF (1.92 μL, 0.025 mmol) were added in an ice bath. Stir for minutes. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (1.0 mL), and benzylamine (79 mg, 0.739 mmol) and DIEA (0.215 mL, 1.23) were added in an ice bath. mmol) was added and stirred at room temperature for 10 minutes. Dichloromethane (3.0 mL) and water (3.0 mL) were added to the reaction solution and stirred, and then the organic layer was collected through a phase separator and evaporated under reduced pressure. The obtained residue was dissolved in NMP (1.0 mL), N-methylpiperazine (0.11 mL, 0.985 mmol) and DIEA (0.215 mL, 1.23 mmol) were added, and microwave irradiation was performed. The mixture was stirred at 150 ° C. for 60 minutes. The reaction solution was purified by preparative LC / MS (Method E) to obtain Compound 2 (79.3 mg, yield 36%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.67 (s, 4H), 2.17 (s, 5H), 2.28 (s, 4H), 2.41 (s, 2H), 26 (s, 2H), 3.60 (s, 4H), 3.68 (s, 2H), 4.13 (s, 2H), 6.46 (s, 1H), 7.24-7.38 (M, 5H), 7.70 (s, 1H)

化合物５の合成

Figure JPOXMLDOC01-appb-C000259

化合物３（４．１４　ｇ，　２０．０８　ｍｍｏｌ）をエタノール（５０　ｍＬ）に溶解し、尿素（６．０３　ｇ，　１００　ｍｍｏｌ）と２８％　ナトリウムメトキシド（メタノール溶液、１１．６　ｇ，　６０．２　ｍｍｏｌ）を加えて、９時間加熱還流した。反応溶液を室温まで放冷後、２ｍｏｌ／Ｌ　塩酸で中和し（ｐＨ＝６）、クロロホルム（５０　ｍＬ）を加えて抽出した。更に水層をクロロホルム／メタノール（２／１）溶液（３０　ｍＬ）で抽出し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、化合物４（２．７０　ｇ，　収率　６６　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：２．０５－２．２０　（ｍ，　２Ｈ），　２．５９　（ｓ，　２Ｈ），　２．６０　（ｔ，　Ｊ　＝　１４．４　Ｈｚ　，　２Ｈ），　１０．９５　（ｓ，　１Ｈ），　１１．１３　（ｓ，　１Ｈ）

Figure JPOXMLDOC01-appb-C000260
化合物４（０．５　ｇ，　２．４７３　ｍｍｏｌ）をオキシ塩化リン（３．０　ｍＬ，　３２．３　ｍｍｏｌ）に溶解し、４時間加熱還流した。溶媒を減圧留去後、氷水（１０　ｍＬ）に溶解し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して化合物５（３４０　ｍｇ，　収率　５８　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：２．３０－２．４５　（ｍ，　２Ｈ），　３．１０　（ｓ，　２Ｈ），　３．３３　（ｔ，　Ｊ　＝　１４．４　Ｈｚ　，　２Ｈ）
Synthesis of compound 5
Figure JPOXMLDOC01-appb-C000259
Compound 3 (4.14 g, 20.08 mmol) was dissolved in ethanol (50 mL), urea (6.03 g, 100 mmol) and 28% sodium methoxide (methanol solution, 11.6 g, 60. 2 mmol) was added and heated to reflux for 9 hours. The reaction solution was allowed to cool to room temperature, neutralized with 2 mol / L hydrochloric acid (pH = 6), and extracted by adding chloroform (50 mL). Further, the aqueous layer was extracted with a chloroform / methanol (2/1) solution (30 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 4 (2.70 g, yield 66%).

1 H-NMR (DMSO-d 6 ) δ ppm: 2.05-2.20 (m, 2H), 2.59 (s, 2H), 2.60 (t, J = 14.4 Hz, 2H), 10.95 (s, 1H), 11.13 (s, 1H)

Figure JPOXMLDOC01-appb-C000260
Compound 4 (0.5 g, 2.473 mmol) was dissolved in phosphorus oxychloride (3.0 mL, 32.3 mmol) and heated to reflux for 4 hours. The solvent was distilled off under reduced pressure, dissolved in ice water (10 mL), and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 5 (340 mg, yield 58%).

1 H-NMR (DMSO-d 6 ) δ ppm: 2.30-2.45 (m, 2H), 3.10 (s, 2H), 3.33 (t, J = 14.4 Hz, 2H)

化合物９（Ｉ－０１２）の合成

Figure JPOXMLDOC01-appb-C000261

化合物１（７００　ｍｇ，　３．４５　ｍｍｏｌ）、化合物６（６６４　ｍｇ，　４．１４　ｍｍｏｌ）をアセトニトリル（７　ｍＬ）に溶解し、ＤＩＥＡ（１．５１　ｍＬ，　８．６２　ｍｍｏｌ）を加えて、７０℃で８時間撹拌した。反応溶液を室温まで放冷後、水（３０　ｍＬ）を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して化合物７（６５６　ｍｇ，　収率　６５　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：１．７２　（ｓ，　４Ｈ），　２．２６　（ｓ，　２Ｈ），　２．５３　（ｓ，　２Ｈ），　３．２６　（ｓ，　２Ｈ），　３．７１　（ｓ，　２Ｈ），　６．９６　（ｓ，　２Ｈ），　７．２０　（ｓ，　１Ｈ）
Figure JPOXMLDOC01-appb-C000262
化合物７（３０　ｍｇ，　０．１０３　ｍｍｏｌ）をＤＭＳＯ（１．０　ｍＬ）に溶解し、Ｎ－Ｂｏｃピペラジン（９６　ｍｇ，　０．５１６　ｍｍｏｌ）を加えてマイクロウェーブ照射下１５０℃で３０分間攪拌した。反応溶液を室温まで放冷後、水（３　ｍＬ）を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（クロロホルム－メタノール－トリエチルアミン）により精製し、化合物８を得た。得られた化合物８を４ｍｏｌ／Ｌ塩酸（酢酸エチル溶液、４．０　ｍＬ）に溶解し、室温にて１５分間攪拌した。溶媒を減圧留去し、化合物９（３６　ｍｇ，　収率　８４　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：１．７２　（ｓ，　４Ｈ），　２．２６　（ｓ，　２Ｈ），　２．５３　（ｓ，　２Ｈ），　３．２０　（ｓ，　４Ｈ），　３．３４　（ｂｒ，　２Ｈ），　３．８１　（ｓ，　２Ｈ），　４．０９　（ｓ，　４Ｈ），　７．０７　（ｓ，　２Ｈ），　９．６５　（ｓ，　２Ｈ），　９．７８　（ｓ，　２Ｈ）
Synthesis of Compound 9 (I-012)
Figure JPOXMLDOC01-appb-C000261
Compound 1 (700 mg, 3.45 mmol), Compound 6 (664 mg, 4.14 mmol) were dissolved in acetonitrile (7 mL), DIEA (1.51 mL, 8.62 mmol) was added, and 70 was added. Stir at 8 ° C. for 8 hours. The reaction solution was allowed to cool to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 7 (656 mg, yield 65%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.72 (s, 4H), 2.26 (s, 2H), 2.53 (s, 2H), 3.26 (s, 2H), 71 (s, 2H), 6.96 (s, 2H), 7.20 (s, 1H)
Figure JPOXMLDOC01-appb-C000262
Compound 7 (30 mg, 0.103 mmol) was dissolved in DMSO (1.0 mL), N-Boc piperazine (96 mg, 0.516 mmol) was added, and the mixture was stirred at 150 ° C. for 30 minutes under microwave irradiation. . The reaction solution was allowed to cool to room temperature, water (3 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol-triethylamine) to give compound 8. The obtained compound 8 was dissolved in 4 mol / L hydrochloric acid (ethyl acetate solution, 4.0 mL) and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure to obtain Compound 9 (36 mg, 84% yield).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.72 (s, 4H), 2.26 (s, 2H), 2.53 (s, 2H), 3.20 (s, 4H), 34 (br, 2H), 3.81 (s, 2H), 4.09 (s, 4H), 7.07 (s, 2H), 9.65 (s, 2H), 9.78 (s, 2H) )

化合物１２（Ｉ－０２２）の合成

Figure JPOXMLDOC01-appb-C000263

化合物１（３００　ｍｇ，　１．４８　ｍｍｏｌ）をＮＭＰ（３．０　ｍＬ）に溶解し、１－Ｂｏｃエチレンジアミン（２８４　ｍｇ，　１．７７　ｍｍｏｌ）、ＤＩＥＡ（０．７７４　ｍＬ，　４．４３　ｍｍｏｌ）を加えて、マイクロウェーブ照射下１００℃で１０分間攪拌した。室温まで放冷後、Ｎ－メチルピペラジン（０．２４７　ｍＬ，　２．２２　ｍｍｏｌ）を加えて、マイクロウェーブ照射下１５０℃で３０分間攪拌した。室温まで放冷後、水（５０　ｍＬ）を加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物１０（２６５　ｍｇ，　収率４６　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：１．３７　（ｓ，　９Ｈ），　１．６７　（ｓ，　４Ｈ），　２．１８　（ｓ，　５Ｈ），　２．２８　（ｓ，　４Ｈ），　２．３９　（ｓ，　２Ｈ），　３．１３　（ｂｒ，　２Ｈ），　３．３５　（ｓ，　２Ｈ），　３．５９　（ｓ，　４Ｈ），　６．２８　（ｓ，　１Ｈ），　６．８８　（ｓ，　１Ｈ）

Figure JPOXMLDOC01-appb-C000264
化合物１０（４５　ｍｇ，　０．１１５　ｍｍｏｌ）を４ｍｏｌ／Ｌ　塩酸（酢酸エチル溶液、１．０　ｍＬ）に溶解し、室温下１時間撹拌した。反応溶液を減圧留去し、化合物１１を得た。これをジクロロメタン（１．０　ｍＬ）に懸濁させ、ｐ－フルオロベンゼンスルホニルクロリド（３３．５　ｍｇ，　０．１７２　ｍｍｏｌ）とＤＩＥＡ（０，１２０　ｍＬ，　０．６８８　ｍｍｏｌ）を加えて室温で１時間撹拌した。溶媒を減圧留去し、
メソッドＥで精製して、化合物　１２（２３　ｍｇ，　収率４５　％）を得た。

１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δｐｐｍ：１．６４　（ｓ，　４Ｈ），　２．１０　（ｓ，　２Ｈ），　２．１８　（ｓ，　３Ｈ），　２．２５　（ｓ，　４Ｈ），　２．３６　（ｓ，　２Ｈ），　２．９６　（ｓ，　２Ｈ），　３．３２　（ｓ，　２Ｈ），　３．５３　（ｓ，　４Ｈ），　６．２３　（ｓ，　１Ｈ），　７．３５　（ｔ，　Ｊ　＝　８．０　Ｈｚ，２Ｈ），　７．７３－７．８０　（ｍ，　３Ｈ）
Synthesis of Compound 12 (I-022)
Figure JPOXMLDOC01-appb-C000263
Compound 1 (300 mg, 1.48 mmol) was dissolved in NMP (3.0 mL), and 1-Boc ethylenediamine (284 mg, 1.77 mmol), DIEA (0.774 mL, 4.43 mmol) were added. In addition, the mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. After allowing to cool to room temperature, N-methylpiperazine (0.247 mL, 2.22 mmol) was added, and the mixture was stirred at 150 ° C. for 30 minutes under microwave irradiation. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 10 (265 mg, yield 46%). .

1 H-NMR (DMSO-d 6 ) δ ppm: 1.37 (s, 9H), 1.67 (s, 4H), 2.18 (s, 5H), 2.28 (s, 4H), 2. 39 (s, 2H), 3.13 (br, 2H), 3.35 (s, 2H), 3.59 (s, 4H), 6.28 (s, 1H), 6.88 (s, 1H )

Figure JPOXMLDOC01-appb-C000264
Compound 10 (45 mg, 0.115 mmol) was dissolved in 4 mol / L hydrochloric acid (ethyl acetate solution, 1.0 mL) and stirred at room temperature for 1 hour. The reaction solution was distilled off under reduced pressure to obtain Compound 11. This was suspended in dichloromethane (1.0 mL), p-fluorobenzenesulfonyl chloride (33.5 mg, 0.172 mmol) and DIEA (0,120 mL, 0.688 mmol) were added, and 1 at room temperature was added. Stir for hours. Remove the solvent under reduced pressure,
Purification by Method E gave Compound 12 (23 mg, 45% yield).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.64 (s, 4H), 2.10 (s, 2H), 2.18 (s, 3H), 2.25 (s, 4H), 2. 36 (s, 2H), 2.96 (s, 2H), 3.32 (s, 2H), 3.53 (s, 4H), 6.23 (s, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.73-7.80 (m, 3H)

化合物１６の合成

Figure JPOXMLDOC01-appb-C000265

第１工程
化合物１３（８１０　ｍｇ，　４．０　ｍｍｏｌ）のエタノール（２５　ｍＬ）溶液に尿素（１．２　ｇ，　２０　ｍｍｏｌ）及び２８％ナトリウムメトキシド－メタノール溶液（２．７　ｇ，　１４　ｍｍｏｌ）を加え、１２０℃で２時間攪拌した。反応液を５％クエン酸水溶液にあけ、酢酸エステル－テトラヒドロフラン（１：１）で抽出し、無水硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣を酢酸エチル－ジイソプロピルエーテル（２：１）に懸濁させ、ろ取し、化合物１４（５４０　ｍｇ，　収率６０％（純度８８．６ｗ／ｗ％，　尿素１１．４ｗ／ｗ％を含む））を得た。
１Ｈ　ＮＭＲ　（ｄ６－ＤＭＳＯ）　δ：　１．４９－１．６６　（ｍ，　３Ｈ），　１．８０－１．９１　（ｍ，　１Ｈ），　１．９５－２．０６　（ｍ，　１Ｈ），　２．１７－２．２８　（ｍ，　１Ｈ），　３．３２（ｓ，　３Ｈ），　３．８６－３．９２　（ｍ，　１Ｈ），　１０．６８　（ｂｒ，　１Ｈ），　１１．０３　（ｂｒ，　１Ｈ）．

第２工程
　塩化ホスホリル（５．３　ｍＬ，　５７．０　ｍｍｏｌ）に化合物１４　（純度８８．６ｗ／ｗ％，　尿素１１．４ｗ／ｗ％を含む）　（５３８　ｍｇ，　２．４３　ｍｍｏｌ）及びＮ，Ｎ－ジメチルアニリン（０．７７０　ｍｌ，　６．０７　ｍｍｏｌ）を加え、１２０℃で１時間攪拌した。反応液を氷約１００ｍｌにあけ、酢酸エチルで洗いこみ、攪拌下、重曹を加えて中和した（ｐＨ８）。水層を再度、酢酸エチルで抽出し、有機層を合わせ無水硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、化合物１５（４９４　ｍｇ、収率８７％）を得た。
１Ｈ　ＮＭＲ　（ＣＤＣｌ３）　δ：　１．７７－１．９５　（ｍ，　２Ｈ），　１．９７－２．１０　（ｍ，　１Ｈ），　２．１５－２．２５　（ｍ，　１Ｈ），　２．５５－２．６８　（ｍ，　１Ｈ），　２．８０－２．９１　（ｍ，　１Ｈ），　３．５７　（ｓ，　３Ｈ），　４．２１－４．２８　（ｍ，　１Ｈ）．

第３工程
　化合物１５（５５　ｍｇ，　０．２１５　ｍｍｏｌ）の塩化メチレン（０．８　ｍＬ）溶液に１　ｍｏｌ／Ｌ三臭化ホウ素－塩化メチレン溶液（３．５４　ｍＬ，　３．５４　ｍｍｏｌ）を加え、室温にて３．５時間攪拌した。反応液を水にあけ、酢酸エチルで洗いこみ、攪拌下、重曹を加え中和し、水層をｐＨ８とした。水層を再度、酢酸エチルで抽出し、有機層を合わせ無水硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、化合物（４）（４８．８　ｍｇ、収率９４％）を得た。
１Ｈ　ＮＭＲ　（ＣＤＣｌ３）　δ：　１．７４－１．９０　（ｍ，　２Ｈ），　２．００－２．１６　（ｍ，　１Ｈ），　２．２１－２．３２　（ｍ，　１Ｈ），　２．６８－２．８６　（ｍ，　２Ｈ），　３．６５　（ｂｒ，　１Ｈ），　４．６１－４．７２　（ｍ，　１Ｈ）．
Synthesis of Compound 16
Figure JPOXMLDOC01-appb-C000265
First Step Compound 13 (810 mg, 4.0 mmol) in ethanol (25 mL) in urea (1.2 g, 20 mmol) and 28% sodium methoxide-methanol solution (2.7 g, 14 mmol) And stirred at 120 ° C. for 2 hours. The reaction mixture was poured into a 5% aqueous citric acid solution, extracted with acetic ester-tetrahydrofuran (1: 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate-diisopropyl ether (2: 1), collected by filtration, and compound 14 (540 mg, yield 60% (purity 88.6 w / w%, urea 11.4 w / w% included) )
1 H NMR (d6-DMSO) δ: 1.49-1.66 (m, 3H), 1.80-1.91 (m, 1H), 1.95-2.06 (m, 1H), 2 17-2.28 (m, 1H), 3.32 (s, 3H), 3.86-3.92 (m, 1H), 10.68 (br, 1H), 11.03 (br, 1H ).

Second Step Phosphoryl chloride (5.3 mL, 57.0 mmol) was added to compound 14 (purity 88.6 w / w%, urea 11.4 w / w% included) (538 mg, 2.43 mmol) and N, N-dimethylaniline (0.770 ml, 6.07 mmol) was added and stirred at 120 ° C. for 1 hour. The reaction solution was poured into about 100 ml of ice, washed with ethyl acetate, and neutralized by adding sodium bicarbonate with stirring (pH 8). The aqueous layer was extracted again with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain compound 15 (494 mg, yield 87%).
1 H NMR (CDCl 3 ) δ: 1.77-1.95 (m, 2H), 1.97-2.10 (m, 1H), 2.15-2.25 (m, 1H), 55-2.68 (m, 1H), 2.80-2.91 (m, 1H), 3.57 (s, 3H), 4.21-4.28 (m, 1H).

Step 3 To a solution of compound 15 (55 mg, 0.215 mmol) in methylene chloride (0.8 mL) was added 1 mol / L boron tribromide-methylene chloride solution (3.54 mL, 3.54 mmol). And stirred at room temperature for 3.5 hours. The reaction solution was poured into water, washed with ethyl acetate, neutralized with sodium bicarbonate with stirring, and the aqueous layer was adjusted to pH 8. The aqueous layer was extracted again with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain compound (4) (48.8 mg, 94% yield).
1 H NMR (CDCl 3 ) δ: 1.74-1.90 (m, 2H), 2.00-2.16 (m, 1H), 2.21-2.32 (m, 1H), 68-2.86 (m, 2H), 3.65 (br, 1H), 4.61-4.72 (m, 1H).

化合物２２（Ｉ－１１１）の合成

Figure JPOXMLDOC01-appb-C000266

第１工程
　化合物１７（６００　ｍｇ，　２．７６　ｍｍｏｌ）の塩化メチレン（６０　ｍＬ）溶液に六塩化タングステン（２．１９　ｇ，　５．１３　ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応液にｍｏｌ／Ｌ水酸化ナトリウム水溶液（３０　ｍＬ）を加え、クロロホルムで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル　＝　８５／１５にて溶出する部分を集め、白色の化合物１８（２９３　ｍｇ，　収率３９　％）を得た。
1H NMR (DMSO-d6) δ: 2.78 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 3.77 (s, 2H).

第２工程
　化合物１８（５０　ｍｇ，　０．１８　ｍｍｏｌ）の１－メチル－２－ピロリドン（１　ｍＬ）溶液に、２－アミノエタンスルホンアミド塩酸塩１９（４４　ｍｇ，　０．２７　ｍｍｏｌ）、次いでＮ，Ｎ－ジイソプロピルエチルアミン（０．１６１　ｍＬ，　０．９２　ｍｍｏｌ）を加え、１００　℃で１時間加熱攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール　＝　９５／５にて溶出する部分を集め、淡黄色の化合物２０（３０　ｍｇ，　収率４５　％）を得た。
1H-NMR (DMSO-d6) δ: 2.69 (m, 2H), 2.84 (t, J = 6.0 Hz, 2H), 3.25-3.40 (m, 4H), 3.70 (m, 2H), 6.97 (s, 2H), 7.51 (s, 1H).

第３工程
　化合物２０（２８　ｍｇ、０．０７８　ｍｍｏｌ）の１－メチル－２－ピロリドン（０．５　ｍＬ）溶液に、１－メチルピペラジン２１（０．０８７　ｍＬ，　０．７８　ｍｍｏｌ）、次いでＮ，Ｎ－ジイソプロピルエチルアミン（０．１３６　ｍＬ，　０．７８　ｍｍｏｌ）を加え、マイクロ波照射下２００　℃で３０分間加熱攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール　＝　９５／５にて溶出する部分を集め、化合物２２（１３　ｍｇ，　収率４３　％）を得た。
1H NMR (DMSO-d6) δ: 2.21 (s, H), 2.33 (brs, 4H), 2.56-2.61 (m, 2H), 2.68-2.74 (m, 2H), 3.19-3.25 (m, 2H), 3.64-3.70 (m, 6H), 6.69 (s, 1H), 6.92 (s, 2H), 7.04 (t, J = 5.5 Hz, 1H).
Synthesis of Compound 22 (I-111)
Figure JPOXMLDOC01-appb-C000266
First Step Tungsten hexachloride (2.19 g, 5.13 mmol) was added to a solution of compound 17 (600 mg, 2.76 mmol) in methylene chloride (60 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a mol / L aqueous sodium hydroxide solution (30 mL), extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 85/15 was collected. White compound 18 (293 mg, yield 39%) was collected. Obtained.
1 H NMR (DMSO-d6) δ: 2.78 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 3.77 (s, 2H).

Second Step A solution of compound 18 (50 mg, 0.18 mmol) in 1-methyl-2-pyrrolidone (1 mL) was added 2-aminoethanesulfonamide hydrochloride 19 (44 mg, 0.27 mmol), then N , N-diisopropylethylamine (0.161 mL, 0.92 mmol) was added, and the mixture was stirred with heating at 100 ° C. for 1 hr. The reaction solution was subjected to silica gel chromatography, and the fractions eluted with chloroform / methanol = 95/5 were collected to obtain pale yellow compound 20 (30 mg, 45% yield).
1 H-NMR (DMSO-d6) δ: 2.69 (m, 2H), 2.84 (t, J = 6.0 Hz, 2H), 3.25-3.40 (m, 4H), 3.70 (m, 2H), 6.97 (s, 2H), 7.51 (s, 1H).

Step 3 To a solution of compound 20 (28 mg, 0.078 mmol) in 1-methyl-2-pyrrolidone (0.5 mL), 1-methylpiperazine 21 (0.087 mL, 0.78 mmol), then N , N-diisopropylethylamine (0.136 mL, 0.78 mmol) was added, and the mixture was stirred with heating at 200 ° C. for 30 minutes under microwave irradiation. The reaction solution was subjected to silica gel chromatography, and the fractions eluted with chloroform / methanol = 95/5 were collected to obtain Compound 22 (13 mg, 43% yield).
1 H NMR (DMSO-d6) δ: 2.21 (s, H), 2.33 (brs, 4H), 2.56-2.61 (m, 2H), 2.68-2.74 (m, 2H), 3.19-3.25 (m, 2H) , 3.64-3.70 (m, 6H), 6.69 (s, 1H), 6.92 (s, 2H), 7.04 (t, J = 5.5 Hz, 1H).

化合物２４（Ｉ－１１３）の合成

Figure JPOXMLDOC01-appb-C000267

第１工程
　化合物２３（６５　ｍｇ，　０．１８５　ｍｍｏｌ）のメタノール（２　ｍＬ）懸濁液に、トリフルオロ酢酸（０．２　ｍＬ）、次いで酸化白金一水和物（１０　ｍｇ，　０．０４４　ｍｍｏｌ）を加え、水素雰囲気下、室温で１時間攪拌した。反応液をセライトで濾過し、濾液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール　＝　９０／１０にて溶出する部分を集め、化合物２４（４　ｍｇ，　収率６　％）を得た。
1H NMR (DMSO-d6) δ: 1.73 (m, 2H), 2.19-2.32 (m, 7H), 2.46-2.53 (m, 2H), 3.50-3.63 (m, 6H), 5.98 (t, J = 5.4 Hz, 1H), 6.05 (s, 1H), 6.88 (s, 2H).
Synthesis of Compound 24 (I-113)
Figure JPOXMLDOC01-appb-C000267
First Step To a suspension of compound 23 (65 mg, 0.185 mmol) in methanol (2 mL), trifluoroacetic acid (0.2 mL) and then platinum oxide monohydrate (10 mg, 0.044 mmol). ) And stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fractions eluted with chloroform / methanol = 90/10 were collected to obtain Compound 24 (4 mg, yield 6%).
1 H NMR (DMSO-d6) δ: 1.73 (m, 2H), 2.19-2.32 (m, 7H), 2.46-2.53 (m, 2H), 3.50-3.63 (m, 6H), 5.98 (t, J = 5.4 Hz, 1H), 6.05 (s, 1H), 6.88 (s, 2H).

化合物２８の合成

Figure JPOXMLDOC01-appb-C000268

第１工程
　水素化ナトリウム（６０ｗｔ％油性）のテトラヒドロフラン（３０ｍｌ）の懸濁液に、化合物２５（２ｇ、１１．６ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を氷冷下で滴下後、１時間攪拌した。反応液に化合物２６（１．６ｍｌ、１２．７７ｍｍｏｌ）を加え、室温で１時間攪拌後、さらに１時間加熱還流した。加熱攪拌後、テトラブチルアンモニウムブロミド（０．９４ｇ、２．９０ｍｍｏｌ）を加え３時間加熱還流した。反応液を氷水－２ｍｏｌ／ｌ塩酸に注ぎ酢酸エチルにて抽出した、有機層を炭酸水素ナトリウム水溶液、次いで水で洗浄し、無水硫酸ナトリウムにて乾燥後減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル　＝１／５にて溶出する部分を集め、無色油状物として化合物２７（２．９４ｇ、収率９０％）を得た。
1H NMR (CDCl3) δ: 1.26 (s, 3H), 1.50-1.70 (m, 4H), 1.84-1.98 (m, 4H), 3.95-4.00 (m, 4H), 4.36 (s, 2H), 6.96-7.06 (m, 2H), 7.27-7.35 (m, 2H)
　
第２工程
　化合物２７（２．９４ｇ、１０．４９　ｍｍｏｌ）のテトラヒドロフラン（３０　ｍＬ）溶液に、２ｍｏｌ／Ｌ塩酸（２１　ｍＬ、４２　ｍｍｏｌ）を加え、８０℃で２．５時間加熱撹拌した。反応液を氷水に注ぎ酢酸エチルにて抽出した。有機層を炭酸水素ナトリウム水溶液、次いで水で洗浄し、無水硫酸ナトリウムにて乾燥後減圧濃縮して化合物２８を淡黄色油状物として得た（２．４６ｇ、収率９９％）
1H-NMR (CDCl3) δ: 1.36 (s, 3H), 1.72-1.86 (m, 2H), 2.18-2.30 (m, 4H), 2.58-2.74 (m, 2H), 4.48 (s, 2H), 7.00-7.09 (m, 2H), 7.28-7.38 (m, 2H)
Synthesis of Compound 28
Figure JPOXMLDOC01-appb-C000268
First Step To a suspension of sodium hydride (60 wt% oily) in tetrahydrofuran (30 ml), a solution of compound 25 (2 g, 11.6 mmol) in tetrahydrofuran (10 ml) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. Compound 26 (1.6 ml, 12.77 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and further heated under reflux for 1 hour. After heating and stirring, tetrabutylammonium bromide (0.94 g, 2.90 mmol) was added, and the mixture was heated to reflux for 3 hours. The reaction solution was poured into ice water-2 mol / l hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 1/5 was collected to obtain Compound 27 (2.94 g, yield 90%) as a colorless oil.
1 H NMR (CDCl 3 ) δ: 1.26 (s, 3H), 1.50-1.70 (m, 4H), 1.84-1.98 (m, 4H), 3.95-4.00 (m, 4H), 4.36 (s, 2H), 6.96-7.06 (m, 2H), 7.27-7.35 (m, 2H)

Second Step 2 mol / L hydrochloric acid (21 mL, 42 mmol) was added to a solution of compound 27 (2.94 g, 10.49 mmol) in tetrahydrofuran (30 mL), and the mixture was heated and stirred at 80 ° C. for 2.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 28 as a pale yellow oil (2.46 g, yield 99%).
1 H-NMR (CDCl 3 ) δ: 1.36 (s, 3H), 1.72-1.86 (m, 2H), 2.18-2.30 (m, 4H), 2.58-2.74 (m, 2H), 4.48 (s, 2H) , 7.00-7.09 (m, 2H), 7.28-7.38 (m, 2H)

化合物３３(Ｉ－０８７）の合成

Figure JPOXMLDOC01-appb-C000269

第一工程
化合物２９（１００　ｍｇ，　０．２６３　ｍｍｏｌ）、化合物３０（１０６　ｍｇ，　０．３４１　ｍｍｏｌ）、ジフェニルホスフィノフェロセンパラジウムジクロリド・ジクロロメタンコンプレックス（１０．７　ｍｇ，　０．０１３　ｍｍｏｌ）をＴＨＦ（１　ｍＬ）に懸濁し、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０．３９４　ｍＬ，　０．７８８　ｍｍｏｌ）を加えて、マイクロウェーブ照射下１３０℃にて３０分間撹拌した。反応溶液を室温まで放冷後、水（３　ｍＬ）を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。有機層を減圧留去後、シリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物３１（１１６　ｍｇ，　８４　％）を得た。

１H-NMR（DMSO-d6）δppm：1.41 (s, 9H), 1.72 (s, 4H), 2.27 (s, 2H), 2.55 (s, 2H), 3.29 (t, J = 6.0 Hz, 2H), 3.47 (br, 2H), 3.75 (m, 2H), 4.00 (s, 2H), 4.14 (d, J = 5.6 Hz, 2H), 6.72 (br, 2H), 6.95 (s, 2H), 7.20-7.35 (m, 5H), 7.69 (t, J = 6.0 Hz, 1H)

第二工程
化合物３１（７０　ｍｇ、　０．１３３　ｍｍｏｌ）を酢酸エチル（２　ｍＬ）に溶解し、パラジウム炭素を加えて水素気流下、室温で２時間半撹拌した。反応溶液をセライトろ過して、溶媒を減圧留去して化合物３２（７８　ｍｇ、　９７　％）を得た。

１H-NMR（DMSO-d6）δppm：1.07 (s, 2H), 1.39 (s, 9H), 1.56 (m, 2H), 1.70 (br, 4H), 1.80 (d, J = 12 Hz, 2H), 2.23 (s, 2H), 2.64 (m, 1H), 2.78 (m, 2H), 3.26 (t, J = 6.4 Hz, 2H), 3.72 (m, 2H), 3.95-3.99 (m, 2H), 4.13 (d, J = 6.0 Hz , 2H), 6.69 (br, 1H), 7.20-7.35 (m, 5H), 7.69 (t, J = 6.4 Hz, 1H)

第三工程
化合物３２（７５　ｍｇ、　０．１４２　ｍｍｏｌ）を４ｍｏｌ／Ｌ塩酸－酢酸エチル溶液（２　ｍＬ）に溶解し、室温で１時間撹拌した。溶媒を減圧留去し、化合物３３（６８　ｍｇ、　９５　％）を得た。

１H-NMR（DMSO-d6）δppm： 1.75 (s, 4H), 2.11 (s, 4H), 2.36 (s, 2H), 2.75 (s, 2H), 3.00 (m, 2H), 3.20-3.36 (m, 5H), 3.86 (br, 2H), 4.13 (d, J = 6.4 Hz , 2H), 7.20-7.35 (m, 5H), 8.02 (br, 1H), 8.93 (s, 1H), 9.19 (m, 1H), 9.33 (m, 1H)
Synthesis of Compound 33 (I-087)
Figure JPOXMLDOC01-appb-C000269
First Step Compound 29 (100 mg, 0.263 mmol), Compound 30 (106 mg, 0.341 mmol), diphenylphosphinoferrocene palladium dichloride / dichloromethane complex (10.7 mg, 0.013 mmol) were dissolved in THF ( 1 mol), 2 mol / L aqueous sodium carbonate solution (0.394 mL, 0.788 mmol) was added, and the mixture was stirred at 130 ° C. for 30 minutes under microwave irradiation. The reaction solution was allowed to cool to room temperature, water (3 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 31 (116 mg, 84%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.41 (s, 9H), 1.72 (s, 4H), 2.27 (s, 2H), 2.55 (s, 2H), 3.29 (t, J = 6.0 Hz, 2H ), 3.47 (br, 2H), 3.75 (m, 2H), 4.00 (s, 2H), 4.14 (d, J = 5.6 Hz, 2H), 6.72 (br, 2H), 6.95 (s, 2H), 7.20 -7.35 (m, 5H), 7.69 (t, J = 6.0 Hz, 1H)

Second step compound 31 (70 mg, 0.133 mmol) was dissolved in ethyl acetate (2 mL), palladium on carbon was added, and the mixture was stirred at room temperature for 2 and a half hours under a hydrogen stream. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain Compound 32 (78 mg, 97%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.07 (s, 2H), 1.39 (s, 9H), 1.56 (m, 2H), 1.70 (br, 4H), 1.80 (d, J = 12 Hz, 2H ), 2.23 (s, 2H), 2.64 (m, 1H), 2.78 (m, 2H), 3.26 (t, J = 6.4 Hz, 2H), 3.72 (m, 2H), 3.95-3.99 (m, 2H) , 4.13 (d, J = 6.0 Hz, 2H), 6.69 (br, 1H), 7.20-7.35 (m, 5H), 7.69 (t, J = 6.4 Hz, 1H)

Third Step Compound 32 (75 mg, 0.142 mmol) was dissolved in 4 mol / L hydrochloric acid-ethyl acetate solution (2 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain Compound 33 (68 mg, 95%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.75 (s, 4H), 2.11 (s, 4H), 2.36 (s, 2H), 2.75 (s, 2H), 3.00 (m, 2H), 3.20-3.36 (m, 5H), 3.86 (br, 2H), 4.13 (d, J = 6.4 Hz, 2H), 7.20-7.35 (m, 5H), 8.02 (br, 1H), 8.93 (s, 1H), 9.19 ( m, 1H), 9.33 (m, 1H)

化合物３６の合成

Figure JPOXMLDOC01-appb-C000270

化合物３４（５６　ｍｇ，　０．１９２　ｍｍｏｌ）をＴＨＦ（１　ｍＬ）に溶解し、化合物３５（７９　ｍｇ，　０．２８８　ｍｍｏｌ）、ポリマー担持トリフェニルホスフィン（３　ｍｍｏｌ／ｇ，　１９２　ｍｇ，　０．５７６　ｍｍｏｌ）、ジイソプロピルアザジカルボキシレート（９５　ｗｔ％，　０．０５９　ｍＬ，　０．２８８　ｍｍｏｌ）を加えて室温で１時間半撹拌した。反応溶液に水（２　ｍＬ）を加えてジクロロメタンで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。有機層を減圧留去後、分取型ＬＣＭＳ（メソッドＥ）により精製し、化合物３６（６　ｍｇ，　５．７　％）を得た。

１H-NMR（DMSO-d6）δppm： 1.31 (s, 9H), 1.65 (m, 4H), 2.11 (br, 2H), 2.20 (s, 3H), 2.31 (br, 4H), 2.38 (br, 2H), 3.24 (m, 2H), 3.60 (s, 4H), 3.68 (m, 2H), 6.06 (br, 1H), 7.15 (m, 3H), 7.34 (t, J = 7.6 Hz, 2H)
Synthesis of Compound 36
Figure JPOXMLDOC01-appb-C000270
Compound 34 (56 mg, 0.192 mmol) was dissolved in THF (1 mL), compound 35 (79 mg, 0.288 mmol), polymer-supported triphenylphosphine (3 mmol / g, 192 mg, 0.576). mmol) and diisopropyl azadicarboxylate (95 wt%, 0.059 mL, 0.288 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Water (2 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure and then purified by preparative LCMS (Method E) to obtain Compound 36 (6 mg, 5.7%).

1 H-NMR (DMSO-d 6 ) δ ppm: 1.31 (s, 9H), 1.65 (m, 4H), 2.11 (br, 2H), 2.20 (s, 3H), 2.31 (br, 4H), 2.38 (br , 2H), 3.24 (m, 2H), 3.60 (s, 4H), 3.68 (m, 2H), 6.06 (br, 1H), 7.15 (m, 3H), 7.34 (t, J = 7.6 Hz, 2H)

化合物４４の合成

Figure JPOXMLDOC01-appb-C000271

第１工程
　ｐ－メトキシベンジルクロリド（２０．５０　ｇ，　１３１　ｍｍｏｌ）のＮ－メチルピリミドン（１００　ｍＬ）溶液に化合物３７（１０　ｇ，　５２．４　ｍｍｏｌ）及び炭酸カリウム（２８．９　ｇ，　２０９　ｍｍｏｌ）を加え、１００℃で１時間攪拌した。反応液を濾過後、ろ液を水に注ぎ、酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた白色固体をジイソプロピルエーテルで洗浄し、白色の化合物３８（２１．８ｇ、収率９６％）を得た。
1H NMR (DMSO-d6) δ: 3.71 (s, 3H), 3.73 (s, 3H), 4.87 (s, 2H), 4.94 (s, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 8.45 (s, 1H).

第２工程
　化合物３８（１０　ｇ，　２３．２　ｍｍｏｌ）及び炭酸水素ナトリウム（３９．０　ｇ，　４６４　ｍｏｌ）をイソプロパノール－水（１：１）（４００　ｍＬ）に溶解させ、１１０℃で１２時間攪拌した。反応液を水に注ぎ、酢酸エチル－テトラヒドロフランで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、黄色の化合物３９（８．４　ｇ、粗収率９８％）を得た。精製することなく次工程に用いた。
1H NMR (DMSO-d6) δ: 3.71 (s, 3H), 3.73 (s, 3H), 4.81 (s, 2H), 4.97 (s, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.34 (s, 1H), 8.78 (s, 1H).

第３工程
　化合物３９（５　ｇ，　１３．６　ｍｍｏｌ）のアセトン（２５　ｍＬ）溶液に炭酸カリウム（１３．１　ｇ，　９５　ｍｍｏｌ）及びプロパルギルブロミド（６．１　ｍｌ、８０　ｍｍｏｌ）を加え、１．５時間加熱還流した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥後した。有機層を減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、黄色の化合物４０（４．８９　ｇ、収率８９％）を得た。
1H NMR (DMSO-d6) δ: 3.61 (s, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 4.66 (s, 2H), 4.84 (s, 2H), 4.92 (s, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.81 (s, 1H).

第４工程
　化合物４０（３．６　ｇ，　８．９　ｍｍｍｏｌ）のトルエン（１４０　ｍＬ）の溶液を１３時間加熱還流した。反応液を減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、黄色の化合物４１（３．３０ｇ、収率９２％）を得た。
1H NMR (CDCl3) δ: 3.76 (s, 3H), 3.77 (s, 3H), 4.63 (d, J = 4.0 Hz, 2H), 5.00 (s, 2H), 5.13 (s, 2H), 5.98 (dt, J = 9.6, 4.0 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 6.82 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H).

第５工程
　化合物４１（２．３７　ｇ，　５．８３　ｍｍｏｌ）をエタノール－テトラヒドロフラン（３：１）（７５　ｍＬ）に溶解させ、２０ｗ／ｗ％炭素担持水酸化パラジウム（４６０　ｍｇ）を加え、１気圧水素雰囲気下、室温で２．５時間攪拌した。反応液をセライト濾過後、瀘液を減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、黄色の化合物４２（１．３６　ｇ，　収率５７％）を得た。
1H NMR (CDCl3) δ: 1.92 (br, 2H), 2.49 (br, 2H), 3.77 (s, 3H), 3.77 (s, 3H), 4.00 (br, 2H), 4.98 (s, 2H), 5.14 (s, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H).

第６工程
　化合物４２（１．８２　ｇ，　４．４６　ｍｍｏｌ）のトリフルオロ酢酸（１８　ｍＬ）溶液に濃硫酸（４９５　μｌ，　８．９１　ｍｍｏｌ）を加え、４５分間加熱還流した。反応液を減圧乾固させ、得られた固体をメタノールで洗浄し、濃緑色の化合物４３（５８３　ｍｇ，　収率７８％）を得た。
1H NMR (DMSO-d6) δ: 1.86 (m, 2H), 2.36 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 4.3 Hz, 2H), 10.39 ( s, 1H), 10.98 (s, 1H).

第７工程
　化合物４３（５０　ｍｇ，　０．２９７　ｍｍｏｌ）をフェニルリン酸ジクロリド（２３２　ｍｇ，　１．１８９　ｍｍｏｌ）に溶解させ、１４０℃で１．５時間及び１６０度で２時間加熱攪拌した。反応液を水に注ぎ、重曹で塩基性にした後、酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、白色の化合物４４（１５．９　ｍｇ、収率２６％）を得た。
1H NMR (CDCl3) δ: 2.17 (m, 2H), 2.95 (t, J = 6.1 Hz, 2H), 4.36 (t, J = 4.8 Hz, 2H).
Synthesis of Compound 44
Figure JPOXMLDOC01-appb-C000271
Step 1 Compound 37 (10 g, 52.4 mmol) and potassium carbonate (28.9 g, 209) were added to a solution of p-methoxybenzyl chloride (20.50 g, 131 mmol) in N-methylpyrimidone (100 mL). mmol) and stirred at 100 ° C. for 1 hour. After filtering the reaction solution, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting white solid was washed with diisopropyl ether to obtain white compound 38 (21.8 g, yield 96%).
1 H NMR (DMSO-d6) δ: 3.71 (s, 3H), 3.73 (s, 3H), 4.87 (s, 2H), 4.94 (s, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 8.45 (s, 1H).

Second Step Compound 38 (10 g, 23.2 mmol) and sodium hydrogen carbonate (39.0 g, 464 mol) were dissolved in isopropanol-water (1: 1) (400 mL) and stirred at 110 ° C. for 12 hours. did. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain yellow compound 39 (8.4 g, crude yield 98%). Used in the next step without purification.
1 H NMR (DMSO-d6) δ: 3.71 (s, 3H), 3.73 (s, 3H), 4.81 (s, 2H), 4.97 (s, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.34 (s, 1H), 8.78 (s, 1H).

Third Step To a solution of compound 39 (5 g, 13.6 mmol) in acetone (25 mL) was added potassium carbonate (13.1 g, 95 mmol) and propargyl bromide (6.1 ml, 80 mmol). The mixture was heated to reflux for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain yellow compound 40 (4.89 g, yield 89%).
1 H NMR (DMSO-d6) δ: 3.61 (s, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 4.66 (s, 2H), 4.84 (s, 2H), 4.92 (s, 2H ), 6.85 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.81 (s, 1H).

Fourth Step A solution of compound 40 (3.6 g, 8.9 mmol) in toluene (140 mL) was heated to reflux for 13 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain yellow compound 41 (3.30 g, yield 92%).
1 H NMR (CDCl 3 ) δ: 3.76 (s, 3H), 3.77 (s, 3H), 4.63 (d, J = 4.0 Hz, 2H), 5.00 (s, 2H), 5.13 (s, 2H), 5.98 (dt, J = 9.6, 4.0 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 6.82 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H).

Step 5 Compound 41 (2.37 g, 5.83 mmol) was dissolved in ethanol-tetrahydrofuran (3: 1) (75 mL), 20 w / w% palladium hydroxide on carbon (460 mg) was added, and 1 The mixture was stirred at room temperature for 2.5 hours under atmospheric hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain yellow compound 42 (1.36 g, yield 57%).
1 H NMR (CDCl 3 ) δ: 1.92 (br, 2H), 2.49 (br, 2H), 3.77 (s, 3H), 3.77 (s, 3H), 4.00 (br, 2H), 4.98 (s, 2H) , 5.14 (s, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H).

Sixth Step Concentrated sulfuric acid (495 μl, 8.91 mmol) was added to a solution of compound 42 (1.82 g, 4.46 mmol) in trifluoroacetic acid (18 mL), and the mixture was heated to reflux for 45 minutes. The reaction solution was dried under reduced pressure, and the resulting solid was washed with methanol to obtain dark green compound 43 (583 mg, yield 78%).
1 H NMR (DMSO-d6) δ: 1.86 (m, 2H), 2.36 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 4.3 Hz, 2H), 10.39 (s, 1H), 10.98 ( s, 1H).

Step 7 Compound 43 (50 mg, 0.297 mmol) was dissolved in phenylphosphoric dichloride (232 mg, 1.189 mmol), and the mixture was heated and stirred at 140 ° C. for 1.5 hours and 160 ° C. for 2 hours. The reaction mixture was poured into water, basified with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain white compound 44 (15.9 mg, yield 26%).
1 H NMR (CDCl 3 ) δ: 2.17 (m, 2H), 2.95 (t, J = 6.1 Hz, 2H), 4.36 (t, J = 4.8 Hz, 2H).

化合物５２の合成

Figure JPOXMLDOC01-appb-C000272

第１工程
　化合物４５（２ｇ、２３．０ｍｍｏｌ）とトリエチルアミン（３．５　ｍＬ、２５．３　ｍｍｏｌ）のジクロロメタン（４０ｍＬ）溶液に化合物４６（４．８ｇ、２３．０　ｍｍｏｌ）　を氷冷下に加え、氷冷下で１．５時間攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した。有機層を無水硫酸ナトリウムにて乾燥し、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール　＝１／１０にて溶出する部分を集め、白色固体の化合物４７（５．２７ｇ、収率８８％）を得た。
1H NMR (DMSO-d6) δ: 1.60-1.78 (m, 2H), 3.01 (dt, J = 0.9, 10.5 Hz 1H), 3.14-3.30 (m, 3H), 4.15 (brs, 1H), 4.87 (d, J = 2.7 Hz, 1H), 7.66 (dd, J = 0.9, 9.3 Hz 2H), 7.78 (dd, J = 0.9, 9.3 Hz 2H).

第２工程
　化合物４７（５．２７ｇ、２０．１　ｍｍｏｌ）とトリエチルアミン（５．６　ｍＬ、４０．３　ｍｍｏｌ）のジクロロメタン－テトラヒドロフラン（１：１，　６０　ｍＬ）溶液に、化合物４８（１．７　ｍＬ、２２．１　ｍｍｏｌ）を氷冷下に加え、氷冷下で２．５時間撹拌した。反応液を氷水に注ぎ、ジクロロメタンで抽出した。有機層を１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した。有機層を無水硫酸ナトリウムにて乾燥し、減圧濃縮した。化合物４９は精製することなく次工程に用いた。
1H-NMR (DMSO-d6) δ: 2.03-2.07 (m, 2H), 3.12 (s, 3H), 3.21-3.37 (m, 2H), 3.46(brs, 2H), 5.17 (brs, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H).

第３工程
　化合物４９（１．５ｇ、４．４１　ｍｍｏｌ）のジメチルホルムアミド（１５　ｍＬ）溶液に、室温で　アジ化ナトリウム５０（０．４３ｇ、６．６２ｍｍｏｌ）を加え、６５　℃で８時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、酢酸エチル／ヘキサン＝２／５にて溶出する部分を集め、白色固体の化合物５１（１．２２ｇ、収率９６％）を得た。
1H NMR (DMSO-d6) δ: 1.82-1.85 (m, 1H), 1.92-1.96 (m, 1H), 3.12-3.39 (m, 4H), 4.28 (brs, 1H), 7.70 (dd, J = 0.6, 8.7 Hz, 2H), 7.84 (dd, J = 0.6, 8.7 Hz, 2H).

第４工程
　化合物５１（０．４０ｇ、１．４０　ｍｍｏｌ）のエタノール－テトラヒドロフラン－ギ酸（５：１：０．１，　１２　ｍＬ）溶液に、パラジウム／炭素（０．３０ｇ、０．２７９ｍｍｏｌ）を加え水素雰囲気下にて１２時間室温で攪拌した。反応液をセライトでろ過し、減圧濃縮した。残渣をクロロホルムに溶解させ、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝１／９にて溶出する部分を集め、淡茶色の化合物５２（０．２０ｇ、収率６４％）を得た。
1H NMR (DMSO-d6) δ: 1.18-1.50 (m, 3H), 1.76 (ddt, J = 6.9, 7.5, 7.5 Hz, 1H), 2.76 (dt, J = 4.2, 8.1 Hz, 1H), 3.12-3.30 (m, 4H), 7.60-7.81 (m, 5H).
Synthesis of Compound 52
Figure JPOXMLDOC01-appb-C000272
Step 1 Compound 46 (4.8 g, 23.0 mmol) was added to a solution of compound 45 (2 g, 23.0 mmol) and triethylamine (3.5 mL, 25.3 mmol) in dichloromethane (40 mL) under ice cooling. The mixture was stirred for 1.5 hours under ice cooling. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the portion eluted with chloroform / methanol = 1/10 was collected to obtain white solid compound 47 (5.27 g, yield 88%).
1 H NMR (DMSO-d6) δ: 1.60-1.78 (m, 2H), 3.01 (dt, J = 0.9, 10.5 Hz 1H), 3.14-3.30 (m, 3H), 4.15 (brs, 1H), 4.87 ( d, J = 2.7 Hz, 1H), 7.66 (dd, J = 0.9, 9.3 Hz 2H), 7.78 (dd, J = 0.9, 9.3 Hz 2H).

Step 2 Compound 48 (1.7 mL) was added to a solution of compound 47 (5.27 g, 20.1 mmol) and triethylamine (5.6 mL, 40.3 mmol) in dichloromethane-tetrahydrofuran (1: 1, 60 mL). 22.1 mmol) was added under ice cooling, followed by stirring for 2.5 hours under ice cooling. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 49 was used in the next step without purification.
1 H-NMR (DMSO-d6) δ: 2.03-2.07 (m, 2H), 3.12 (s, 3H), 3.21-3.37 (m, 2H), 3.46 (brs, 2H), 5.17 (brs, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H).

Third Step To a solution of compound 49 (1.5 g, 4.41 mmol) in dimethylformamide (15 mL) was added sodium azide 50 (0.43 g, 6.62 mmol) at room temperature, and the mixture was stirred at 65 ° C. for 8 hours. . The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fractions eluted with ethyl acetate / hexane = 2/5 were collected to obtain Compound 51 (1.22 g, yield 96%) as a white solid.
1 H NMR (DMSO-d6) δ: 1.82-1.85 (m, 1H), 1.92-1.96 (m, 1H), 3.12-3.39 (m, 4H), 4.28 (brs, 1H), 7.70 (dd, J = 0.6, 8.7 Hz, 2H), 7.84 (dd, J = 0.6, 8.7 Hz, 2H).

Step 4 To a solution of compound 51 (0.40 g, 1.40 mmol) in ethanol-tetrahydrofuran-formic acid (5: 1: 0.1, 12 mL) was added palladium / carbon (0.30 g, 0.279 mmol). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was dissolved in chloroform and washed sequentially with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fractions eluted with hexane / ethyl acetate = 1/9 were collected to obtain pale brown compound 52 (0.20 g, yield 64%).
1 H NMR (DMSO-d6) δ: 1.18-1.50 (m, 3H), 1.76 (ddt, J = 6.9, 7.5, 7.5 Hz, 1H), 2.76 (dt, J = 4.2, 8.1 Hz, 1H), 3.12 -3.30 (m, 4H), 7.60-7.81 (m, 5H).

化合物５７（Ｉ－０７８）の合成

Figure JPOXMLDOC01-appb-C000273

第１工程
　化合物５３（４０　ｍｇ，　０．２　ｍｍｏｌ）の１－メチル－２－ピロリドン（１．０　ｍＬ）溶液に、化合物５４（６６　ｍｇ，　０．２６　ｍｍｏｌ）、次いでＮ，Ｎ－ジイソプロピルエチルアミン（０．０８８　ｍＬ，　０．５０　ｍｍｏｌ）を加え、１００　℃で５分間加熱攪拌した。得られた化合物５５を含む反応混合物を、そのまま次反応に使用した。

第２工程
　第１工程で得られた反応混合物に，化合物５６（０．０６６　ｍＬ，　０．６　ｍｍｏｌ）を加え、マイクロ波照射下１５０℃で３０分間加熱攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール　＝　９８／２にて溶出する部分を集めて濃縮した。濃縮残渣にヘキサン－酢酸エチルにより固化させて，化合物５７（３４　ｍｇ，　収率３８　％）を、白色固体として得た。
1H NMR (DMSO-d6) δ: 2.26 (s, 3H), 2.42 (br, 4H), 3.68 (br, 4H), 3.81 (m, 2H), 3.87 (s, 3H), 4.16 (d, 2H), 6.85 (br, 1H), 7.25-7.40 (m, 5H), 7.76 (br, 1H), 7.88 (s, 1H).
Synthesis of Compound 57 (I-078)
Figure JPOXMLDOC01-appb-C000273
First Step To a solution of compound 53 (40 mg, 0.2 mmol) in 1-methyl-2-pyrrolidone (1.0 mL), compound 54 (66 mg, 0.26 mmol) and then N, N-diisopropylethylamine (0.088 mL, 0.50 mmol) was added, and the mixture was heated and stirred at 100 ° C. for 5 minutes. The reaction mixture containing the obtained compound 55 was used for the next reaction as it was.

Second Step Compound 56 (0.066 mL, 0.6 mmol) was added to the reaction mixture obtained in the first step, and the mixture was heated and stirred at 150 ° C. for 30 minutes under microwave irradiation. The reaction solution was subjected to silica gel chromatography, and portions eluted with chloroform / methanol = 98/2 were collected and concentrated. The concentrated residue was solidified with hexane-ethyl acetate to obtain Compound 57 (34 mg, 38% yield) as a white solid.
1 H NMR (DMSO-d6) δ: 2.26 (s, 3H), 2.42 (br, 4H), 3.68 (br, 4H), 3.81 (m, 2H), 3.87 (s, 3H), 4.16 (d, 2H ), 6.85 (br, 1H), 7.25-7.40 (m, 5H), 7.76 (br, 1H), 7.88 (s, 1H).

化合物６７（Ｉ－３４０）の合成

Figure JPOXMLDOC01-appb-C000274

第１工程
　エチル－１－ベンジル－４－オキソピペリジン－３－カルボキシレート（化合物５８）（１０ｇ、３８．３ｍｍｏｌ）とウレア（５９）（１１．４９ｇ、１９１ｍｍｏｌ）のエタノール（３００ｍＬ）溶液にナトリウムメトキシド（２５．８ｇ、１３４ｍｍｏｌ）を加え、１２０℃で５時間攪拌した。反応容器を室温に戻し、一晩静置した。溶媒を留去し、水を３０ｍｌ加え、１５％クエン酸水溶液でｐＨを７にし、固体を析出させた。反応容器を０℃にし、３時間撹拌した後、固体をろ取し、水で洗った。固体を乾燥させ、薄黄色の化合物（６０）（４．８７ｇ、収率４９．５％）を得た。
1H-NMR (DMSO-d6) δ: 10.91 (2H, br s), 7.31 (5H, s), 3.61 (2H, s), 2.99 (2H, s), 2.62 (2H, t, J = 5.49 Hz), 2.42-2.38 (2H, m).

第２工程
　化合物６０（１ｇ、３．８９ｍｍｏｌ）に、オキシ塩化リン（３．６ｍＬ、３８．９ｍｍｏｌ）を加え、１２０℃で１．５時間撹拌した。反応液を室温まで下げ、氷浴に注ぎ、飽和炭酸水素ナトリウム水溶液でｐＨを７に調整し、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗い、飽和食塩水で洗浄後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、酢酸エチル／ヘキサン＝１／５にて溶出する部分を集め化合物６１（６７９．７ｍｇ、収率５９．４％）を得た。化合物６１は精製することなく次工程に用いた。
1H-NMR (CDCl3) δ: 7.33-7.30 (5H, m), 3.77 (2H, s), 3.62 (2H, s), 2.99 (2H, t, J = 5.72 Hz), 2.81 (2H, t, J = 5.80 Hz).

第３工程
　化合物６１（２００ｍｇ、０．６８ｍｍｏｌ）のＮＭＰ（０．５ｍＬ）溶液に、室温で２－アミノ－Ｎ－イソプロピルエタンスルフォンアミド塩酸塩（６２）（１６５ｍｇ、０．８１６ｍｍｏｌ）、次いでＤＩＰＥＡ（０．３５６ｍＬ、２．０４ｍｍｏｌ）を加えマイクロウェーブで１４０℃２０分間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水洗し、飽和食塩水にて洗浄後、減圧濃縮した。化合物６３は精製することなく次工程に用いた。

第４工程
　化合物６３のＮＭＰ（０．５ｍＬ）溶液に、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（２５３ｍｇ、１．３６ｍｍｏｌ）、次いでＤＩＰＥＡ（０．３５６ｍｌ、２．０４ｍｍｏｌ）を加え、マイクロウェーブで１６０℃３０分間加熱攪拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、酢酸エチル／ｎ－ヘキサン＝１／１にて溶出する部分を集め、淡茶色の化合物６４（第３工程から、２６３．７ｍｇ、収率６７．６％）を得た。
1H-NMR (CDCl3) δ: 7.34-7.29 (5H, m), 3.92-3.90 (1H, m), 3.72-3.70 (4H, m), 3.70 (2H, s), 3.45 (4H, t, J = 4.88 Hz), 3.28 (2H, t, J = 5.95 Hz), 3.23 (2H, s), 2.71-2.67 (4H, m), 1.47 (9H, s), 1.19 (6H, d, J = 6.41 Hz).

第５工程
　化合物６４（２００ｍｇ、０．３４９ｍｍｏｌ）のメタノール（１ｍＬ）／ＴＨＦ（０．５ｍｌ）溶液に、室温で水酸化パラジウム（４９ｍｇ、０．０７ｍｍｏｌ）を加え、水素雰囲気下、室温で２時間撹拌した。反応液をセライトろ過し、減圧濃縮し、化合物６５（１６５．６ｍｇ、９８．５％）を得た。化合物６５は精製することなく次工程に用いた。
1H-NMR (CDCl3) δ: 5.12 (1H, s), 3.94 (2H, d, J = 5.37 Hz), 3.71 (4H, t, J = 4.87 Hz), 3.63 (2H, s), 3.46 (4H, t, J = 5.04 Hz), 3.30 (2H, t, J = 5.71 Hz), 3.11 (2H, t, J = 5.79 Hz), 2.60 (2H, t, J = 5.46 Hz), 1.48 (9H, s), 1.21 (6H, d, J = 6.55 Hz).

第６工程
　化合物６５（７０ｍｇ、０．１４５ｍｍｏｌ）のピリジン（０．５ｍｌ）溶液に、無水酢酸（０．０１６ｍｌ，０．１７４ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応液を１５％クエン酸水溶液で希釈し、クロロホルムで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄し、減圧濃縮した。残渣をクロロホルム／メタノール＝１０／１にて溶出する部分を集め、白色固体の化合物６６（４３．３ｍｇ，収率５３％）を得た。
1H-NMR (CDCl3) δ: 4.32 (2H, s), 3.95-3.92 (2H, m), 3.73 (4H, t, J = 4.96 Hz), 3.67 (2H, t, J = 5.95 Hz), 3.60 (m, 1H), 3.46 (4H, t, J = 5.03 Hz), 3.32 (2H, t, J = 6.02 Hz), 2.71-2.68 (2H, m), 2.19 (3H, s), 1.48 (9H, s), 1.20 (6H, d, J = 6.41 Hz).
Synthesis of Compound 67 (I-340)
Figure JPOXMLDOC01-appb-C000274
First Step Ethyl-1-benzyl-4-oxopiperidine-3-carboxylate (Compound 58) (10 g, 38.3 mmol) and urea (59) (11.49 g, 191 mmol) in a solution of sodium methoxy in ethanol (300 mL) (25.8 g, 134 mmol) was added, and the mixture was stirred at 120 ° C. for 5 hours. The reaction vessel was returned to room temperature and allowed to stand overnight. The solvent was distilled off, 30 ml of water was added, and the pH was adjusted to 7 with a 15% aqueous citric acid solution to precipitate a solid. The reaction vessel was brought to 0 ° C. and stirred for 3 hours, and then the solid was collected by filtration and washed with water. The solid was dried to obtain pale yellow compound (60) (4.87 g, yield 49.5%).
1H-NMR (DMSO-d6) δ: 10.91 (2H, br s), 7.31 (5H, s), 3.61 (2H, s), 2.99 (2H, s), 2.62 (2H, t, J = 5.49 Hz) , 2.42-2.38 (2H, m).

Second Step Phosphorous oxychloride (3.6 mL, 38.9 mmol) was added to compound 60 (1 g, 3.89 mmol), and the mixture was stirred at 120 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, poured into an ice bath, adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with ethyl acetate / hexane = 1/5 was collected to obtain Compound 61 (679.7 mg, yield 59.4%). Compound 61 was used in the next step without purification.
1H-NMR (CDCl3) δ: 7.33-7.30 (5H, m), 3.77 (2H, s), 3.62 (2H, s), 2.99 (2H, t, J = 5.72 Hz), 2.81 (2H, t, J = 5.80 Hz).

Step 3 Compound 61 (200 mg, 0.68 mmol) in NMP (0.5 mL) was stirred at room temperature with 2-amino-N-isopropylethanesulfonamide hydrochloride (62) (165 mg, 0.816 mmol), then DIPEA ( 0.356 mL, 2.04 mmol) was added, and the mixture was stirred with microwave at 140 ° C. for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated brine, and concentrated under reduced pressure. Compound 63 was used in the next step without purification.

Fourth Step To a solution of compound 63 in NMP (0.5 mL), tert-butylpiperazine-1-carboxylate (253 mg, 1.36 mmol) and then DIPEA (0.356 ml, 2.04 mmol) were added, and 160 μg was added by microwave. The mixture was heated and stirred at 30 ° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with ethyl acetate / n-hexane = 1/1 was collected to obtain pale brown compound 64 (from the third step, 263.7 mg, yield 67.6%). Obtained.
1H-NMR (CDCl3) δ: 7.34-7.29 (5H, m), 3.92-3.90 (1H, m), 3.72-3.70 (4H, m), 3.70 (2H, s), 3.45 (4H, t, J = 4.88 Hz), 3.28 (2H, t, J = 5.95 Hz), 3.23 (2H, s), 2.71-2.67 (4H, m), 1.47 (9H, s), 1.19 (6H, d, J = 6.41 Hz) .

Fifth Step To a solution of compound 64 (200 mg, 0.349 mmol) in methanol (1 mL) / THF (0.5 ml) was added palladium hydroxide (49 mg, 0.07 mmol) at room temperature, and in a hydrogen atmosphere at room temperature for 2 hours. Stir. The reaction solution was filtered through Celite and concentrated under reduced pressure to obtain Compound 65 (165.6 mg, 98.5%). Compound 65 was used in the next step without purification.
1H-NMR (CDCl3) δ: 5.12 (1H, s), 3.94 (2H, d, J = 5.37 Hz), 3.71 (4H, t, J = 4.87 Hz), 3.63 (2H, s), 3.46 (4H, t, J = 5.04 Hz), 3.30 (2H, t, J = 5.71 Hz), 3.11 (2H, t, J = 5.79 Hz), 2.60 (2H, t, J = 5.46 Hz), 1.48 (9H, s) , 1.21 (6H, d, J = 6.55 Hz).

Step 6 Acetic anhydride (0.016 ml, 0.174 mmol) was added to a solution of compound 65 (70 mg, 0.145 mmol) in pyridine (0.5 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with 15% aqueous citric acid solution and extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. Portions eluting the residue with chloroform / methanol = 10/1 were collected to obtain Compound 66 (43.3 mg, 53% yield) as a white solid.
1H-NMR (CDCl3) δ: 4.32 (2H, s), 3.95-3.92 (2H, m), 3.73 (4H, t, J = 4.96 Hz), 3.67 (2H, t, J = 5.95 Hz), 3.60 ( m, 1H), 3.46 (4H, t, J = 5.03 Hz), 3.32 (2H, t, J = 6.02 Hz), 2.71-2.68 (2H, m), 2.19 (3H, s), 1.48 (9H, s ), 1.20 (6H, d, J = 6.41 Hz).

第７工程
　化合物６６（４０ｍｇ，０．０７６ｍｍｏｌ）に４ｍｏｌ／Ｌの塩酸酢酸エチル溶液を（０．５ｍｌ）加え、室温で１６時間攪拌した。反応液を濃縮し、酢酸エチルで再結晶し、化合物６７（３３．２ｍｇ、総収率９４．４％）を得た。
1H-NMR (DMSO-d6) δ: 9.43 (2H, bs), 7.20 (2H, d, J = 7.22 Hz), 4.29 (2H, s), 4.09-4.06 (4H, br m), 3.82-3.79 (2H, m), 3.71 (2H, t, J = 5.54 Hz), 3.25-3.22 (7H, br m), 2.91-2.88 (2H, m), 2.14 (3H, s), 1.15 (6H, d, J = 6.38 Hz). 
Step 7 To a compound 66 (40 mg, 0.076 mmol) was added a 4 mol / L ethyl acetate solution (0.5 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and recrystallized with ethyl acetate to obtain Compound 67 (33.2 mg, total yield 94.4%).
1H-NMR (DMSO-d6) δ: 9.43 (2H, bs), 7.20 (2H, d, J = 7.22 Hz), 4.29 (2H, s), 4.09-4.06 (4H, br m), 3.82-3.79 ( 2H, m), 3.71 (2H, t, J = 5.54 Hz), 3.25-3.22 (7H, br m), 2.91-2.88 (2H, m), 2.14 (3H, s), 1.15 (6H, d, J = 6.38 Hz).

化合物６９（Ｉ－３４２）の合成

Figure JPOXMLDOC01-appb-C000275

第一工程
実施例１４第５工程で得られた化合物６５（１００ｍｇ、０．２０７ｍｍｏｌ）のＴＨＦ（０．５ｍｌ）溶液に、ＤＩＰＥＡ（０．１０８ｍｌ，０．６２０ｍｍｏｌ）とトリフルオロメタンスルホン酸チリフルオロメチルエーテル（０．１４９ｍｌ、１．０３４ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を水で希釈し、酢酸エチルで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄し、減圧濃縮した。残渣をヘキサン／酢酸エチル＝１／１にて溶出する部分を集め、白色固体の化合物６８（４２．１ｍｇ，収率３６％）を得た。

第二工程
化合物６８を用い、実施例１４第７工程に準じて反応を行い、化合物６９を得た。
1H-NMR (DMSO-d6) δ: 9.48 (2H, s), 8.46 (1H, s), 7.19 (1H, d, J = 7.47 Hz), 4.08-4.05 (4H, m), 3.78-3.75 (2H, m), 3.46 (s, 2H), 3.27 (2H, t, J = 7.24 Hz), 3.23-3.19 (4H, m), 2.98-2.94 (2H, m), 2.81-2.78 (2H, m), 1.12 (6H, d, J = 6.25 Hz).
Synthesis of Compound 69 (I-342)
Figure JPOXMLDOC01-appb-C000275
First Step Example 14 To a solution of compound 65 (100 mg, 0.207 mmol) obtained in the fifth step in THF (0.5 ml), DIPEA (0.108 ml, 0.620 mmol) and trifluoromethanesulfonic acid trifluoromethyl Ether (0.149 ml, 1.034 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was eluted with hexane / ethyl acetate = 1/1 to collect Compound 68 (42.1 mg, yield 36%) as a white solid.

The reaction was performed according to the seventh step of Example 14 using the second step compound 68, to obtain a compound 69.
1H-NMR (DMSO-d6) δ: 9.48 (2H, s), 8.46 (1H, s), 7.19 (1H, d, J = 7.47 Hz), 4.08-4.05 (4H, m), 3.78-3.75 (2H , m), 3.46 (s, 2H), 3.27 (2H, t, J = 7.24 Hz), 3.23-3.19 (4H, m), 2.98-2.94 (2H, m), 2.81-2.78 (2H, m), 1.12 (6H, d, J = 6.25 Hz).

化合物７１（Ｉ－３３８）の合成

Figure JPOXMLDOC01-appb-C000276

第一工程
実施例１４第５工程で得られた化合物６５（４５ｍｇ、０．０９３ｍｍｏｌ）のピリジン（０．５ｍｌ）溶液に、メシルクロライド（０．０１１ｍｌ、０．１４０ｍｍｏｌ）を加え、室温で４５分間攪拌した。反応液を水で希釈し、酢酸エチルで抽出し、有機層を１ｍｏｌ／Ｌ塩酸水溶液、飽和塩化ナトリウム水溶液で洗浄し、減圧濃縮することにより黄色固体の化合物７０（６２．９ｍｇ，収率＞９９％）を得た。化合物７０は精製することなく次工程に用いた。
1H-NMR (CDCl3) δ: 4.04 (2H, s), 3.95 (2H, d, J = 6.25 Hz), 3.74 (4H, t, J = 4.96 Hz), 3.67-3.63 (1H, m), 3.52 (2H, t, J = 5.64 Hz), 3.46 (4H, t, J = 4.96 Hz), 3.30 (2H, t, J = 5.80 Hz), 2.87 (3H, s), 2.78 (2H, t, J = 5.64 Hz), 1.48 (9H, s), 1.23 (6H, d, J = 6.41 Hz).

第二工程
化合物７０を用い、実施例１４の第７工程に準じて反応を行い、化合物７１を得た。
1H-NMR (DMSO-d6) δ: 9.39 (2H, br s), 7.18 (1H, d, J = 7.17 Hz), 4.04 (4H, s), 3.75 (2H, d, J = 6.41 Hz), 3.64 (2H, s), 3.56 (2H, s), 3.22-3.18 (4H, m), 3.00 (3H, s), 2.86-2.84 (2H, m), 1.12 (6H, d, J = 6.25 Hz).
Synthesis of Compound 71 (I-338)
Figure JPOXMLDOC01-appb-C000276
First Step Example 14 To a solution of compound 65 (45 mg, 0.093 mmol) obtained in the fifth step in pyridine (0.5 ml), mesyl chloride (0.011 ml, 0.140 mmol) was added, and room temperature was 45 minutes. Stir. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 mol / L aqueous hydrochloric acid solution and saturated aqueous sodium chloride solution, and concentrated under reduced pressure to give yellow solid compound 70 (62.9 mg, yield> 99). %). Compound 70 was used in the next step without purification.
1H-NMR (CDCl3) δ: 4.04 (2H, s), 3.95 (2H, d, J = 6.25 Hz), 3.74 (4H, t, J = 4.96 Hz), 3.67-3.63 (1H, m), 3.52 ( 2H, t, J = 5.64 Hz), 3.46 (4H, t, J = 4.96 Hz), 3.30 (2H, t, J = 5.80 Hz), 2.87 (3H, s), 2.78 (2H, t, J = 5.64 Hz), 1.48 (9H, s), 1.23 (6H, d, J = 6.41 Hz).

The reaction was conducted according to the seventh step of Example 14 using the second step compound 70, to give a compound 71.
1H-NMR (DMSO-d6) δ: 9.39 (2H, br s), 7.18 (1H, d, J = 7.17 Hz), 4.04 (4H, s), 3.75 (2H, d, J = 6.41 Hz), 3.64 (2H, s), 3.56 (2H, s), 3.22-3.18 (4H, m), 3.00 (3H, s), 2.86-2.84 (2H, m), 1.12 (6H, d, J = 6.25 Hz).

化合物７８（Ｉ－２８０）の合成

Figure JPOXMLDOC01-appb-C000277

第一工程
　５－ブロモ－２，４－ジクロロピリミジン（化合物７２、０．０５６ｍｌ，０．４３９ｍｍｏｌ）のＮ－メチル－２－ピロリジノン（１．５ｍＬ）溶液に２－アミノ－Ｎ－イソプロピルエタンスルホンアミド（化合物７３、８８ｍｇ，０．５２７ｍｍｏｌ）とＮ，Ｎ－ジイソプロピルエチルアミン（０．３８３ｍｌ，２．１９ｍｍｏｌ）を加え、１００℃で１５分攪拌した。ＴＬＣで反応の進行を確認した後に、ｔｅｒｔ－ブチルピペラジン－１－カルボキシラート（化合物７４、２４５ｍｇ，１．３２ｍｍｏｌ）を加え、さらに４５分攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝１／１にて溶出する部分を集め、黄色の固体化合物７５（１９７．７ｍｇ、収率８９％）を得た。
1H NMR (DMSO-d6) δ: 1.12 (d, J = 6.3 Hz, 6H), 1.42 (s, 9H), 3.23-3.46 (m, 7H), 3.63-3.74 (m, 6H), 6.99 (t, J = 5.7 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.95 (s, 1H).

第二工程
化合物７５（９０ｍｇ，０．１７７ｍｍｏｌ）のエチレングリコールジメチルエーテル／エタノール（１．５ｍｌ，２：１）溶液に４－フルオロフェニルボロン酸（化合物７６、３７．２ｍｇ，０．２６６ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１０．３ｍｇ，０．００８９ｍｍｏｌ）、炭酸ナトリウム水溶液（１ｍｏｌ／Ｌ，１ｍｌ）を加え８５℃で２時間攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝１／１にて溶出する部分を集め、白色化合物７７（７６．９ｍｇ、収率８３％）を得た。
1H NMR (DMSO-d6) δ: 1.10 (d, J = 6.6 Hz, 6H), 1.43 (s, 9H), 3.24 (t, J = 6.6 Hz, 2H), 3.38-3.43 (m, 5H), 3.70-3.72 (m, 6H), 6.54 (t, J = 5.4 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 8.7 Hz, 2H), 7.38 (t, J = 8.7 Hz, 2H), 7.70 (s, 1H).

第三工程
化合物７７（６８ｍｇ，０．１３０ｍｍｏｌ）の酢酸エチル／塩化メチレン（２ｍｌ，１：１）溶液に塩酸（０．１６ｍｌ，４ｍｏｌ／Ｌ酢酸エチル溶液）を氷冷下にて加え、室温で３時間攪拌した。反応溶液を濃縮し、得られた粗生成物を酢酸エチル／メタノールで再結晶することで淡黄色化合物７８（５６．１ｍｇ，９４％）を得た。
1H NMR (DMSO-d6) δ: 1.10 (d, J = 6.6 Hz, 6H), 3.24-3.30 (m, 6H), 3.40 (q, 6.6 Hz, 1H), 3.75-3.77 (m, 2H), 4.11 (brs, 4H), 7.20 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 8.7 Hz, 2H), 7.45 (t, J = 8.7 Hz, 2H), 7.68 (s, 1H), 7.96 (brs, 1H), 9.79 (brs, 1H).
Synthesis of Compound 78 (I-280)
Figure JPOXMLDOC01-appb-C000277
First Step 2-Amino-N-isopropylethanesulfonamide in a solution of 5-bromo-2,4-dichloropyrimidine (Compound 72, 0.056 ml, 0.439 mmol) in N-methyl-2-pyrrolidinone (1.5 mL) (Compound 73, 88 mg, 0.527 mmol) and N, N-diisopropylethylamine (0.383 ml, 2.19 mmol) were added, and the mixture was stirred at 100 ° C. for 15 minutes. After confirming the progress of the reaction by TLC, tert-butyl piperazine-1-carboxylate (Compound 74, 245 mg, 1.32 mmol) was added, and the mixture was further stirred for 45 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fractions eluted with hexane / ethyl acetate = 1/1 were collected to obtain yellow solid compound 75 (197.7 mg, yield 89%).
1 H NMR (DMSO-d6) δ: 1.12 (d, J = 6.3 Hz, 6H), 1.42 (s, 9H), 3.23-3.46 (m, 7H), 3.63-3.74 (m, 6H), 6.99 (t , J = 5.7 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.95 (s, 1H).

Second Step Compound 75 (90 mg, 0.177 mmol) in an ethylene glycol dimethyl ether / ethanol (1.5 ml, 2: 1) solution of 4-fluorophenylboronic acid (Compound 76, 37.2 mg, 0.266 mmol), tetrakistri Phenylphosphine palladium (10.3 mg, 0.0089 mmol) and an aqueous sodium carbonate solution (1 mol / L, 1 ml) were added, and the mixture was stirred at 85 ° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the portion eluted with hexane / ethyl acetate = 1/1 was collected to obtain white compound 77 (76.9 mg, yield 83%).
1 H NMR (DMSO-d6) δ: 1.10 (d, J = 6.6 Hz, 6H), 1.43 (s, 9H), 3.24 (t, J = 6.6 Hz, 2H), 3.38-3.43 (m, 5H), 3.70-3.72 (m, 6H), 6.54 (t, J = 5.4 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 8.7 Hz, 2H), 7.38 (t, J = 8.7 Hz, 2H), 7.70 (s, 1H).

Hydrochloric acid (0.16 ml, 4 mol / L ethyl acetate solution) was added to a solution of the third step compound 77 (68 mg, 0.130 mmol) in ethyl acetate / methylene chloride (2 ml, 1: 1) under ice-cooling at room temperature. Stir for 3 hours. The reaction solution was concentrated, and the resulting crude product was recrystallized from ethyl acetate / methanol to obtain a pale yellow compound 78 (56.1 mg, 94%).
1 H NMR (DMSO-d6) δ: 1.10 (d, J = 6.6 Hz, 6H), 3.24-3.30 (m, 6H), 3.40 (q, 6.6 Hz, 1H), 3.75-3.77 (m, 2H), 4.11 (brs, 4H), 7.20 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 8.7 Hz, 2H), 7.45 (t, J = 8.7 Hz, 2H), 7.68 (s, 1H), 7.96 (brs, 1H), 9.79 (brs, 1H).

化合物８０（Ｉ－３０４）の合成

Figure JPOXMLDOC01-appb-C000278

化合物８０の合成は、国際公開番号ＷＯ０３/０８７３８１Ａ１に記載の方法により作製した。Ａｍｙｃｏｌａｔｏｐｓｉｓ　ｏｒｉｅｎｔａｌｉｓ由来ＣＹＰ１４６遺伝子が挿入された発現ベクターを導入した大腸菌（Ｅｓｃｈｅｒｉｃｈｉａ　Ｃｏｌｉ　ＢＬ２１（ＤＥ３））を用い行った。滅菌した種培養培地（６．７８ｇ／Ｌ　Ｎａ２ＨＰＯ４（無水），３ｇ／Ｌ　ＫＨ２ＰＯ４，０．５ｇ／Ｌ　ＮａＣｌ，１ｇ／Ｌ　ＮＨ４Ｃｌ，１０ｇ／Ｌ　カザミノ酸，４ｇ／Ｌ　グルコース，２０ｍｇ／Ｌ　チミン，１１ｍｇ／Ｌ　ＣａＣｌ２，９５ｍｇ／Ｌ　ＭｇＣｌ２，２８ｍｇ／Ｌ　ＦｅＳＯ４，１００ｍｇ／Ｌ　Ｃａｒｂｅｎｉｃｉｌｌｉｎ）に植菌し、３００ｒｐｍの往復振とう機で２５℃、２４時間培養したものを種母とした。滅菌した本培養培地（６．７８ｇ／Ｌ　Ｎａ２ＨＰＯ４（無水），３ｇ／Ｌ　ＫＨ２ＰＯ４，０．５ｇ／Ｌ　ＮａＣｌ，１ｇ／Ｌ　ＮＨ４Ｃｌ，１０ｇ／Ｌ　カザミノ酸，２０ｍｇ／Ｌ　チミン，１１ｍｇ／Ｌ　ＣａＣｌ２，２８ｍｇ／Ｌ　ＦｅＳＯ４，８０ｍｇ／Ｌ　５－アミノレブリン酸，１００ｍｇ／Ｌ　Ｃａｒｂｅｎｉｃｉｌｌｉｎ，メルク社製０ｖｅｒｎｉｇｈｔ　ＡｕｔｏＩｎｄｕｃｔｉｏｎ　Ｓｙｓｔｅｍ－Ｓｏｌｕｔｉｏｎ　Ｉ　２０ｍｌ／Ｌ，－Ｓｏｌｕｔｉｏｎ　ＩＩ　５０ｍｌ／Ｌ，－Ｓｏｌｕｔｉｏｎ　ＩＩＩ　１ｍｌ／Ｌ）を５Ｌ容通気攪拌培養装置２台に３Ｌずつ分注し、続いて種母を１５ｍｌずつ植菌して２５℃、２４時間、４００ｒｐｍで通気培養（３Ｌ／ｍｉｎ）した。培養液を遠心管に集めて４０００ｒｐｍで１０分間遠心し、上清を除去した菌体に１．２Ｌのリン酸ナトリウム緩衝液（５０ｍｍｏｌ／Ｌ　リン酸ナトリウム（ｐＨ７．４），２％グリセロール，５０ｍｇ／ＬＣａｒｂｅｎｉｃｉｌｌｉｎ，２４ｍｇ／Ｌ　イソプロピル－β－チオガラクトピラノシド）を加えて懸濁し、５倍濃縮菌体液を調製した。５倍濃縮菌体液を５００ｍｌ容広口フラスコ３０本に４０ｍｌずつ分注し、続いて、Ｎ－メチルピペラジンを用いて実施例３に準じて合成した化合物７９のＤＭＳＯ溶液（２４０ｍｇ、０．６８ｍｍｏｌの化合物７９を３０ｍｌのＤＭＳＯに溶解）を各１ｍｌずつ添加して反応を開始した。旋回振とう機を用いて２８℃，２４時間，２００ｒｐｍで反応後、反応物を遠心管に集めて４０００ｒｐｍで１０分間遠心し、上清をＨＰ２０ＳＳカラム（２０φｘ１５０ｍｍ，溶出液：アセトニトリル／水）で粗精製した。さらに粗精製物をＣ３０カラム（Ｄｅｖｅｌｏｓｉｌ　ＲＰＡＱＵＥＯＵＳ，２０φｘ２５０ｍｍ）を用いて中性条件（溶出液：５０ｍｍｏｌ／Ｌ　酢酸アンモニウム水溶液／アセトニトリル）及び酸性条件（溶出液：０．１％ＴＦＡ－水／０．１％ＴＦＡ－アセトニトリル）で繰り返し精製し、化合物８０を得た（２２ｍｇ，０．０５９ｍｍｏｌ）。
1H NMR (DMSO-d6) δ:1.59 (m, 1H), 1.84 (m, 1H), 2.15 (m, 1H), 2.182 (s, 3H), 2.28 (m, 1H), 2.29 (m, 4H), 2.316 (dd, J=17.1, 6.8 Hz, 1H), 2.606 (dd, J=17.1, 4.3 Hz, 1H), 3.22 (m, 2H), 3.59 (m, 4H), 3.69 (m, 2H), 3.86 (m, 1H), 6.47 (brt, J=～6Hz, 1H), 6.91 (brs, 2H)
Synthesis of Compound 80 (I-304)
Figure JPOXMLDOC01-appb-C000278
Compound 80 was synthesized by the method described in International Publication No. WO03 / 088381A1. This was carried out using Escherichia coli BL21 (DE3) into which an expression vector into which the CYP146 gene derived from Amycolatopsis orientalis was inserted was introduced. Sterilized seed culture medium (6.78 g / L Na 2 HPO 4 (anhydrous), 3 g / L KH 2 PO 4 , 0.5 g / L NaCl, 1 g / L NH 4 Cl, 10 g / L casamino acid, 4 g / L Glucose, 20 mg / L thymine, 11 mg / L CaCl 2 , 95 mg / L MgCl 2 , 28 mg / L FeSO 4 , 100 mg / L Carbicillin) and cultured at 25 ° C. for 24 hours on a reciprocating shaker at 300 rpm Was the seed mother. Sterilized main culture medium (6.78 g / L Na 2 HPO 4 (anhydrous), 3 g / L KH 2 PO 4 , 0.5 g / L NaCl, 1 g / L NH 4 Cl, 10 g / L casamino acid, 20 mg / L Thymine, 11 mg / L CaCl 2 , 28 mg / L FeSO 4 , 80 mg / L 5-aminolevulinic acid, 100 mg / L Carbillillin, Merck's 0 version AutoInduction System-Solution I 20 ml / L, -Solution III 50 1 ml / L) was dispensed 3 L at a time into two 5 L aeration and agitation culture apparatuses, then 15 ml of the seed mother was inoculated and aerated (3 L / min) at 25 ° C. for 24 hours at 400 rpm. The culture broth was collected in a centrifuge tube, centrifuged at 4000 rpm for 10 minutes, and the supernatant was removed. Then, 1.2 L of sodium phosphate buffer (50 mmol / L sodium phosphate (pH 7.4), 2% glycerol, 50 mg / LC Carbicillin, 24 mg / L isopropyl-β-thiogalactopyranoside) was added and suspended to prepare a 5-fold concentrated bacterial solution. Dispense 40-fold portions of 5-fold concentrated bacterial body solution into 30 500 ml wide-necked flasks, followed by DMSO solution of compound 79 synthesized according to Example 3 using N-methylpiperazine (240 mg, 0.68 mmol of compound) 79 was dissolved in 30 ml of DMSO, and 1 ml each was added to initiate the reaction. After reaction at 200 ° C. for 24 hours at 28 ° C. using a rotary shaker, the reaction product was collected in a centrifuge tube, centrifuged at 4000 rpm for 10 minutes, and the supernatant was crudely collected on a HP20SS column (20φ × 150 mm, eluent: acetonitrile / water). Purified. Further, the crude product was subjected to neutral conditions (eluent: 50 mmol / L ammonium acetate aqueous solution / acetonitrile) and acidic conditions (eluent: 0.1% TFA-water / 0.1 using a C30 column (Develosil RPAQUEOUS, 20φ × 250 mm). % TFA-acetonitrile) to obtain compound 80 (22 mg, 0.059 mmol).
1 H NMR (DMSO-d6) δ: 1.59 (m, 1H), 1.84 (m, 1H), 2.15 (m, 1H), 2.182 (s, 3H), 2.28 (m, 1H), 2.29 (m, 4H ), 2.316 (dd, J = 17.1, 6.8 Hz, 1H), 2.606 (dd, J = 17.1, 4.3 Hz, 1H), 3.22 (m, 2H), 3.59 (m, 4H), 3.69 (m, 2H) , 3.86 (m, 1H), 6.47 (brt, J = ~ 6Hz, 1H), 6.91 (brs, 2H)

化合物８１（Ｉ－３４１）の合成

Figure JPOXMLDOC01-appb-C000279

実施例１８で得られた化合物８０（６．６ｍｇ，１８μｍｏｌ）のテトラヒドロフラン（１．３ｍｌ）溶液にピリジン（２９μｌ）、塩化チオニル（５２μｌ）加え、室温で３０分攪拌後，さらに塩化チオニル（２６μｌ）を加え１．５時間反応させた。反応液に水，メタノールを加え減圧乾燥し、再びテトラヒドロフラン（１．３ｍｌ）に溶解させ，ピリジン（２９μｌ）、塩化チオニル（５２μｌ）加え、室温で２時間反応させた。反応液に水，メタノールを加え減圧乾燥し、ＯＤＳカラム（ＳｕｎＦｉｒｅ　Ｐｒｅｐ　Ｃ１８　５μｍ　１０φｘ１５０ｍｍ）を用い酸性条件（溶出液：０．１％ＴＦＡ－水／０．１％ＴＦＡ－アセトニトリル）で精製することで、化合物８１を得た（１．１ｍｇ，２．８μｍｏｌ）。
1H NMR (DMSO-d6) δ: 2.08 (m, 1H), 2.13 (m, 1H), 2.39 (m, 2H), 2.81 (m, 1H), 2.83 (s, 3H), 3.05 (m, 2H), 3.13 (m, 1H), 3.24 (m, 2H), 3.248 (t, J=7.3 Hz, 2H), 3.49 (m, 2H), 3.77 (m, 2H) 4.60 (m, 2H) 4.70 (m, 1H)
Synthesis of Compound 81 (I-341)
Figure JPOXMLDOC01-appb-C000279
Pyridine (29 μl) and thionyl chloride (52 μl) were added to a solution of compound 80 (6.6 mg, 18 μmol) obtained in Example 18 in tetrahydrofuran (1.3 ml), and the mixture was stirred at room temperature for 30 minutes, and further thionyl chloride (26 μl). Was allowed to react for 1.5 hours. Water and methanol were added to the reaction solution, dried under reduced pressure, dissolved again in tetrahydrofuran (1.3 ml), pyridine (29 μl) and thionyl chloride (52 μl) were added, and the mixture was reacted at room temperature for 2 hours. Water and methanol were added to the reaction solution, dried under reduced pressure, and purified under acidic conditions (eluent: 0.1% TFA-water / 0.1% TFA-acetonitrile) using an ODS column (SunFire Prep C18 5 μm 10φ × 150 mm). Compound 81 was obtained (1.1 mg, 2.8 μmol).
1 H NMR (DMSO-d6) δ: 2.08 (m, 1H), 2.13 (m, 1H), 2.39 (m, 2H), 2.81 (m, 1H), 2.83 (s, 3H), 3.05 (m, 2H ), 3.13 (m, 1H), 3.24 (m, 2H), 3.248 (t, J = 7.3 Hz, 2H), 3.49 (m, 2H), 3.77 (m, 2H) 4.60 (m, 2H) 4.70 (m , 1H)

化合物８５（Ｉ－２７７）の合成

Figure JPOXMLDOC01-appb-C000280

第１工程
　化合物８２（７１０ｍｇ，２．３７ｍｍｏｌ）のクロロホルム（１８ｍＬ）溶液に、Ｎ－クロロスクシミド（１．５８ｇ，１１．９ｍｍｏｌ）を加え、８０℃で３時間攪拌した。反応液を水に注ぎ、クロロホルムで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝７０／３０にて溶出する部分を集め減圧濃縮することにより、白色固体８３（３５６ｍｇ，収率４５％）を得た。
1H NMR (CDCl3) δ: 4.49 (2H, t, J = 4.5 Hz), 3.24 (2H, t, J = 4.4 Hz), 2.97 (3H, s).

第２工程
　化合物８３（２７５ｍｇ，０．８２ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４３２ｍＬ，２．４７ｍｍｏｌ）、１－メチルピペラジン（０．１３８ｍＬ，１．２４ｍｍｏｌ）を加え、５０℃で３０分間攪拌した。反応液を水に注ぎ、クロロホルムで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮することにより、黄色油状化合物８４（１９０ｍｇ，収率８１％）を得た。
1H NMR (CDCl3) δ: 4.40 (2H, t, J = 4.5 Hz), 3.75 (4H, t, J = 5.0 Hz), 3.13 (2H, t, J = 4.5 Hz), 2.77 (3H, s), 2.43 (4H, t, J = 5.1 Hz), 2.32 (3H, s).

第３工程
　化合物８４（５０ｍｇ，０．１７ｍｍｏｌ）の１，４－ジオキサン（１ｍＬ）溶液に、２－アミノ－Ｎ－イソプロピルエタンスルホンアミド塩酸塩（４４ｍｇ，０．２６ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１６ｍｇ，０．０２ｍｍｏｌ）、２－ジシクロヘキシルホスフィノ－２’，６’－ジイソプロポキシ－１，１’－ビフェニル（３３ｍｇ，０．０７ｍｍｏｌ）、ナトリウム－ｔｅｒｔ－ブトキシド（５１ｍｇ，０．５３ｍｍｏｌ）を加え、１００℃で２時間攪拌した。反応液を水に注ぎ、クロロホルムで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮し、ジエチルエーテルで再結晶することにより、白色固体として化合物８５（１１ｍｇ，収率１５％）を得た。
1H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 7.2 Hz), 6.47 (1H, t, J = 5.9 Hz), 4.24 (2H, t, J = 4.2 Hz), 3.67 (2H, q, J = 7.5 Hz), 3.54 (4H, brs), 3.41 (1H, m), 3.24 (2H, t, J = 7.1 Hz), 2.92 (2H, t, J = 4.4 Hz), 2.45 (3H, s), 2.29 (4H, brs), 2.19 (3H, s), 1.12 (6H, d, J = 6.6 Hz).
Synthesis of Compound 85 (I-277)
Figure JPOXMLDOC01-appb-C000280
First Step N-chlorosuccinimide (1.58 g, 11.9 mmol) was added to a solution of compound 82 (710 mg, 2.37 mmol) in chloroform (18 mL), and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was poured into water and extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the portion eluted with hexane / ethyl acetate = 70/30 was collected and concentrated under reduced pressure to give a white solid 83 (356 mg, yield 45). %).
1 H NMR (CDCl3) δ: 4.49 (2H, t, J = 4.5 Hz), 3.24 (2H, t, J = 4.4 Hz), 2.97 (3H, s).

Second Step To a solution of compound 83 (275 mg, 0.82 mmol) in tetrahydrofuran (5 mL), N, N-diisopropylethylamine (0.432 mL, 2.47 mmol) and 1-methylpiperazine (0.138 mL, 1.24 mmol) were added. In addition, the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was poured into water, extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure to give yellow oily compound 84 (190 mg, yield 81). %).
1 H NMR (CDCl3) δ: 4.40 (2H, t, J = 4.5 Hz), 3.75 (4H, t, J = 5.0 Hz), 3.13 (2H, t, J = 4.5 Hz), 2.77 (3H, s) , 2.43 (4H, t, J = 5.1 Hz), 2.32 (3H, s).

Third Step To a solution of compound 84 (50 mg, 0.17 mmol) in 1,4-dioxane (1 mL), 2-amino-N-isopropylethanesulfonamide hydrochloride (44 mg, 0.26 mmol), tris (dibenzylideneacetone) Di-palladium (0) (16 mg, 0.02 mmol), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1′-biphenyl (33 mg, 0.07 mmol), sodium-tert-butoxide (51 mg , 0.53 mmol) and stirred at 100 ° C. for 2 hours. The reaction solution was poured into water, extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was subjected to amino silica gel chromatography. The fraction eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure, and recrystallized with diethyl ether to give a white solid. As a compound 85 (11 mg, 15% yield).
1 H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 7.2 Hz), 6.47 (1H, t, J = 5.9 Hz), 4.24 (2H, t, J = 4.2 Hz), 3.67 (2H, q, J = 7.5 Hz), 3.54 (4H, brs), 3.41 (1H, m), 3.24 (2H, t, J = 7.1 Hz), 2.92 (2H, t, J = 4.4 Hz), 2.45 (3H, s), 2.29 (4H, brs), 2.19 (3H, s), 1.12 (6H, d, J = 6.6 Hz).

化合物８９（Ｉ－２７９）の合成

Figure JPOXMLDOC01-appb-C000281

第１工程
　化合物８６（１００ｍｇ，０．４６ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）／メタノール（１ｍＬ）溶液に、氷冷下で水素化ホウ素ナトリウム（１７ｍｇ，０．４６ｍｍｏｌ）を加えた後、室温で３０分間攪拌した。反応液を１ｍｏｌ／Ｌ塩酸水溶液に注ぎ、酢酸エチルで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝３０／７０にて溶出する部分を集め減圧濃縮することにより、黄色固体８７（５２ｍｇ，収率５２％）を得た。
1H NMR (CDCl3) δ: 4.43-4.37 (1H, m), 3.25-2.80 (4H, m), 2.07 (2H, dd, J = 12.3, 6.21 Hz), 1.71 (1H, d, J = 3.7 Hz).

第２工程
　化合物８７（５０ｍｇ，０．２３ｍｍｏｌ）のＮ－メチルピロリドン（１ｍＬ）溶液に、２－アミノ－エタンスルホンアミド塩酸塩（５５ｍｇ，０．３４ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピエルエチルアミン（０．１２０ｍＬ，０．６９ｍｍｏｌ）を加えた後、１００℃で３０分間攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮することにより、黄色固体８８（９８ｍｇ）を混合物として得た。化合物８８はこれ以上精製することなく、そのまま次の反応に用いた。

第３工程
　化合物８８（９８ｍｇ）のＮ－メチルピロリドン（１ｍＬ）溶液に、１－メチルピペラジン（０．２５４ｍＬ，２．２８ｍｍｏｌ）を加えた後、マイクロウェーブ照射下１８０℃で３０分間攪拌した。反応液をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮し、酢酸エチルで再結晶することにより、白色固体として化合物８９（４５ｍｇ，収率５３％）を得た。
1H-NMR (DMSO-d6) δ: 6.91 (2H, s), 6.48 (1H, s), 4.80 (1H, d, J = 4.1 Hz), 3.87 (1.0H, brs), 3.68-3.61 (6H, m), 3.22 (2H, t, J = 7.0 Hz), 2.55-2.42 (2H, m), 2.29 (4H, brs), 2.18 (3H, s), 2.09-1.99 (1H, m), 1.81-1.78 (1H, m), 1.63-1.61 (1H, m).
Synthesis of Compound 89 (I-279)
Figure JPOXMLDOC01-appb-C000281
Step 1 To a solution of compound 86 (100 mg, 0.46 mmol) in tetrahydrofuran (2 mL) / methanol (1 mL) was added sodium borohydride (17 mg, 0.46 mmol) under ice-cooling, followed by stirring at room temperature for 30 minutes. did. The reaction solution was poured into a 1 mol / L hydrochloric acid aqueous solution, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 30/70 was collected and concentrated under reduced pressure to give a yellow solid 87 (52 mg, yield 52). %).
1 H NMR (CDCl3) δ: 4.43-4.37 (1H, m), 3.25-2.80 (4H, m), 2.07 (2H, dd, J = 12.3, 6.21 Hz), 1.71 (1H, d, J = 3.7 Hz ).

Second Step To a solution of compound 87 (50 mg, 0.23 mmol) in N-methylpyrrolidone (1 mL), 2-amino-ethanesulfonamide hydrochloride (55 mg, 0.34 mmol), N, N-diisopropylethylamine (0 120 mL, 0.69 mmol) was added, followed by stirring at 100 ° C. for 30 minutes. The reaction solution was subjected to silica gel chromatography, and the portions eluted with chloroform / methanol = 90/10 were collected and concentrated under reduced pressure to obtain a yellow solid 88 (98 mg) as a mixture. Compound 88 was directly used in the next reaction without further purification.

Third Step To a solution of compound 88 (98 mg) in N-methylpyrrolidone (1 mL) was added 1-methylpiperazine (0.254 mL, 2.28 mmol), and the mixture was stirred at 180 ° C. for 30 minutes under microwave irradiation. The reaction solution was subjected to amino silica gel chromatography, and the portion eluted with chloroform / methanol = 90/10 was collected, concentrated under reduced pressure, and recrystallized with ethyl acetate to give Compound 89 (45 mg, 53% yield) as a white solid. )
1 H-NMR (DMSO-d6) δ: 6.91 (2H, s), 6.48 (1H, s), 4.80 (1H, d, J = 4.1 Hz), 3.87 (1.0H, brs), 3.68-3.61 (6H , m), 3.22 (2H, t, J = 7.0 Hz), 2.55-2.42 (2H, m), 2.29 (4H, brs), 2.18 (3H, s), 2.09-1.99 (1H, m), 1.81- 1.78 (1H, m), 1.63-1.61 (1H, m).

化合物９７（Ｉ－３３６）の合成

Figure JPOXMLDOC01-appb-C000282

第１工程
　ｎ－ヘキサンで３回洗浄した６０％水素化ナトリウム（１．５３ｇ，３８．３ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液に、炭酸ジエチル（３．７７ｇ，３２．３ｍｍｏｌ）を加えた後、８０℃で５分間攪拌した。加熱攪拌下、反応液に化合物９０（２．７９ｇ，１２．８ｍｍｏｌ）のテトラヒドフラン（１０ｍＬ）を滴下し、８０℃でさらに５時間攪拌した。反応液を１ｍｏｌ／Ｌ塩酸水溶液に注ぎ、ジエチルエーテルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、黄色油状化合物９１（３．７９ｇ）を混合物として得た。化合物９１はこれ以上精製することなく、そのまま次の反応に用いた。

第２工程
　化合物９１（３．７９ｇ）のエタノール（３０ｍＬ）溶液に、２８％ナトリウムメトキシド（７．５５ｇ，３９．２ｍｍｏｌ）、尿素（３．９２ｇ，６５．３ｍｍｏｌ）を加えた後、９５℃で２時間攪拌した。反応液を減圧濃縮し、濃塩酸を用いてｐＨを３．５に調整することで、黄色固体が析出した。固体をろ過した後、得られた固体を水で洗浄し、減圧乾燥することにより、黄色固体９２（２．０６ｇ，２段階収率５５％）を得た。
1H NMR (DMSO-d6) δ: 10.86 (1H, s), 10.64 (1H, s), 7.40-7.18 (5H, m), 4.46-4.32 (2H, m), 2.61-2.06 (4H, m), 2.03-1.91 (1H, m), 1.72-1.59 (1H, m), 1.31 (3H, s).

第３工程
　化合物９２（２．０６ｇ，７．１９ｍｍｏｌ）に、オキシ塩化リン（１０．０ｍＬ，１０８ｍｍｏｌ）を加えた後、１００℃で４時間攪拌した。反応液を減圧濃縮し、氷冷下で水を加えた後、水酸化ナトリウムで中和した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝９０／１０にて溶出する部分を集め減圧濃縮することにより、黄色固体として化合物９３（４００ｍｇ，収率２６％）を得た。
1H NMR (CDCl3) δ: 6.42 (1H, dd, J = 3.0, 1.7 Hz), 3.03 (2H, t, J = 8.5 Hz), 2.47 (2H, t, J = 8.5 Hz), 2.03 (3H, d, J = 1.1 Hz).

第４工程
　化合物９３（２５０ｍｇ，１．１６ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液に、ｍ－クロロ過安息香酸（４０１ｍｇ，２．３３ｍｍｏｌ）を加えた後、室温で２時間攪拌した。反応液をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝８０／２０にて溶出する部分を集め減圧濃縮することにより、白色固体として化合物９４（１８１ｍｇ，収率６７％）を得た。
1H NMR (CDCl3) δ: 4.08 (1H, s), 2.94-2.75 (2H, m), 2.40-2.30 (1H, m), 1.98-1.84 (1H, m), 1.61 (3H, s).

第５工程
　化合物９４（１７８ｍｇ，０．７７ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、氷冷下で水素化リチウムアルミニウム（２８ｍｇ，０．７７ｍｍｏｌ）を加えた後、室温で一晩攪拌した。反応液に氷冷下で水を加えた後、反応液を水に注ぎ、クロロホルムで抽出し、有機層を飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝７０／３０にて溶出する部分を集め減圧濃縮することにより、無色油状化合物として化合物９５（７３ｍｇ，収率４１％）を得た。
1H NMR (CDCl3) δ: 3.27-3.11 (1H, m), 2.98-2.83 (2H, m), 2.72 (1H, d, J = 18.0 Hz), 2.06-1.96 (2H, m), 1.90-1.77 (1H, m), 1.49 (3H, s), 1.38 (1H, s).

第６工程
　化合物９５（９４ｍｇ，０．４０ｍｍｏｌ）のＮ－メチルピロリドン（１．５ｍＬ）溶液に、２－アミノ－Ｎ－イソプロピルエタンスルホンアミド塩酸塩（９８ｍｇ，０．４８ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピエルエチルアミン（０．１６９ｍＬ，０．９７ｍｍｏｌ）を加えた後、１００℃で３０分間攪拌した。さらに反応液にｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（３７６ｍｇ，２．０２ｍｍｏｌ）を加えた後、マイクロウェーブ照射下１５０℃で１時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９５／５にて溶出する部分を集め減圧濃縮することにより、黄色油状化合物６９（２７７ｍｇ）を混合物として得た。化合物９６はこれ以上精製することなく、そのまま次の反応に用いた。

第７工程
　化合物９６（２７７ｍｇ）の塩化メチレン（４ｍＬ）溶液に、トリフルオロ酢酸（０．８ｍＬ）を加えた後、室温で一晩攪拌した。反応液を減圧濃縮し、塩基性になるまでトリエチルアミンを加えた後、反応液をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮し、ジエチルエーテル／酢酸エチルで再結晶することにより、白色固体として化合物９７（８５ｍｇ，収率５１％）を得た。
1H NMR (DMSO-d6) δ: 7.08 (1H, d, J = 7.3 Hz), 6.40 (1H, t, J = 5.1 Hz), 4.40 (1H, s), 3.65 (2H, dd, J = 13.8, 6.5 Hz), 3.57-3.48 (4H, m), 3.46-3.35 (1H, m), 3.26-3.19 (2H, m), 2.72-2.53 (5H, m), 2.39-2.15 (3H, m), 1.73-1.50 (2H, m), 1.20 (3H, s), 1.11 (6H, d, J = 6.4 Hz).
Synthesis of Compound 97 (I-336)
Figure JPOXMLDOC01-appb-C000282
First Step Diethyl carbonate (3.77 g, 32.3 mmol) was added to a solution of 60% sodium hydride (1.53 g, 38.3 mmol) in tetrahydrofuran (30 mL) washed three times with n-hexane, and then 80 Stir at 5 ° C. for 5 minutes. Under heating and stirring, tetrahydrofuran (10 mL) of Compound 90 (2.79 g, 12.8 mmol) was added dropwise to the reaction solution, and the mixture was further stirred at 80 ° C. for 5 hours. The reaction solution was poured into a 1 mol / L hydrochloric acid aqueous solution and extracted with diethyl ether, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, yellow oily compound 91 (3.79 g) was obtained as a mixture. Compound 91 was directly used in the next reaction without further purification.

Second Step To a solution of compound 91 (3.79 g) in ethanol (30 mL) was added 28% sodium methoxide (7.55 g, 39.2 mmol) and urea (3.92 g, 65.3 mmol), and then 95 ° C. For 2 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3.5 using concentrated hydrochloric acid to precipitate a yellow solid. After filtering the solid, the obtained solid was washed with water and dried under reduced pressure to obtain a yellow solid 92 (2.06 g, 2-step yield 55%).
1 H NMR (DMSO-d6) δ: 10.86 (1H, s), 10.64 (1H, s), 7.40-7.18 (5H, m), 4.46-4.32 (2H, m), 2.61-2.06 (4H, m) , 2.03-1.91 (1H, m), 1.72-1.59 (1H, m), 1.31 (3H, s).

Third Step After adding phosphorus oxychloride (10.0 mL, 108 mmol) to compound 92 (2.06 g, 7.19 mmol), the mixture was stirred at 100 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added under ice cooling, and then neutralized with sodium hydroxide. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was subjected to silica gel chromatography. The fraction eluted with hexane / ethyl acetate = 90/10 was collected and concentrated under reduced pressure to give Compound 93 (400 mg, yield) as a yellow solid. 26%).
1 H NMR (CDCl3) δ: 6.42 (1H, dd, J = 3.0, 1.7 Hz), 3.03 (2H, t, J = 8.5 Hz), 2.47 (2H, t, J = 8.5 Hz), 2.03 (3H, d, J = 1.1 Hz).

Fourth Step To a solution of compound 93 (250 mg, 1.16 mmol) in methylene chloride (5 mL) was added m-chloroperbenzoic acid (401 mg, 2.33 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was subjected to silica gel chromatography, and the portions eluted with hexane / ethyl acetate = 80/20 were collected and concentrated under reduced pressure to obtain Compound 94 (181 mg, 67% yield) as a white solid.
1 H NMR (CDCl3) δ: 4.08 (1H, s), 2.94-2.75 (2H, m), 2.40-2.30 (1H, m), 1.98-1.84 (1H, m), 1.61 (3H, s).

Step 5 To a solution of compound 94 (178 mg, 0.77 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (28 mg, 0.77 mmol) under ice-cooling, and the mixture was stirred overnight at room temperature. After adding water to the reaction solution under ice-cooling, the reaction solution was poured into water, extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 70/30 was collected and concentrated under reduced pressure to give Compound 95 (73 mg, 73 mg, Yield 41%).
1 H NMR (CDCl3) δ: 3.27-3.11 (1H, m), 2.98-2.83 (2H, m), 2.72 (1H, d, J = 18.0 Hz), 2.06-1.96 (2H, m), 1.90-1.77 (1H, m), 1.49 (3H, s), 1.38 (1H, s).

Step 6 To a solution of compound 95 (94 mg, 0.40 mmol) in N-methylpyrrolidone (1.5 mL), 2-amino-N-isopropylethanesulfonamide hydrochloride (98 mg, 0.48 mmol), N, N-di After adding isopropyl ethylamine (0.169 mL, 0.97 mmol), the mixture was stirred at 100 ° C. for 30 minutes. Further, tert-butyl piperazine-1-carboxylate (376 mg, 2.02 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was subjected to silica gel chromatography. The fraction eluted with chloroform / methanol = 95/5 was collected and concentrated under reduced pressure to give yellow oily compound 69 (277 mg) as a mixture. Obtained. Compound 96 was directly used in the next reaction without further purification.

Step 7 To a solution of compound 96 (277 mg) in methylene chloride (4 mL) was added trifluoroacetic acid (0.8 mL), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, triethylamine was added until basic, and the reaction solution was subjected to amino silica gel chromatography. The portion eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure, and diethyl ether / Recrystallization with ethyl acetate gave Compound 97 (85 mg, 51% yield) as a white solid.
1 H NMR (DMSO-d6) δ: 7.08 (1H, d, J = 7.3 Hz), 6.40 (1H, t, J = 5.1 Hz), 4.40 (1H, s), 3.65 (2H, dd, J = 13.8 , 6.5 Hz), 3.57-3.48 (4H, m), 3.46-3.35 (1H, m), 3.26-3.19 (2H, m), 2.72-2.53 (5H, m), 2.39-2.15 (3H, m), 1.73-1.50 (2H, m), 1.20 (3H, s), 1.11 (6H, d, J = 6.4 Hz).

化合物１０４（Ｉ－３４４）の合成

Figure JPOXMLDOC01-appb-C000283

第１工程
　２－（ベンジルオキシ）エタンスルホニルクロライド（化合物９８、５．８０ｇ，２４．８ｍｍｏｌ）のテトラヒドロフラン（６０ｍＬ）溶液に、氷冷下でイソプロピルアミン（１０．６ｍＬｇ，１２４ｍｍｏｌ）を加えた後、室温で１時間攪拌した。反応液を水に注ぎ、ジエチルエーテルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝５０／５０にて溶出する部分を集め減圧濃縮することにより、淡黄色油状化合物として化合物９９（５．８８ｇ，収率９２％）を得た。
1H NMR (CDCl3) δ: 7.43-7.27 (5H, m), 4.54 (2H, s), 4.17 (1H, s), 3.91 (2H, t, J = 5.9 Hz), 3.66-3.51 (1H, m), 3.30 (2H, t, J = 5.9 Hz), 1.14 (6H, d, J = 6.0 Hz).

第２工程
　化合物９９（５．８７ｇ，２２．８ｍｍｏｌ）のメタノール（１２０ｍＬ）溶液に、２０％水酸化パラジウム（１０．６ｍＬｇ，１２４ｍｍｏｌ）を加えた後、水素雰囲気下、室温で２時間攪拌した。反応液をセライトろ過後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮することにより、無色油状化合物として２－ヒドロキシ－Ｎ－イソプロピルエタンスルホンアミド（化合物１００、３．６０ｇ，収率９４％）を得た。
1H NMR (CDCl3) δ: 4.57-4.49 (1H, m), 4.06 (2H, q, J = 5.1 Hz), 3.72-3.59 (1H, m), 3.29-3.25 (2H, m), 2.88-2.81 (1H, m), 1.26 (6H, dd, J = 6.6, 0.86 Hz).

第３工程
　化合物１０１（２００ｍｇ，０．７２ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、ｔｅｒｔ－ブチル－４－カルボイミドイルピペラジン－１－カルボキシレート塩酸塩（２３０ｍｇ，０．８７ｍｍｏｌ）、１規定ナトリムメトキシド／メタノール溶液（１．８１ｍＬ，１．８１ｍｍｏｌ）を加えた後、室温で一晩攪拌した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をジイソプロピルエーテルで洗浄することにより、白色固体として化合物１０２（２７４ｍｇ，収率８６％）を得た。
1H NMR (CDCl3) δ: 11.80 (1H, brs), 7.42-7.25 (5H, m), 4.64 (2H, s), 3.85 (1.0H, t, J = 4.7 Hz), 3.73-3.63 (4H, m), 3.57-3.49 (4H, m), 2.80-2.66 (2H, m), 2.57-2.45 (2H, m), 2.03-1.94 (2H, m), 1.50 (9H, s).

第４工程
　化合物１０２（１５９ｍｇ，０．３６ｍｍｏｌ）の１，４－ジオキサン（３ｍＬ）溶液に、トリフェニルホスフィン（１２３ｍｇ，０．４７ｍｍｏｌ）、２．２Ｍジエチルアゾジカルボキシレート／トルエン溶液（０．２１３ｍＬ，０．４７ｍｍｏｌ）、化合物１００（７２ｍｇ，０．４３ｍｍｏｌ）の１，４－ジオキサン（０．５ｍＬ）溶液を加え、室温で２時間攪拌した。さらにトリフェニルホスフィン（１２３ｍｇ，０．４７ｍｍｏｌ）、２．２Ｍジエチルアゾジカルボキシレート／トルエン溶液（０．２１３ｍＬ，０．４７ｍｍｏｌ）、化合物１００（７２ｍｇ，０．４３ｍｍｏｌ）の１，４－ジオキサン（０．５　ｍＬ）溶液を１時間毎に２度加え、室温で１時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣を逆相のＨＰＬＣに付し、０．３％ギ酸を含む水／アセトニトリル＝４０／６０にて溶出する部分を集め減圧濃縮することにより、黄色油状化合物として化合物１０３（１０５ｍｇ）を混合物として得た。化合物１０３はこれ以上精製することなく、そのまま次の反応に用いた。

第５工程
　化合物１０３（１０３ｍｇ）のメタノール（１２ｍＬ）溶液を連続水素化反応装置を用いて、８０気圧水素雰囲気下、１０％パラジウム炭素を触媒として、８０℃で２時間攪拌した。反応液を減圧濃縮した後、塩化メチレン（５ｍＬ）、トリフルオロ酢酸（１ｍＬ）を加え、室温で１時間攪拌した。反応液を減圧濃縮し、塩基性になるまでトリエチルアミンを加えた後、反応液をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮し、ジエチルエーテル／酢酸エチルで再結晶することにより、白色固体として化合物１０４（３１ｍｇ，２段階収率２２％）を得た。
1H NMR (DMSO-d6) δ: 7.18 (1H, d, J = 7.3 Hz), 4.78 (1H, s), 4.56 (2H, brs), 3.86 (1H, brs), 3.62 (4H, brs), 3.51-3.36 (3H, m), 2.77 (4H, brs), 2.69-2.53 (3H, m), 2.29-2.17 (1H, m), 1.89-1.78 (1H, m), 1.72-1.60 (1H, m), 1.11 (6H, d, J = 5.6 Hz).
Synthesis of Compound 104 (I-344)
Figure JPOXMLDOC01-appb-C000283
Step 1 To a solution of 2- (benzyloxy) ethanesulfonyl chloride (compound 98, 5.80 g, 24.8 mmol) in tetrahydrofuran (60 mL) was added isopropylamine (10.6 mL g, 124 mmol) under ice cooling, Stir at room temperature for 1 hour. The reaction solution was poured into water and extracted with diethyl ether, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 50/50 was collected and concentrated under reduced pressure to give Compound 99 (5 .88 g, 92% yield).
1 H NMR (CDCl3) δ: 7.43-7.27 (5H, m), 4.54 (2H, s), 4.17 (1H, s), 3.91 (2H, t, J = 5.9 Hz), 3.66-3.51 (1H, m ), 3.30 (2H, t, J = 5.9 Hz), 1.14 (6H, d, J = 6.0 Hz).

Second Step 20% palladium hydroxide (10.6 mLg, 124 mmol) was added to a solution of compound 99 (5.87 g, 22.8 mmol) in methanol (120 mL), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure to give 2-hydroxy-N— as a colorless oily compound. Isopropylethanesulfonamide (Compound 100, 3.60 g, 94% yield) was obtained.
1 H NMR (CDCl3) δ: 4.57-4.49 (1H, m), 4.06 (2H, q, J = 5.1 Hz), 3.72-3.59 (1H, m), 3.29-3.25 (2H, m), 2.88-2.81 (1H, m), 1.26 (6H, dd, J = 6.6, 0.86 Hz).

Step 3 To a solution of compound 101 (200 mg, 0.72 mmol) in methanol (2 mL) was added tert-butyl-4-carbomidoylpiperazine-1-carboxylate hydrochloride (230 mg, 0.87 mmol), 1N sodium methoxide. / Methanol solution (1.81 mL, 1.81 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to obtain Compound 102 (274 mg, yield 86%) as a white solid.
1 H NMR (CDCl3) δ: 11.80 (1H, brs), 7.42-7.25 (5H, m), 4.64 (2H, s), 3.85 (1.0H, t, J = 4.7 Hz), 3.73-3.63 (4H, m), 3.57-3.49 (4H, m), 2.80-2.66 (2H, m), 2.57-2.45 (2H, m), 2.03-1.94 (2H, m), 1.50 (9H, s).

Step 4 Compound 102 (159 mg, 0.36 mmol) in 1,4-dioxane (3 mL) was added to triphenylphosphine (123 mg, 0.47 mmol), 2.2 M diethylazodicarboxylate / toluene solution (0.213 mL). , 0.47 mmol), and a solution of compound 100 (72 mg, 0.43 mmol) in 1,4-dioxane (0.5 mL) were added and stirred at room temperature for 2 hours. Further, triphenylphosphine (123 mg, 0.47 mmol), 2.2 M diethylazodicarboxylate / toluene solution (0.213 mL, 0.47 mmol), compound 100 (72 mg, 0.43 mmol) in 1,4-dioxane (0 0.5 mL) solution was added twice every hour and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was subjected to reverse phase HPLC, and the fraction eluted with water / acetonitrile containing 0.3% formic acid = 40/60 was collected and concentrated under reduced pressure to give a yellow oil. Compound 103 (105 mg) was obtained as a mixture as a compound. Compound 103 was directly used in the next reaction without further purification.

Fifth Step A methanol (12 mL) solution of compound 103 (103 mg) was stirred at 80 ° C. for 2 hours using 10% palladium on carbon as a catalyst in a hydrogen atmosphere of 80 atm using a continuous hydrogenation reactor. The reaction mixture was concentrated under reduced pressure, methylene chloride (5 mL) and trifluoroacetic acid (1 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, triethylamine was added until basic, and the reaction solution was subjected to amino silica gel chromatography. The portion eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure, and diethyl ether / Recrystallization from ethyl acetate gave Compound 104 (31 mg, two-stage yield 22%) as a white solid.
1 H NMR (DMSO-d6) δ: 7.18 (1H, d, J = 7.3 Hz), 4.78 (1H, s), 4.56 (2H, brs), 3.86 (1H, brs), 3.62 (4H, brs), 3.51-3.36 (3H, m), 2.77 (4H, brs), 2.69-2.53 (3H, m), 2.29-2.17 (1H, m), 1.89-1.78 (1H, m), 1.72-1.60 (1H, m ), 1.11 (6H, d, J = 5.6 Hz).

化合物１１１（Ｉ－３５１）の合成

Figure JPOXMLDOC01-appb-C000284

第１工程
　化合物１０５（５ｇ，２６．６ｍｍｏｌ）のエタノール（４０ｍＬ）溶液に、２８％ナトリウムメトキシド（１５．３７ｇ，８０．０ｍｍｏｌ）、尿素（７．９８ｇ，１３３ｍｍｏｌ）を加え、９５℃で２時間攪拌した。氷冷下で反応液に濃塩酸を加えｐＨを３．５に調整した後、減圧濃縮した。残渣に水を加えろ取した後、大量の水で洗浄し、減圧乾燥することにより、白色固体１０６（１．９６ｇ，収率４０％）を得た。
1H NMR (DMSO-d6) δ: 11.04 (1H, brs), 10.76 (1H, brs), 3.27 (2H, s), 2.80 (2H, t, J = 5.8 Hz), 2.57 (2H, t, J = 5.6 Hz).

第２工程
　化合物１０６（１．９５ｇ，１０．６　ｍｍｏｌ）に、オキシ塩化リン（９．８４ｍＬ，１０６ｍｍｏｌ）、Ｎ，Ｎ－ジメチルホルムアミド（触媒量）を加え、１００℃で３時間攪拌した。反応液をゆっくりと氷水に注ぎ、析出した固体をろ取した後、大量の水で洗浄し、減圧乾燥することにより、白色固体１０７（２ｇ，収率８６％）を得た。
1H NMR (CDCl3) δ: 3.81 (2H, s), 3.23 (2H, t, J = 6.0 Hz), 2.96 (2H, t, J = 6.1 Hz).

第３工程
　化合物１０７（５００ｍｇ，２．２６ｍｍｏｌ）の塩化メチレン（１０ｍＬ）溶液に、氷冷下でｍ－クロロ過安息香酸（５８５ｍｇ，３．３９ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９７／３にて溶出する部分を集め減圧濃縮することにより、混合物として化合物１０８（５９６ｍｇ）を得た。化合物１０８はこれ以上精製することなく、次の反応に用いた。
1H NMR (CDCl3) δ: 4.21 (1H, dd, J = 17.2, 2.4 Hz), 3.79-3.68 (2H, m), 3.48-3.40 (1H, m), 3.22 (1H, dt, J = 18.9, 4.0 Hz), 2.86 (1H, dt, J = 19.5, 6.4 Hz).

第４工程
　化合物１０８（１９５ｍｇ）の塩化メチレン（４ｍＬ）溶液に、氷冷下でｍ－クロロ過安息香酸（２１３ｍｇ，１．２３ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を１ｍｏｌ／Ｌ水酸化ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、白色固体として化合物１０９（１５４ｍｇ，２段階収率７４％）を得た。
1H NMR (CDCl3) δ: 4.35 (2H, s), 3.66 (2H, t, J = 6.6 Hz), 3.46 (2H, t, J = 6.6 Hz).

第５工程
　化合物１０９（９６ｍｇ，０．３８ｍｍｏｌ）のＮ－メチルピロリドン（１．５ｍＬ）溶液に、２－アミノ－Ｎ－イソプロピルエタンスルホンアミド塩酸塩（９２ｍｇ，０．４６ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピエルエチルアミン（０．１６６ｍＬ，０．９５ｍｍｏｌ）を加えた後、１００℃で３０分間攪拌した。さらに反応液にｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（２１２ｍｇ，１．１４ｍｍｏｌ）を加えた後、マイクロウェーブ照射下１５０℃で１時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、クロロホルムで再結晶することにより、白色固体として化合物１１０（１５２ｍｇ，収率７５％）を得た。
1H NMR (DMSO-d6) δ: 7.14 (1H, d, J = 7.1 Hz), 6.93 (1H, t, J = 5.3 Hz), 3.98 (2H, s), 3.69 (4H, brs), 3.45 (2H, t, J = 5.8 Hz), 3.26 (2H, t, J = 7.3 Hz), 3.02 (2H, t, J = 6.4 Hz), 1.44 (9H, s), 1.14 (6H, d, J = 6.6 Hz).

第６工程
　化合物１１０（１４９ｍｇ，０．２８ｍｍｏｌ）の塩化メチレン（４ｍＬ）溶液に、トリフルオロ酢酸（０．８ｍＬ）を加えた後、室温で１時間攪拌した。反応液を減圧濃縮し、塩基性になるまでトリエチルアミンを加えた後、反応液をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９５／５にて溶出する部分を集め減圧濃縮し、酢酸エチルで再結晶することにより、白色固体として化合物１１１（５７ｍｇ，収率４７％）を得た。
1H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 7.2 Hz), 6.83 (1H, t, J = 6.0 Hz), 3.94(2H, s), 3.68-3.58 (6H, m), 3.43-3.20 (6H, m), 2.98 (2H, t, J = 6.6 Hz), 2.68 (4H, brs), 1.11 (6H, d, J = 6.6 Hz)
Synthesis of Compound 111 (I-351)
Figure JPOXMLDOC01-appb-C000284
First Step 28% sodium methoxide (15.37 g, 80.0 mmol) and urea (7.98 g, 133 mmol) were added to a solution of compound 105 (5 g, 26.6 mmol) in ethanol (40 mL), and 2% at 95 ° C. Stir for hours. Concentrated hydrochloric acid was added to the reaction solution under ice cooling to adjust the pH to 3.5, followed by concentration under reduced pressure. Water was added to the residue and collected by filtration, washed with a large amount of water, and dried under reduced pressure to obtain a white solid 106 (1.96 g, yield 40%).
1 H NMR (DMSO-d6) δ: 11.04 (1H, brs), 10.76 (1H, brs), 3.27 (2H, s), 2.80 (2H, t, J = 5.8 Hz), 2.57 (2H, t, J = 5.6 Hz).

Second Step To compound 106 (1.95 g, 10.6 mmol), phosphorus oxychloride (9.84 mL, 106 mmol) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction solution was slowly poured into ice water, and the precipitated solid was collected by filtration, washed with a large amount of water, and dried under reduced pressure to obtain a white solid 107 (2 g, yield 86%).
1 H NMR (CDCl3) δ: 3.81 (2H, s), 3.23 (2H, t, J = 6.0 Hz), 2.96 (2H, t, J = 6.1 Hz).

Third Step m-Chloroperbenzoic acid (585 mg, 3.39 mmol) was added to a methylene chloride (10 mL) solution of Compound 107 (500 mg, 2.26 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was subjected to silica gel chromatography, and the fraction eluted with chloroform / methanol = 97/3 was collected and concentrated under reduced pressure to obtain Compound 108 (596 mg) as a mixture. Compound 108 was used in the next reaction without further purification.
1 H NMR (CDCl3) δ: 4.21 (1H, dd, J = 17.2, 2.4 Hz), 3.79-3.68 (2H, m), 3.48-3.40 (1H, m), 3.22 (1H, dt, J = 18.9, 4.0 Hz), 2.86 (1H, dt, J = 19.5, 6.4 Hz).

Fourth Step To a solution of compound 108 (195 mg) in methylene chloride (4 mL) was added m-chloroperbenzoic acid (213 mg, 1.23 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a 1 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain Compound 109 (154 mg, two-stage yield 74%) as a white solid.
1 H NMR (CDCl3) δ: 4.35 (2H, s), 3.66 (2H, t, J = 6.6 Hz), 3.46 (2H, t, J = 6.6 Hz).

Fifth Step To a solution of compound 109 (96 mg, 0.38 mmol) in N-methylpyrrolidone (1.5 mL), 2-amino-N-isopropylethanesulfonamide hydrochloride (92 mg, 0.46 mmol), N, N-di After adding isopropyl ethylamine (0.166 mL, 0.95 mmol), the mixture was stirred at 100 ° C. for 30 minutes. Further, tert-butyl piperazine-1-carboxylate (212 mg, 1.14 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from chloroform to give Compound 110 (152 mg, yield 75%) as a white solid.
1 H NMR (DMSO-d6) δ: 7.14 (1H, d, J = 7.1 Hz), 6.93 (1H, t, J = 5.3 Hz), 3.98 (2H, s), 3.69 (4H, brs), 3.45 ( 2H, t, J = 5.8 Hz), 3.26 (2H, t, J = 7.3 Hz), 3.02 (2H, t, J = 6.4 Hz), 1.44 (9H, s), 1.14 (6H, d, J = 6.6 Hz).

Step 6 To a solution of compound 110 (149 mg, 0.28 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (0.8 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, triethylamine was added until basic, and the reaction solution was subjected to amino silica gel chromatography. The portion eluted with chloroform / methanol = 95/5 was collected and concentrated under reduced pressure. Recrystallization gave compound 111 (57 mg, 47% yield) as a white solid.
1 H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 7.2 Hz), 6.83 (1H, t, J = 6.0 Hz), 3.94 (2H, s), 3.68-3.58 (6H, m), 3.43-3.20 (6H, m), 2.98 (2H, t, J = 6.6 Hz), 2.68 (4H, brs), 1.11 (6H, d, J = 6.6 Hz)

化合物１１４（Ｉ－３５２）の合成

Figure JPOXMLDOC01-appb-C000285

第１工程
　実施例２４第２工程で得られた化合物１０７（１００ｍｇ，０．４５ｍｍｏｌ）のＮ－メチルピロリドン（１．５ｍＬ）溶液に、２－アミノ－Ｎ－イソプロピルエタンスルホンアミド塩酸塩（１１０ｍｇ，０．５４ｍｍｏｌ）、Ｎ，Ｎ－ジイソプロピエルエチルアミン（０．１９７ｍＬ，１．１３ｍｍｏｌ）を加えた後、１００℃で３０分間攪拌した。さらに反応液にｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（２５３ｍｇ，１．３６　ｍｍｏｌ）を加えた後、マイクロウェーブ照射下１５０℃で１時間攪拌した。反応液を水に注ぎ、酢酸エチルで抽出し、有機層を水、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーに付し、ヘキサン／酢酸エチル＝　４０／６０にて溶出する部分を集め減圧濃縮することにより、無色粉末として化合物１１２（１８８ｍｇ，収率８３％）を得た。
1H NMR (CDCl3) δ: 5.19 (1H, t, J = 5.6 Hz), 4.15 (1H, d, J = 7.3 Hz), 3.96 (2H, q, J = 5.7 Hz), 3.74-3.58 (5H, m), 3.46 (4H, t, J = 5.1 Hz), 3.36 (2H, s), 3.30 (2H, t, J = 5.5 Hz), 2.91-2.81 (4H, m), 1.49 (9H, s), 1.23 (6H, d, J = 6.6 Hz). 

第２工程
　化合物１１２（１８６ｍｇ，０．３７ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液に、氷冷下でｍ－クロロ過安息香酸（９６ｍｇ，０．５６ｍｍｏｌ）を加え、室温で４時間攪拌した。反応液をシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮することにより、混合物として化合物１１３（１５１ｍｇ）を得た。化合物１１３はこれ以上精製することなく、次の反応に用いた。

第３工程
　化合物１１３（１４９ｍｇ）の塩化メチレン（４ｍＬ）溶液に、トリフルオロ酢酸（０．８ｍＬ）を加えた後、室温で１時間攪拌した。反応液を減圧濃縮し、塩基性になるまでトリエチルアミンを加えた後、反応液をアミノシリカゲルクロマトグラフィーに付し、クロロホルム／メタノール＝９０／１０にて溶出する部分を集め減圧濃縮し、酢酸エチルで再結晶することにより、白色固体として化合物１１４（９４ｍｇ，２段階収率６１％）を得た。
1H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 6.9 Hz), 6.82 (1H, brs), 3.68-3.21(9H, m), 3.13-2.91 (4H, m), 2.69-2.62 (6H, m), 1.11 (6H, d, J = 6.6 Hz)
Synthesis of Compound 114 (I-352)
Figure JPOXMLDOC01-appb-C000285
First Step Example 24 To a solution of compound 107 (100 mg, 0.45 mmol) obtained in the second step in N-methylpyrrolidone (1.5 mL), 2-amino-N-isopropylethanesulfonamide hydrochloride (110 mg, 0.54 mmol) and N, N-diisopropylethylamine (0.197 mL, 1.13 mmol) were added, followed by stirring at 100 ° C. for 30 minutes. Further, tert-butyl piperazine-1-carboxylate (253 mg, 1.36 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 40/60 was collected and concentrated under reduced pressure to give Compound 112 (188 mg, yield) as a colorless powder. 83%).
1 H NMR (CDCl3) δ: 5.19 (1H, t, J = 5.6 Hz), 4.15 (1H, d, J = 7.3 Hz), 3.96 (2H, q, J = 5.7 Hz), 3.74-3.58 (5H, m), 3.46 (4H, t, J = 5.1 Hz), 3.36 (2H, s), 3.30 (2H, t, J = 5.5 Hz), 2.91-2.81 (4H, m), 1.49 (9H, s), 1.23 (6H, d, J = 6.6 Hz).

Second Step To a solution of compound 112 (186 mg, 0.37 mmol) in methylene chloride (5 mL) was added m-chloroperbenzoic acid (96 mg, 0.56 mmol) under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was subjected to silica gel chromatography, and the portion eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure to obtain Compound 113 (151 mg) as a mixture. Compound 113 was used in the next reaction without further purification.

Third Step To a solution of compound 113 (149 mg) in methylene chloride (4 mL) was added trifluoroacetic acid (0.8 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, triethylamine was added until basic, and the reaction solution was subjected to amino silica gel chromatography. The portion eluted with chloroform / methanol = 90/10 was collected and concentrated under reduced pressure. Recrystallization gave compound 114 (94 mg, 2-step yield 61%) as a white solid.
1 H NMR (DMSO-d6) δ: 7.11 (1H, d, J = 6.9 Hz), 6.82 (1H, brs), 3.68-3.21 (9H, m), 3.13-2.91 (4H, m), 2.69-2.62 (6H, m), 1.11 (6H, d, J = 6.6 Hz)

　一般的製造法および実施例に記載の方法に準じて以下の化合物を得た。構造および物性を以下に示す。
（化合物の同定方法）
　本発明の化合物のＬＣ／ＭＳデータは、以下の９つの条件（メソッドＡ～Ｆ、Ｓ、Ｙ、Ｚ）のいずれかで測定し、保持時間および［Ｍ＋Ｈ］＋を示した。 The following compounds were obtained according to the general production methods and the methods described in the examples. The structure and physical properties are shown below.
(Compound identification method)
The LC / MS data of the compounds of the present invention were measured under any of the following nine conditions (Methods A to F, S, Y, Z) and indicated retention time and [M + H] + .

（メソッドＡ）
カラム：Ｘｂｒｉｄｇｅ　Ｃ１８（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：３　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。

（メソッドＢ）
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
流速：１．６　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。

（メソッドＣ）
カラム：Ｇｅｍｉｎｉ－ＮＸ　（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：３　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有メタノール溶液
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。

（メソッドＤ）
カラム：Ｇｅｍｉｎｉ－ＮＸ　（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：３　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は１０ｍＭ炭酸アンモニウム含有水溶液、［Ｂ］はメタノール
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。

（メソッドＥ）
カラム：：Ｇｅｍｉｎｉ－ＮＸ　（Ｃ１８，　５μｍ　ＡＸＩＡ　Ｐａｃｋｅｄ　，　ｉ．ｄ．２１．２　ｘ　５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：２５　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は１０ｍＭ炭酸アンモニウム含有水溶液、［Ｂ］はメタノール
グラジェント：４分間のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。

（メソッドＦ）
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ　ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
流速：０．９　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。

（メソッドＳ）
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ　ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
流速：０．８　ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は１０ｍＭ炭酸アンモニウム含有水溶液、［Ｂ］はアセトニトリル
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。

（メソッドＹ）
カラム：Ｄｅｖｅｌｏｓｉｌ　Ｃ３０－ＵＧ－５　４．６ｘ１５０　（野村化学）
流速：１．０　ｍＬ／分
ＵＶ検出波長：２３０ｎｍ
移動相：［Ａ］は０．０５％ＴＦＡ含有水溶液、［Ｂ］は０．０５％ＴＦＡ含有アセトニトリル
グラジェント：３分間で２％溶媒［Ｂ］を維持し、次いで５分間で２－２０％溶媒［Ｂ］のグラジエントを行った。

（メソッドＺ）
カラム：ＳｕｎＦｉｒｅ　Ｃ１８　３．５μｍ　４．６ｘ５０　（ｗａｔｅｒｓ）
流速：１．０　ｍＬ／分
ＵＶ検出波長：２３０ｎｍ
移動相：［Ａ］は０．１％ＴＦＡ含有水溶液、［Ｂ］は０．１％ＴＦＡ含有アセトニトリル
グラジェント：８分間で２－２０％溶媒［Ｂ］のグラジエントを行った。
(Method A)
Column: Xbridge C18 (5 μm, id 4.6 × 50 mm) (Waters)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.

(Method B)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.

(Method C)
Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing methanol solution. 100% solvent [B] was maintained for 0.5 minutes.

(Method D)
Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 10 mM ammonium carbonate-containing aqueous solution, [B] is a methanol gradient: 5% -100% solvent [B] is linearly gradient over 3.5 minutes, and 100% solvent [B] is added for 0.5 minutes. B] was maintained.

(Method E)
Column :: Gemini-NX (C18, 5 μm AXIA Packed, id 21.2 × 50 mm) (Phenomenex)
Flow rate: 25 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] was a 10 mM ammonium carbonate-containing aqueous solution, [B] was a methanol gradient: linear gradient of 4 minutes, and 100% solvent [B] was maintained for 1 minute.

(Method F)
Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.9 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3.5 minutes 100% solvent [B] was maintained for 0.5 minutes.

(Method S)
Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile gradient: linear gradient of 5% -100% solvent [B] is performed for 3.5 minutes, and 100% solvent [B] is added for 0.5 minutes. B] was maintained.

(Method Y)
Column: Develosil C30-UG-5 4.6x150 (Nomura Chemical)
Flow rate: 1.0 mL / min UV detection wavelength: 230 nm
Mobile phase: [A] is 0.05% TFA-containing aqueous solution, [B] is 0.05% TFA-containing acetonitrile gradient: 2% solvent [B] is maintained for 3 minutes, then 2-20% for 5 minutes A gradient of solvent [B] was performed.

(Method Z)
Column: SunFire C18 3.5 μm 4.6 × 50 (waters)
Flow rate: 1.0 mL / min UV detection wavelength: 230 nm
Mobile phase: [A] was 0.1% TFA-containing aqueous solution, [B] was 0.1% TFA-containing acetonitrile gradient: 2-20% solvent [B] was gradient over 8 minutes.

Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286

Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287

Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288

Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289

Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290

Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291

Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000292

Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000293

Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000294

Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000295

Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000296

Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000297

Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000298

Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000299

Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000300

Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000301

Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000302

Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000303

Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000304

Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000305

Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000306

Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000307

Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000308

Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000309

Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000310

Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000311

Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000312

Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000313

Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000314

Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000315

Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000316

Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000317

Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000318

Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000319

Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000320

Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000321

Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000322

Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000323

Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000324

Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000325

Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000326

Figure JPOXMLDOC01-appb-T000327
Figure JPOXMLDOC01-appb-T000327

Figure JPOXMLDOC01-appb-T000328
Figure JPOXMLDOC01-appb-T000328

Figure JPOXMLDOC01-appb-T000330
Figure JPOXMLDOC01-appb-T000330

Figure JPOXMLDOC01-appb-T000331
Figure JPOXMLDOC01-appb-T000331

Figure JPOXMLDOC01-appb-T000333
Figure JPOXMLDOC01-appb-T000333

Figure JPOXMLDOC01-appb-T000334
Figure JPOXMLDOC01-appb-T000334

Figure JPOXMLDOC01-appb-T000335
Figure JPOXMLDOC01-appb-T000335

Figure JPOXMLDOC01-appb-T000336
Figure JPOXMLDOC01-appb-T000336

Figure JPOXMLDOC01-appb-T000337
Figure JPOXMLDOC01-appb-T000337

Figure JPOXMLDOC01-appb-T000338
Figure JPOXMLDOC01-appb-T000338

Figure JPOXMLDOC01-appb-T000339
Figure JPOXMLDOC01-appb-T000339

Figure JPOXMLDOC01-appb-T000340
Figure JPOXMLDOC01-appb-T000340

Figure JPOXMLDOC01-appb-T000341
Figure JPOXMLDOC01-appb-T000341

Figure JPOXMLDOC01-appb-T000342
Figure JPOXMLDOC01-appb-T000342

Figure JPOXMLDOC01-appb-T000343
Figure JPOXMLDOC01-appb-T000343

Figure JPOXMLDOC01-appb-T000344
Figure JPOXMLDOC01-appb-T000344

Figure JPOXMLDOC01-appb-T000345
Figure JPOXMLDOC01-appb-T000345

Figure JPOXMLDOC01-appb-T000346
Figure JPOXMLDOC01-appb-T000346

Figure JPOXMLDOC01-appb-T000347
Figure JPOXMLDOC01-appb-T000347

Figure JPOXMLDOC01-appb-T000348
Figure JPOXMLDOC01-appb-T000348

Figure JPOXMLDOC01-appb-T000349
Figure JPOXMLDOC01-appb-T000349

Figure JPOXMLDOC01-appb-T000350
Figure JPOXMLDOC01-appb-T000350

Figure JPOXMLDOC01-appb-T000351
Figure JPOXMLDOC01-appb-T000351

Figure JPOXMLDOC01-appb-T000352
Figure JPOXMLDOC01-appb-T000352

Figure JPOXMLDOC01-appb-T000353
Figure JPOXMLDOC01-appb-T000353

Figure JPOXMLDOC01-appb-T000354
Figure JPOXMLDOC01-appb-T000354

Figure JPOXMLDOC01-appb-T000355
Figure JPOXMLDOC01-appb-T000355

Figure JPOXMLDOC01-appb-T000356
Figure JPOXMLDOC01-appb-T000356

Figure JPOXMLDOC01-appb-T000357
Figure JPOXMLDOC01-appb-T000357

試験例　ヒスタミンＨ４受容体の結合試験
　ヒトヒスタミンＨ４受容体強制発現ＣＨＯ－Ｋ１細胞膜画分（ＰｅｒｋｉｎＥｌｍｅｒ）、放射リガンド［３Ｈ］－Ｈｉｓｔａｍｉｎｅ（ＰｅｒｋｉｎＥｌｍｅｒ）を使用し、結合用緩衝液（５０ｍｍｏｌ／L　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４，　５ｍｍｏｌ／L　ＥＤＴＡ）中で受容体結合アッセイを実施した。
　ヒトヒスタミンＨ４受容体発現膜画分１５μｇを懸濁した結合用緩衝液中に終濃度１５ｎｍｏｌ／Lの［３Ｈ］－Ｈｉｓｔａｍｉｎｅを添加し、反応体積１５０μＬで室温、６０分間インキュベートした。非特異的結合は、１００μｍｏｌ／Lの非標識ヒスタミン二塩酸塩（Ｎａｋａｌａｉ　Ｔｅｓｑｕｅ）存在下でインキュベートすることで測定した。ＰｅｒｋｉｎＥｌｍｅｒセルハーベスターを使用した急速ろ過で０．５％　ＰＥＩコートＵｎｉｆｉｌｔｅｒｐｌａｔｅ　ＧＦ／Ｂ（ＰｅｒｋｉｎＥｌｍｅｒ）上に膜画分を回収し、３５０μＬの氷冷５０ｍｍｏｌ／L　Ｔｒｉｓ－ＨＣｌ，ｐＨ７．４で６回洗浄した。フィルターを風乾後、シンチレーションカクテルＭｉｃｒｏｓｃｉｎｔｉ－ＭＳ（ＰｅｒｋｉｎＥｌｍｅｒ）と混和し、Ｔｏｐｃｏｕｎｔ液体シンチレーション・カウンター（ＰｅｒｋｉｎＥｌｍｅｒ）でフィルターにトラップされた放射能を測定した。
　化合物の存在下で前記の反応を行うことにより、被検化合物の［３Ｈ］－Ｈｉｓｔａｍｉｎｅに対する競合能を測定した。化合物希釈列により６点線量応答曲線を作成し、エクセルおよびＸＬ－ｆｉｔを使用してＩＣ５０を求めた。Ｋｉ値はＣｈｅｎｇ－Ｐｒｕｓｏｆｆ式によってＩＣ５０を変換して導出した。
Test Example Binding test of histamine H4 receptor Human histamine H4 receptor forced expression CHO-K1 cell membrane fraction (PerkinElmer), radioligand [3H] -histamine (PerkinElmer) was used, and binding buffer (50 mmol / L Tris- Receptor binding assays were performed in HCl pH 7.4, 5 mmol / L EDTA).
[3H] -Histamine with a final concentration of 15 nmol / L was added to a binding buffer in which 15 μg of the human histamine H4 receptor-expressing membrane fraction was suspended, and incubated at a reaction volume of 150 μL at room temperature for 60 minutes. Nonspecific binding was determined by incubating in the presence of 100 μmol / L unlabeled histamine dihydrochloride (Nakalai Tesque). Membrane fractions were collected on 0.5% PEI coated Unifilterplate GF / B (PerkinElmer) by rapid filtration using a PerkinElmer cell harvester and washed 6 times with 350 μL ice-cold 50 mmol / L Tris-HCl, pH 7.4. . The filter was air-dried, mixed with a scintillation cocktail Microscinti-MS (PerkinElmer), and the radioactivity trapped on the filter was measured with a Topcount liquid scintillation counter (PerkinElmer).
By conducting the above reaction in the presence of the compound, the ability of the test compound to compete with [3H] -histamine was measured. A 6-point dose response curve was generated by the compound dilution series, and IC 50 was determined using Excel and XL-fit. The Ki value was derived by converting IC 50 using the Cheng-Prusoff equation.

本発明化合物のヒスタミンＨ４受容体の結合試験の結果を以下の表に示す。表中の単位ｎＭは、ｎｍｏｌ／Ｌを示す。

Figure JPOXMLDOC01-appb-T000358

Figure JPOXMLDOC01-appb-T000359
Figure JPOXMLDOC01-appb-T000360
 The results of the histamine H4 receptor binding test of the compounds of the present invention are shown in the following table. The unit nM in the table indicates nmol / L.
Figure JPOXMLDOC01-appb-T000358
Figure JPOXMLDOC01-appb-T000359
Figure JPOXMLDOC01-appb-T000360

試験例　ヒスタミンＨ３受容体の結合試験
　ヒト由来ヒスタミンＨ３受容体強制発現ＣＨＯ－Ｋ１細胞膜画分（ＰｅｒｋｉｎＥｌｍｅｒ）、放射リガンド［３Ｈ］－Ｈｉｓｔａｍｉｎｅ（ＰｅｒｋｉｎＥｌｍｅｒ）を使用し、結合用緩衝液（５０ｍｍｏｌ／L　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４，　５ｍｍｏｌ／L　ＥＤＴＡ）中で受容体結合アッセイを実施した。
　ヒスタミンＨ３受容体発現膜画分１５μｇを懸濁した結合用緩衝液中に終濃度１５ｎｍｏｌ／Lの［３Ｈ］－Ｈｉｓｔａｍｉｎｅを添加し、反応体積１５０μＬで室温、６０分間インキュベートした。非特異的結合は、１００μｍｏｌ／Lの非標識ヒスタミン二塩酸塩（Ｎａｋａｌａｉ　Ｔｅｓｑｕｅ）存在下でインキュベートすることで測定した。ＰｅｒｋｉｎＥｌｍｅｒセルハーベスターを使用した急速ろ過で０．５％　ＰＥＩコートＵｎｉｆｉｌｔｅｒｐｌａｔｅ　ＧＦ／Ｂ（ＰｅｒｋｉｎＥｌｍｅｒ）上に膜画分を回収し、３５０μＬの氷冷５０ｍＭ　Ｔｒｉｓ－ＨＣｌ，ｐＨ７．４で６回洗浄した。フィルターを風乾後、シンチレーションカクテルＭｉｃｒｏｓｃｉｎｔｉ－ＭＳ（ＰｅｒｋｉｎＥｌｍｅｒ）と混和し、Ｔｏｐｃｏｕｎｔ液体シンチレーション・カウンター（ＰｅｒｋｉｎＥｌｍｅｒ）でフィルターにトラップされた放射能を測定した。
　化合物の存在下で前記の反応を行うことにより、被検化合物の［３Ｈ］－Ｈｉｓｔａｍｉｎｅに対する競合能を測定した。化合物希釈列により６点線量応答曲線を作成し、エクセルおよびＸＬ－ｆｉｔを使用してＩＣ５０を求めた。Ｋｉ値はＣｈｅｎｇ－Ｐｒｕｓｏｆｆ式によってＩＣ５０を変換して導出した。
（結果）ヒスタミンＨ３受容体の結合試験の結果を以下に示す。
Ｉ－００１：　２７００ｎｍｏｌ／Ｌ
Ｉ－００２：　＞３０００ｎｍｏｌ／Ｌ
Ｉ－００７：　２３００ｎｍｏｌ／Ｌ
Ｉ－０１０：　＞３０００ｎｍｏｌ／Ｌ
Ｉ－１１９：　＞３０００ｎｍｏｌ／Ｌ
Ｉ－１２４：　＞３０００ｎｍｏｌ／Ｌ
Ｉ－１３３：　＞３０００ｎｍｏｌ／Ｌ
Ｉ－２３６：　＞３０００ｎｍｏｌ／Ｌ
Test Example Histamine H3 receptor binding test Human-derived histamine H3 receptor forced expression CHO-K1 cell membrane fraction (PerkinElmer), radioligand [3H] -histamine (PerkinElmer), binding buffer (50 mmol / L Tris) Receptor binding assays were performed in HCl pH 7.4, 5 mmol / L EDTA).
[3H] -Histamine with a final concentration of 15 nmol / L was added to a binding buffer in which 15 μg of the histamine H3 receptor-expressing membrane fraction was suspended, and incubated at room temperature for 60 minutes at a reaction volume of 150 μL. Nonspecific binding was determined by incubating in the presence of 100 μmol / L unlabeled histamine dihydrochloride (Nakalai Tesque). Membrane fractions were collected on 0.5% PEI coated Unifilterplate GF / B (PerkinElmer) by rapid filtration using a PerkinElmer cell harvester and washed 6 times with 350 μL ice-cold 50 mM Tris-HCl, pH 7.4. The filter was air-dried, mixed with a scintillation cocktail Microscinti-MS (PerkinElmer), and the radioactivity trapped on the filter was measured with a Topcount liquid scintillation counter (PerkinElmer).
By conducting the above reaction in the presence of the compound, the ability of the test compound to compete with [3H] -histamine was measured. A 6-point dose response curve was generated by the compound dilution series, and IC 50 was determined using Excel and XL-fit. The Ki value was derived by converting IC 50 using the Cheng-Prusoff equation.
(Results) The results of the histamine H3 receptor binding test are shown below.
I-001: 2700 nmol / L
I-002:> 3000 nmol / L
I-007: 2300 nmol / L
I-010:> 3000 nmol / L
I-119:> 3000 nmol / L
I-124:> 3000 nmol / L
I-133:> 3000 nmol / L
I-236:> 3000 nmol / L

試験例　ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による化合物のＣＹＰ３Ａ４阻害の増強を調べる試験であり、酵素に大腸菌発現ＣＹＰ３Ａ４を用いて、７-ベンジルオキシトリフルオロメチルクマリン（ＢＦＣ）がＣＹＰ３Ａ４酵素により脱ベンジル化し、蛍光を発する代謝物７-ハイドロキシトリフルオロメチルクマリン（ＨＦＣ）を生成する反応を指標として行う。
　反応条件は以下のとおり：基質、５.６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ，反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；被検薬物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、被検薬物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定する。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ）
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、被検薬物溶液を加えたそれぞれの濃度での残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。ＩＣ５０値の差が５μＭ以上の場合を（＋）とし、３μＭ以下の場合を（－）とする。
Test Example CYP3A4 Fluorescence MBI Test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (BFC) as a CYP3A4 enzyme using E. coli-expressed CYP3A4 as an enzyme. The reaction is debenzylated to produce a metabolite 7-hydroxytrifluoromethylcoumarin (HFC) that emits fluorescence.
The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
Enzyme and test drug solution are added to K-Pi buffer (pH 7.4) as a pre-reaction solution in a 96-well plate with the above pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted to 1/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After a predetermined time reaction, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1. The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. Used to calculate IC 50 by inverse estimation with a logistic model. The case where the difference in IC 50 value is 5 μM or more is (+), and the case where it is 3 μM or less is (−).

試験例　ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、　デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が被検化合物によって阻害される程度を評価する。
　反応条件は以下のとおり：基質、０．５　μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００　μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０　μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１　μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム　０．２ｍｇ　タンパク質／ｍＬ；被検薬物濃度、１、５、１０、２０　μｍｏｌ／Ｌ（４点）。
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ　緩衝液中に各５種の基質、ヒト肝ミクロソーム、被検薬物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始し、３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液を添加することで反応を停止する。３０００ｒｐｍ、１５分間の遠心操作後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで、トルブタミド水酸化体　（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量する。
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、被検薬物溶液を加えたそれぞれの濃度での残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。
Test Example CYP Inhibition Test O-deethylation of 7-ethoxyresorufin (CYP1A2) as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes ), Methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the amount of product produced is inhibited by the test compound is evaluated.
The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 μmol / L (4 points).
As a reaction solution in a 96-well plate, each of 5 types of substrates, human liver microsomes, and test drugs are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH as a coenzyme is added as an indicator for metabolic reaction. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multilabel counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. Used to calculate IC 50 by inverse estimation with a logistic model.

試験例　代謝安定性試験
　文献（Japanese journal of pharmacology, 33 (1), p.41-56, Feb 1983）に準じて調製したプールドラット肝ミクロソームまたは市販のプールドヒト肝ミクロソームを用いて、対象化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、肝で代謝される程度を評価する。
　ラットまたはヒト肝ミクロソーム０．５ｍｇ　タンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、　１５０ｍｍｏｌ／Ｌ　塩化カリウム、　１０　ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させる（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０　μＬを添加、混合し、３０００ｒｐｍで１５分間遠心する。その遠心上清中の試験化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の試験化合物の残存量を０分反応時の化合物量を１００％として計算する。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施する。
Test example Metabolic stability test Using pooled rat liver microsomes prepared according to the literature (Japanese journal of pharmacology, 33 (1), p.41-56, Feb 1983) or commercially available pooled human liver microsomes The reaction is performed for a certain period of time, the residual rate is calculated by comparing the reaction sample and the unreacted sample, and the degree of metabolism in the liver is evaluated.
1 mmol / L NADPH in 0.2 mL buffer (50 mmol / L tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL rat or human liver microsomes The reaction is carried out at 37 ° C. for 0 minutes or 30 minutes in the presence (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant is quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction is calculated with the amount of the compound at 0 minute reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.

試験例　ＢＡ及び全身クリアランス試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはラットを使用する。
（２）飼育条件：マウス及びラットは、固形飼料および滅菌水道水を自由摂取させる。
（３）投与量、群分けの設定：経口投与、静脈内投与を所定の投与量により投与する。以下のように群を設定する。（化合物ごとで投与量は変更する）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液または懸濁液として投与する。静脈内投与は可溶化して投与する。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与する。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与する。
（６）評価項目：経時的に採血し、血漿中薬物濃度をＬＣ／ＭＳ／ＭＳを用いて測定する。
（７）統計解析：血漿中濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）及び全身クリアランス（Ｃｌｔ）を算出し、経口投与群と静脈内投与群のＡＵＣからバイオアベイラビリティ（ＢＡ）を算出する。
（結果）ラット、経口投与１ｍｇ／ｋｇでの値を示す。
ＢＡ値
Ｉ－００５：　２１％
Ｉ－２６５：　２４％
Ｃｌｔ値
Ｉ－３０４：　１８．２ ｍＬ／ｍｉｎ／ｋｇ
Ｉ－３０８：　１８．５ ｍＬ／ｍｉｎ／ｋｇ
Ｉ－３３１：　１７．８ ｍＬ／ｍｉｎ／ｋｇ
Ｉ－３３６：　１５．６ ｍＬ／ｍｉｎ／ｋｇ
Ｉ－３３８：　３２．７ ｍＬ／ｍｉｎ／ｋｇ
Ｉ－３４０：　２１．７ ｍＬ／ｍｉｎ／ｋｇ
Test Example BA and systemic clearance test Examination of oral absorbability Experimental materials and methods (1) Animals used: Mice or rats are used.
(2) Breeding conditions: Mice and rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dose and grouping: oral administration and intravenous administration are administered at a predetermined dose. Set the group as follows. (Dosage varies for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood is collected over time, and the drug concentration in plasma is measured using LC / MS / MS.
(7) Statistical analysis: For the plasma concentration transition, the area under the plasma concentration-time curve (AUC) and systemic clearance (Clt) were calculated using the non-linear least squares program WinNonlin (registered trademark). Bioavailability (BA) is calculated from the AUC of the intravenous administration group.
(Results) Values for rats, orally administered at 1 mg / kg are shown.
BA value I-005: 21%
I-265: 24%
Clt value I-304: 18.2 mL / min / kg
I-308: 18.5 mL / min / kg
I-331: 17.8 mL / min / kg
I-336: 15.6 mL / min / kg
I-338: 32.7 mL / min / kg
I-340: 21.7 mL / min / kg

試験例　ＦＡＴ試験
　凍結保存しているネズミチフス菌（Salmonella typhimurium TA98株、TA100株）20μLを10 mL液体栄養培地（2.5% Oxoid nutrient broth No.2）に接種し37℃にて10 時間、振盪前培養する。TA98株は9mLの菌液を遠心（2000×g、10 分間）して培養液を除去し、9mLのMicro F緩衝液(K2HPO4：3.5 g/L、 KH2PO4：1 g/L、 (NH4)2SO4：1g/L、 クエン酸三ナトリウム二水和物：0.25 g/L、 MgSO4・7H20：0.1g/L)に菌を懸濁し、110 mLのExposure培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、 グルコース：8 mg/mLを含むMicroF緩衝液)に添加し、TA100株は3.16mL菌液に対しExposure培地120mLに添加し試験菌液を調製する。被験物質DMSO溶液（最高用量50mg/mLから2倍公比で8段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50 μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、 TA100株に対しては0.25 μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミド DMSO溶液、 代謝活性化条件ではTA98株に対して40μg/mLの2-アミノアントラセンDMSO溶液、 TA100株に対しては20 μg/mLの2-アミノアントラセンDMSO溶液それぞれ12 μL と試験菌液588μL（代謝活性化条件では試験菌液498 μLとS9 mix 90 μLの混合液）を混和し、37℃にて90分間、振盪培養した。被験物質を暴露した菌液460 μLを、Indicator培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、グルコース：8 mg/mL、ブロモクレゾールパープル：37.5 μg/mLを含むMicroF緩衝液)2300μLに混和し50 μLずつマイクロプレート48ウェル/用量に分注し、37℃にて 3日間、 静置培養する。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。 Test example FAT test Cryopreserved Salmonella typhimurium TA98 strain, TA100 strain 20 μL was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and cultured at 37 ° C for 10 hours before shaking. To do. For TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), 110 mL of Exposure Add to medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: MicroF buffer containing 8 mg / mL), TA100 strain to 3.16 mL bacterial solution, add 120 mL of exposure medium to test medium To prepare. Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 μg / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 μg / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 μg / mL 2-aminoanthracene DMSO solution each 12 μL and test bacterial solution 588 μL (under metabolic activation conditions, test bacterial solution 498 μL and S9 mix 90 μL of the mixture), and cultured with shaking at 37 ° C. for 90 minutes. 2300 μL of 460 μL of bacterial solution exposed to the test substance in Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) Add 50 μL each to a 48-well / dose microplate and incubate at 37 ° C for 3 days. Since wells containing bacteria that have acquired growth ability due to mutations in the amino acid (histidine) synthase gene turn from purple to yellow due to pH change, count the number of bacterial growth wells that turn yellow in 48 wells per dose. Evaluation is made in comparison with the negative control group.

試験例　溶解性試験
　化合物の溶解度は、1%DMSO添加条件下で決定する。DMSOにて10mｍｏｌ／Ｌ化合物溶液を調製し、化合物溶液6 μLをpH 6.8 人工腸液（0.2 mol/L リン酸二水素カリウム試液 250 mL に 0.2 mol/L　NaOH 試液 118 mL、水を加えて 1000 mL とする） 594μLに添加する。25℃で16時間静置させた後、混液を吸引濾過する。濾液をメタノール/水= 1/1にて2倍希釈し、絶対検量線法によりHPLCまたはLC/MS/MSを用いてろ液中濃度を測定する。 Test Example Solubility test The solubility of a compound is determined under the condition of addition of 1% DMSO. Prepare 10 mMol / L compound solution in DMSO, add 6 μL of the compound solution to pH 6.8 artificial intestinal fluid (250 mL of 0.2 mol / L potassium dihydrogen phosphate reagent solution, 118 mL of 0.2 mol / L NaOH reagent solution, add 1000 mL of water) Add to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. Dilute the filtrate twice with methanol / water = 1/1, and measure the concentration in the filtrate using HPLC or LC / MS / MS by the absolute calibration method.

試験例　ｈＥＲＧ試験
　心電図QT間隔延長のリスク評価を目的として、human ether-a-go-go related gene (hERG) チャンネルを発現させたHEK293細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流K+電流 (IKr) への作用を検討する。
　全自動パッチクランプシステム (PatchXpress 7000A, Axon Instruments Inc.) を用い、ホールセルパッチクランプ法により、細胞を-80 mVの膜電位に保持した後、+50 mVの脱分極刺激を2秒間、さらに-50 mVの再分極刺激を2秒間与えた際に誘発されるIKrを記録する。発生する電流が安定した後、被検物質を目的の濃度で溶解させた細胞外液 (NaCl: 137 mmol/L、 KCl: 4 mmol/L、 CaCl2・2H2O: 1.8 mmol/L、 MgCl2・6H2O: 1 mmol/L、 グルコース: 10 mmol/L、 HEPES（4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）: 10 mmol/L、 pH = 7.4) を室温条件下で、10分間細胞に適用させる。得られるIKrから、解析ソフト (DataXpress ver. 1、 Molecular Devices Corporation) を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、被検物質適用前の最大テール電流に対する阻害率を算出し、媒体適用群 (0.1 % ジメチルスルホキシド溶液) と比較して、被検物質のIKrへの影響を評価する。
（結果）化合物濃度１μmol/ｌでの阻害率を示す。
Ｉ－００５：　１％
Ｉ－０６５：　１％
Ｉ－０６７：　７％
Ｉ－２１２：　４％
Ｉ－２３６：　１％
Ｉ－２７９：　３％
Ｉ－３０１：　２％
Ｉ－３４２：　８％
Test example hERG test A delay that plays an important role in the ventricular repolarization process using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of risk assessment of ECG QT interval prolongation Consider the effect on rectified K + current (I Kr ).
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of -80 mV using the whole cell patch clamp method, a +50 mV depolarization stimulus was further applied for 2 seconds. Record the I Kr elicited when a 50 mV repolarization stimulus is applied for 2 seconds. After the generated current stabilizes, the extracellular fluid (NaCl: 137 mmol / L, KCl: 4 mmol / L, CaCl 2・ 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES ( 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, 4- (2- hydroxyethyl) -1-piperazine-ethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current is measured using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the test substance on I Kr is evaluated.
(Result) The inhibition rate at a compound concentration of 1 μmol / l is shown.
I-005: 1%
I-065: 1%
I-067: 7%
I-212: 4%
I-236: 1%
I-279: 3%
I-301: 2%
I-342: 8%

試験例　粉末溶解度試験
　適当な容器に検体を適量入れ、JP-1液(塩化ナトリウム2.0g、塩酸7.0mLに水を加えて1000mLとする)、JP-2液(pH6.8のリン酸塩緩衝液500mLに水500mLを加える)、20mmol/L TCA(タウロコール酸ナトリウム)/JP-2液(TCA 1.08gに水を加え100mLとする)を200μLずつ添加する。試験液添加後に溶解した場合には、適宜原末を追加する。密閉し37℃で1時間振とうする。濾過し、各濾液100μLにメタノール100μLを添加して2倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないかを確認し、密閉して振とうする。絶対検量線法によりHPLCを用いて定量を行う。
Test example Powder solubility test Put an appropriate amount of sample in a suitable container, JP-1 solution (2.0 g sodium chloride, 7.0 mL hydrochloric acid to 1000 mL), JP-2 solution (pH 6.8 phosphate buffer) Add 500 mL of water to 500 mL of solution), and add 200 μL of 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (add water to 1.08 g of TCA to make 100 mL). If dissolved after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C for 1 hour. Filter, add 100 μL of methanol to 100 μL of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. Quantify using HPLC with the absolute calibration curve method.

製剤例１
　以下の成分を含有する顆粒剤を製造する。
　成分　　式（Ｉ）で示される化合物　　　　　　　　 　10 mg
　　　　　乳糖　　　　　　　　　　　　　　　　　　　700 mg
　　　　　コーンスターチ　　　　　　　　　　　　　　274 mg
　　　　　HPC-L　　　　　　　　　　　　　　　　　　　16 mg
　式（Ｉ）で示される化合物と乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末にHPC-L（低粘度ヒドロキシプロピルセルロース）水溶液を添加し、練合、造粒（押し出し造粒 孔径0.5～1mm）、乾燥工程する。得られた乾燥顆粒を振動ふるい（12/60メッシュ）で櫛過し顆粒剤を得る。 Formulation Example 1
A granule containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 10 mg
Lactose 700 mg
Corn starch 274 mg
HPC-L 16 mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer. Add HPC-L (low-viscosity hydroxypropylcellulose) aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1mm), and dry. The obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.

製剤例２
　以下の成分を含有するカプセル充填用顆粒剤を製造する。
　成分　　式（Ｉ）で示される化合物　　　　　　　　 15 mg
　　　　　乳糖　　　　　　　　　　　　　　　　　　 90 mg
　　　　　コーンスターチ　　　　　　　　　　　　　 42 mg
　　　　　HPC-L　　　　　　　　　　　　　　　　　　 3 mg
　式（Ｉ）で示される化合物、乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらを混合し、混合末にHPC-L溶液を添加して練合、造粒、乾燥する。得られた乾燥顆粒を整粒後、その150mgを4号硬ゼラチンカプセルに充填する。 Formulation Example 2
A capsule filling granule containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 15 mg
Lactose 90 mg
Corn starch 42 mg
HPC-L 3 mg
The compound of formula (I), lactose, is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.

製剤例３
　以下の成分を含有する錠剤を製造する。
　成分　　式（Ｉ）で示される化合物　　　　　　　   10 mg
　　　　　乳糖　　　　　　　　　　　　　　　　　　 90 mg
　　　　　微結晶セルロース　　　　　　　　　　　　 30 mg
　　　　　CMC-Na　　　　　　　　　　　　　　　　   15 mg
　　　　　ステアリン酸マグネシウム　　　　　　　　　5 mg
　式（Ｉ）で示される化合物、乳糖、微結晶セルロース、CMC-Na（カルボキシメチルセルロース　ナトリウム塩）を60メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウム混合し、製錠用混合末を得る。本混合末を直打し、150mgの錠剤を得る。 Formulation Example 3
A tablet containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 10 mg
Lactose 90 mg
Microcrystalline cellulose 30 mg
CMC-Na 15 mg
Magnesium stearate 5 mg
The compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.

製剤例４
　以下の成分を加温混合後、滅菌して注射剤とする。
　成分　　式（Ｉ）で示される化合物　　　　　　　　 3 mg
　　　　　非イオン界面活性剤　　　　　　　　　　　15 mg
　　　　　注射用精製水　　　　　　　　　　　　　　 1 ml Formulation Example 4
The following ingredients are heated and mixed and then sterilized to give an injection.
Ingredient Compound represented by formula (I) 3 mg
Nonionic surfactant 15 mg
Purified water for injection 1 ml

製剤例５
　以下の成分を含有するハップ剤を製造する。
　成分　式（Ｉ）で示される化合物　　　　　　　　　　　　　　　 50 mg
　　　　水性基剤（5%エタノール/5%ブチレングリコール/90%精製水）950mg
　　　　グリセリン
　　　　　カオリン
　　　　　ポリビニルアルコール水溶液
　水性基剤に式（Ｉ）で示される化合物を添加し、超音波を15分ほど照射した後、十分に攪拌し、溶液とする。グリセリン5部、カオリン1部、ポリビニルアルコール水溶液5部を均一に混合し、調製した溶液1部を添加する。これをさらに混合してペースト状物とし、不織布上に塗布してポリエステルフィルムで覆い、ハップ剤とする。

　本出願は、日本で出願された特願２００９－２９００３３および特願２０１０－０８１４９０を基礎としており、その内容は本明細書にすべて包含されるものである。
Formulation Example 5
A haptic agent containing the following components is produced.
Ingredient Compound represented by formula (I) 50 mg
Aqueous base (5% ethanol / 5% butylene glycol / 90% purified water) 950 mg
Glycerin Kaolin Polyvinyl alcohol aqueous solution The compound represented by the formula (I) is added to an aqueous base, and after ultrasonic irradiation for about 15 minutes, the mixture is sufficiently stirred to obtain a solution. 5 parts of glycerin, 1 part of kaolin and 5 parts of an aqueous polyvinyl alcohol solution are uniformly mixed, and 1 part of the prepared solution is added. This is further mixed to obtain a paste, which is coated on a non-woven fabric and covered with a polyester film to obtain a happing agent.

This application is based on patent application Nos. 2009-290033 and 2010-081490 filed in Japan, the contents of which are incorporated in full herein.

　本発明の化合物は、ヒスタミンＨ４受容体に対する調節作用を有し、ヒスタミンＨ４受容体が関与する疾患または状態、例えば、気管支喘息、アレルギー性鼻炎、慢性閉塞性肺疾患（ＣＯＰＤ）などの呼吸器系疾患；慢性関節リウマチ、アトピー性皮膚炎、アレルギー性結膜炎、乾癬、炎症性大腸炎、潰瘍性大腸炎、狼瘡、アテローム硬化症などの炎症性疾患；神経性疼痛または侵害性疼痛を含む疼痛緩和などに対して有用である。 The compound of the present invention has a modulatory action on the histamine H4 receptor, and diseases or conditions involving the histamine H4 receptor such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), etc. Diseases; rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus, atherosclerosis, and other inflammatory diseases; pain relief including neuropathic or nociceptive pain Useful for.

Claims (15)

　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000001
［式中、
環Ａは、芳香族複素環；
Ｘ１は、ＮまたはＣ（Ｒｘ１）；
Ｘ２は、ＮまたはＣ（Ｒｘ２）；
Ｘ３は、ＮまたはＣ（Ｒｘ３）；
Ｘ４は、ＮまたはＣ（Ｒｘ４）；
Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４は、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａ（置換基群Ａ：置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリールおよび置換もしくは非置換のヘテロアリール）から選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；または、
Ｒｘ２およびＲｘ３、またはＲｘ３およびＲｘ４は、それぞれ隣接する環構成原子と一緒になってＣ環を形成してもよく；
Ｃ環は、
Figure JPOXMLDOC01-appb-C000002
（式中、
Ｗ１は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ａ）、Ｓ、Ｓ（Ｏ）またはＳ（Ｏ）２；
Ｗ２は、それぞれ独立して、Ｏ、Ｎ（Ｒ２ｂ）またはＳ；
Ｒ２ａおよびＲ２ｂは、それぞれ独立して、水素、置換もしくは非置換のアルキル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニルまたは置換もしくは非置換のアシル；
ｎ１は、０～４の整数；
ｎ２は、０～３の整数；
ｎ３は、０～２の整数；
ｎ４は、０または１の整数；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、
a)ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ、または、
Ｒ１aは、以下のｂ）群～ｅ）群からなる群から選択される１以上の基であってもよい；
ｂ）２つのＲ１aが、同一の炭素原子に結合して、＝Ｏならびに＝ＮＲ３、
ｃ）２つのＲ１aが、同一の炭素原子に結合して－（ＣＲ４ａＲ４ｂ）ｘ－または－Ｏ－（ＣＲ４ａＲ４ｂ）ｘ－Ｏ－、
ｄ）２つのＲ１aが、隣接する炭素原子に結合して－（ＣＲ５ａＲ５ｂ）ｙ－、および
ｅ）２つのＲ１aが、同一でなく、かつ隣接しない炭素原子に結合して－（ＣＲ６ａＲ６ｂ）ｚ－、
ただし、Ｒ１aは、ｃ）群、ｄ）群およびｅ）群から同時に２以上選択される場合はない；
Ｒ３は、水素、置換もしくは非置換のアルキル、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシ；
Ｒ４ａ、Ｒ４ｂ、Ｒ５ａ、Ｒ５ｂ、Ｒ６ａおよびＲ６ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｘは、２～７の整数；
ｙは、１～５の整数；
ｚは、１～３の整数）で示される環；
－Ｂ１は、式：－Ｘ－（ＣＲ８ａＲ８ｂ）ｍ－Ｙ
（式中、
Ｘは、Ｎ（Ｒ７ｃ）またはＯ；
Ｒ７ｃは、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシル；
Ｒ８ａおよびＲ８ｂは、それぞれ独立して、水素、ハロゲンまたは置換もしくは非置換のアルキル；
ｍは、０～５の整数；
ただし、Ｙが、置換基群Ａから選択される置換基で置換されたスルホニルによって環を構成する窒素原子が置換されている含窒素非芳香族複素環基以外の基である場合は、ｍは１～４の整数である；
Ｙは、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール）で示される基；
Ｂ２は、
Figure JPOXMLDOC01-appb-C000003
（式中、
Ｒ９ａおよびＲ９ｂは、それぞれ独立して、水素または置換もしくは非置換のアルキル；
Ｒ１０は、それぞれ独立して、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアミノ、または２つのＲ１０が一緒になってオキソもしくはチオキソ；
Ｒ１１は、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のシクロアルキル；
Ｒ１２は、置換もしくは非置換のアルキル、ハロゲン、ヒドロキシまたは置換もしくは非置換のアルキルオキシ；
ｐは０～４の整数）で示される基または置換もしくは非置換のアミノで置換されたアルキレン］で示される化合物（ただし、
（i）Ａ環がＣ環と縮合せず、Ｙが置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである化合物、
（ii）ｍが０であり、ＸがＮ（Ｒ７ｃ）であり、Ｒ７ｃが水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアシルであり、Ｙが置換もしくは非置換のヘテロアリールまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換されたインドリンである化合物、
（iii）Ｒ１１がヘテロアリールで置換されたアミノおよびチオキソで置換されたアルキルである化合物、
および
（iv）以下に示す化合物：
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
（式中、Ｍｅはメチルであり、Ｅｔはエチルである）
を除く。）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
Formula (I):
Figure JPOXMLDOC01-appb-C000001
[Where:
Ring A is an aromatic heterocycle;
X 1 is N or C (R x1 );
X 2 is N or C (R x2 );
X 3 is N or C (R x3 );
X 4 is N or C (R x4 );
R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyl Ruoxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A (substituent group A: Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted Or substituted aryl or substituted heteroaryl), carbamoyl substituted with a substituent selected from substituents selected from substituent group A, sulfamoyl substituted with substituent selected from substituent group A, substituent group A Sulfur substituted with a substituent selected from Nyl, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or non-substituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, Substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy; or
R x2 and R x3 , or R x3 and R x4 , together with adjacent ring members, may form a C ring;
Ring C is
Figure JPOXMLDOC01-appb-C000002
(Where
Each W 1 is independently O, N (R 2a ), S, S (O) or S (O) 2 ;
Each W 2 independently represents O, N (R 2b ) or S;
R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, unsubstituted sulfamoyl, a sulfamoyl substituted with a substituent selected from substituent group A, or a substituent selected from substituent group A A sulfinyl substituted with a group, a sulfonyl substituted with a substituent selected from Substituent Group A, or a substituted or unsubstituted acyl;
n 1 is an integer from 0 to 4;
n 2 is an integer from 0 to 3;
n 3 is an integer from 0 to 2;
n 4 is an integer of 0 or 1;
R 1a and R 1b are each independently
a) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl From bonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, carbamoyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, substituent group A Sulfamoyl substituted with a selected substituent, sulfinyl substituted with a substituent selected from substituent group A, sulfonyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonyl Oxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group Substituted or unsubstituted aryl, substituted or non-substituted Substituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted hetero Aryloxy or
R 1a may be one or more groups selected from the group consisting of the following groups b) to e);
b) two R 1a are bonded to the same carbon atom, and ═O and ═NR 3 ,
c) when two R 1a are bonded to the same carbon atom to form — (CR 4a R 4b ) x— or —O— (CR 4a R 4b ) x—O—,
d) two R 1a bonded to adjacent carbon atoms-(CR 5a R 5b ) y-, and e) two R 1a bonded to non-identical and non-adjacent carbon atoms- ( CR 6a R 6b ) z-,
Provided that R 1a is not selected from two or more of c), d) and e) simultaneously;
R 3 is hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy;
R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
x is an integer of 2 to 7;
y is an integer of 1 to 5;
z is an integer of 1 to 3);
—B 1 represents the formula: —X— (CR 8a R 8b ) mY
(Where
X is N (R 7c ) or O;
R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 8a and R 8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
m is an integer from 0 to 5;
However, when Y is a group other than a nitrogen-containing non-aromatic heterocyclic group in which the nitrogen atom constituting the ring is substituted by a sulfonyl substituted with a substituent selected from the substituent group A, m is An integer from 1 to 4;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl Sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Nitrogen-containing non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from substituent group A A group represented by
B 2 is,
Figure JPOXMLDOC01-appb-C000003
(Where
R 9a and R 9b are each independently hydrogen or substituted or unsubstituted alkyl;
Each R 10 independently represents substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or two R 10 taken together to form oxo or thioxo;
R 11 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
R 12 represents substituted or unsubstituted alkyl, halogen, hydroxy, or substituted or unsubstituted alkyloxy;
p is an integer of 0 to 4) or a alkylene represented by a substituted or unsubstituted amino group] (provided that,
(I) a compound wherein A ring is not fused to C ring and Y is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
(Ii) m is 0, X is N (R 7c ), R 7c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl, and Y is substituted or unsubstituted heteroaryl or A compound in which the nitrogen atom constituting the ring is an indoline substituted with a sulfonyl substituted with a substituent selected from the substituent group A;
(Iii) the compound wherein R 11 is amino substituted with heteroaryl and alkyl substituted with thioxo,
And (iv) the following compounds:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
(Wherein Me is methyl and Et is ethyl)
except for. Or a pharmaceutically acceptable salt thereof or a solvate thereof.
Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であり、Ｒｘ３およびＲｘ４が、それぞれ隣接する環構成原子と一緒になってＣ環を形成するか、または、Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮであり、Ｒｘ２およびＲｘ３が、それぞれ隣接する環構成原子と一緒になってＣ環を形成し；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基であり；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000006
（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは請求項１と同意義）で示される基である請求項１記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), and R x3 and R x4 are each taken together with adjacent ring atoms to form C Form a ring, or X 1 is N, X 2 is C (R x2 ), X 3 is C (R x3 ), and X 4 is N, and R x2 and R x3 are each adjacent rings Together with the constituent atoms form a C ring;
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent;
B 2 is,
Figure JPOXMLDOC01-appb-C000006
(Wherein R 9a , R 9b , R 10 , R 11 and p are as defined in claim 1), or a pharmaceutically acceptable salt thereof or a solvent thereof. Japanese products.
Ｃ環が、
Figure JPOXMLDOC01-appb-C000007
（式中、Ｗ１、Ｗ２、Ｒ１ａ、Ｒ１ｂ、ｎ１、ｎ２、ｎ３およびｎ４は、請求項１と同意義）で示される環である請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ring C is
Figure JPOXMLDOC01-appb-C000007
(Wherein W 1 , W 2 , R 1a , R 1b , n 1 , n 2 , n 3 and n 4 have the same meaning as in claim 1), or a compound according to claim 2, or The pharmaceutically acceptable salt or solvate thereof.
Ｃ環が、
Figure JPOXMLDOC01-appb-C000008
（式中、Ｗ１、Ｒ１ａおよびｎ１は、請求項１と同意義）で示される環である請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ring C is
Figure JPOXMLDOC01-appb-C000008
(Wherein W 1 , R 1a and n 1 have the same meaning as in claim 1), or a pharmaceutically acceptable salt or solvate thereof.
Ｒｘ１、Ｒｘ２、Ｒｘ３およびＲｘ４が、それぞれ独立して、水素、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、非置換カルバモイル、置換基群Ａから選択される置換基で置換されたカルバモイル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、置換もしくは非置換のアルキルスルホニルオキシ、置換もしくは非置換のアリールスルホニルオキシ、シアノ、ニトロ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシ、または置換もしくは非置換のヘテロアリールオキシ；
Ｘが、Ｎ（Ｒ７ｃ）（式中、Ｒ７ｃは請求項１と同意義）；
Ｙが、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換基群Ａから選択される置換基で置換されたスルフィニル、置換基群Ａから選択される置換基で置換されたスルホニル、非置換スルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のアミノスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノ、または環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基；
Ｂ２が、
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ９ａ、Ｒ９ｂ、Ｒ１０、Ｒ１１およびｐは請求項１と同意義）で示される基である請求項１記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
R x1 , R x2 , R x3 and R x4 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, hydroxy, carboxy Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyl A substituent selected from ruoxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, unsubstituted carbamoyl, substituent group A Selected from carbamoyl, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from Substituent Group A, sulfinyl substituted with a substituent selected from Substituent Group A, Substituent Group A Substituted sulfonyl, substituted or unsubstituted alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted Non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic hetero Ring oxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;
X is N (R 7c ) (wherein R 7c is as defined in claim 1);
Y is substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted nonaromatic heterocyclic thio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituent Sulfinyl substituted with a substituent selected from group A, sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, Substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted aminosulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted Cycloalkenyl The sulfonylamino, substituted or unsubstituted non-aromatic heterocyclic sulfonylamino, substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or the nitrogen atom constituting the ring is selected from the substituent group A A nitrogen-containing non-aromatic heterocyclic group substituted with a sulfonyl substituted with a substituent;
B 2 is,
Figure JPOXMLDOC01-appb-C000009
(Wherein R 9a , R 9b , R 10 , R 11 and p are as defined in claim 1), or a pharmaceutically acceptable salt thereof or a solvent thereof. Japanese products.
Ｘ１がＮ、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であるか、または
Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＮである、請求項５記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
X 1 is N, X 2 is N, X 3 is C (R x3 ), and X 4 is C (R x4 ), or X 1 is N, X 2 is C (R x2 ), and X 3 is 6. The compound according to claim 5, wherein C (R x3 ) and X 4 are N, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
Ｘ１がＮ、Ｘ２がＣ（Ｒｘ２）、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）であるか、または
Ｘ１がＣ（Ｒｘ１）、Ｘ２がＮ、Ｘ３がＣ（Ｒｘ３）、およびＸ４がＣ（Ｒｘ４）である、請求項５記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
X 1 is N, X 2 is C (R x2 ), X 3 is C (R x3 ), and X 4 is C (R x4 ), or X 1 is C (R x1 ), X 2 is N The compound according to claim 5, wherein X 3 is C (R x3 ), and X 4 is C (R x4 ), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
Ｂ２が、
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ１０、Ｒ１１、およびｐは請求項１と同意義）で示される基である、請求項１～７のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
B 2 is,
Figure JPOXMLDOC01-appb-C000010
(Wherein R 10 , R 11 , and p are as defined in claim 1), or a pharmaceutically acceptable salt thereof or a group thereof Solvates.
Ｙが、置換基群Ａから選択される置換基で置換されたスルホニル、非置換のスルファモイル、置換基群Ａから選択される置換基で置換されたスルファモイル、置換もしくは非置換のアルキルスルホニルアミノ、置換もしくは非置換のアルケニルスルホニルアミノ、置換もしくは非置換のアルキニルスルホニルアミノ、置換もしくは非置換のシクロアルキルスルホニルアミノ、置換もしくは非置換のシクロアルケニルスルホニルアミノ、置換もしくは非置換の非芳香族複素環スルホニルアミノ、置換もしくは非置換のアリールスルホニルアミノ、置換もしくは非置換のヘテロアリールスルホニルアミノまたは環を構成する窒素原子が置換基群Ａから選択される置換基で置換されたスルホニルで置換された含窒素非芳香族複素環基である、請求項１～８のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
Y is sulfonyl substituted with a substituent selected from substituent group A, unsubstituted sulfamoyl, sulfamoyl substituted with a substituent selected from substituent group A, substituted or unsubstituted alkylsulfonylamino, substituted Or unsubstituted alkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino, substituted or unsubstituted cycloalkylsulfonylamino, substituted or unsubstituted cycloalkenylsulfonylamino, substituted or unsubstituted nonaromatic heterocyclic sulfonylamino, Substituted or unsubstituted arylsulfonylamino, substituted or unsubstituted heteroarylsulfonylamino, or nitrogen-containing non-aromatic in which a nitrogen atom constituting the ring is substituted with a sulfonyl substituted with a substituent selected from Substituent Group A Claims that are heterocyclic groups Compound, or a pharmaceutically acceptable salt or solvate thereof according to any one of 1 to 8.
Ｙが、置換基群Ａから選択される置換基で置換されたスルホニル、非置換のスルファモイル、または置換基群Ａから選択される置換基で置換されたスルファモイルである、請求項１～９のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
Y is sulfonyl substituted with a substituent selected from Substituent Group A, unsubstituted sulfamoyl, or sulfamoyl substituted with a substituent selected from Substituent Group A. Or a pharmaceutically acceptable salt or solvate thereof.
ｍが、１～３の整数である請求項１～１０のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is an integer of 1 to 3.
請求項１～１１のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
ヒスタミンＨ４調節剤である、請求項１２記載の医薬組成物。
The pharmaceutical composition according to claim 12, which is a histamine H4 modulator.
請求項１～１１のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ヒスタミンＨ４受容体が関与する疾患または状態の治療および／または予防方法。
Treatment of a disease or condition involving histamine H4 receptor, and / or administration of a compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a solvate thereof Prevention method.
ヒスタミンＨ４受容体が関与する疾患または状態の治療および／または予防のための、請求項１～１１のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, or a solvate thereof, for the treatment and / or prevention of a disease or condition involving histamine H4 receptor.
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