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WO2011078143A1 - Dérivés de pyrimidine et composition pharmaceutique les contenant - Google Patents

Dérivés de pyrimidine et composition pharmaceutique les contenant 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
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English (en)
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/fr
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    • 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
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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

La présente invention concerne un nouveau composé qui présente une activité de modulation du récepteur à l'histamine H4. L'invention concerne spécifiquement un composé représenté par la formule (I), son sel pharmaceutiquement acceptable, ou un solvat du composé ou du sel. (Dans la formule, le cycle A représente un cycle hétérocyclique aromatique; -B1 représente un groupe représenté par -X-(CR8aR8b)m-Y; X représente un groupe représenté par by N(R7c) ou similaire; R7c représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué ou similaire; R8a et R8b représentent chacun indépendamment un atome d'hydrogène, un atome d'halogène ou similaire; m représente un nombre entier valant 0 à 5; Y représente un groupe cycloalkylthio substitué ou non substitué ou similaire; et -B2 représente un groupe représenté par la formule (II) (où R10s représentent chacun indépendamment un groupe alkyle substitué ou non substitué ou similaire; R11 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué ou similaire; et p représente un nombre entier valant 0 à 4) ou similaire).
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