WO2019054386A1 - Heterocyclic compound or salt thereof, gpr35 agonist, and pharmaceutical composition - Google Patents

Heterocyclic compound or salt thereof, gpr35 agonist, and pharmaceutical composition Download PDF

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WO2019054386A1
WO2019054386A1 PCT/JP2018/033694 JP2018033694W WO2019054386A1 WO 2019054386 A1 WO2019054386 A1 WO 2019054386A1 JP 2018033694 W JP2018033694 W JP 2018033694W WO 2019054386 A1 WO2019054386 A1 WO 2019054386A1
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substituted
group
heterocyclic compound
alkyl group
gpr35
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PCT/JP2018/033694
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French (fr)
Japanese (ja)
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松野　研司
大野　修
田中　智之
和幸 古田
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学校法人工学院大学
国立大学法人岡山大学
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Priority to JP2019542072A priority Critical patent/JP7148769B2/en
Publication of WO2019054386A1 publication Critical patent/WO2019054386A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions.
  • GPR35 which belongs to rhodopsin-like class AGPCR, is an orphan receptor whose expression is seen in the immune system, digestive system and other visceral tissues. Although many of the effects of GPR35 have not been elucidated, their association with blood pressure, nociception, immune reaction, inflammatory bowel disease, diabetes, arteriosclerosis and the like has been reported. Therefore, agonists of GPR35 are expected as therapeutic agents for various diseases, and a search for candidate compounds is being made.
  • Non-Patent Document 1 reports that a compound having the following formula or a similar structure has activity as a GPR35 agonist.
  • GPR35 is characterized by a large species difference in ligand responsiveness as compared to other GPCRs.
  • the compound described in Non-patent Document 1 has been confirmed to have activity against human GPR35, but its activity against rat GPR35 is extremely weak and there are species differences.
  • the present invention has been made in view of the above-mentioned circumstances, and an object of an embodiment of the present invention is to provide a heterocyclic compound or a salt thereof, a GPR35 agonist and a pharmaceutical composition.
  • Means for solving the above problems include the following embodiments. ⁇ 1> A heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
  • X represents O or NH
  • R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group
  • R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substitute
  • N attached to R 2 represents the number of R 2, is an integer of 0-3.
  • the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is a heterocyclic compound described in ⁇ 1> or the heterocyclic compound represented by the following general formula (I-1) Pharmacologically acceptable salt.
  • R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I).
  • the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is a heterocyclic compound described in ⁇ 1> or the heterocyclic compound represented by the following general formula (I-2) Pharmacologically acceptable salt.
  • R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I).
  • ⁇ 4> The heterocyclic compound according to any one of ⁇ 1> to ⁇ 3>, wherein X is O, or a pharmacologically acceptable salt of the heterocyclic compound.
  • ⁇ 5> The heterocyclic compound according to any one of ⁇ 1> to ⁇ 4>, wherein R 2 is NR 5 R 6 or NR 7 COR 8 or a pharmacologically acceptable salt of the heterocyclic compound. .
  • R 1 has no substituent, or is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom, or a substituted or unsubstituted group Alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted alkyl group) ), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted Alkyl group), SR (R is a hydrogen atom or a substituted
  • ⁇ 7> The heterocyclic compound according to any one of ⁇ 1> to ⁇ 6>, wherein R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), or a pharmacological of the heterocyclic compound Acceptable salt.
  • R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), or a pharmacological of the heterocyclic compound Acceptable salt.
  • R 2 is NH 2 or NHCOR 8 or a pharmacologically acceptable salt of the heterocyclic compound.
  • ⁇ 9> The heterocyclic compound according to any one of ⁇ 1> to ⁇ 8>, wherein R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group), or a pharmacologically acceptable of the heterocyclic compound. Salt.
  • R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group), or a pharmacologically acceptable of the heterocyclic compound. Salt.
  • ⁇ 11> The heterocyclic compound according to ⁇ 10> or a pharmacologically acceptable salt of the heterocyclic compound having activity against at least one of human GPR35 and non-human animal GPR35.
  • ⁇ 12> The heterocyclic compound according to ⁇ 10> or ⁇ 11> or a pharmacologically acceptable salt of the heterocyclic compound, which has activity against both human GPR35 and non-human animal GPR35.
  • ⁇ 13> The heterocyclic compound according to ⁇ 11> or ⁇ 12>, wherein the non-human animal is a rodent, or a pharmacologically acceptable salt of the heterocyclic compound.
  • a GPR35 agonist which is a heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
  • X represents O or NH
  • R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group
  • R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substitute
  • N attached to R 2 represents the number of R 2, is an integer of 0-3.
  • R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I).
  • ⁇ 17> The GPR35 agonist according to any one of ⁇ 14> to ⁇ 16>, wherein X is O.
  • ⁇ 18> The GPR35 agonist according to any one of ⁇ 14> to ⁇ 17>, wherein R 2 is NR 5 R 6 or NR 7 COR 8 .
  • R 1 has no substituent, or is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted Alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted alkyl group) ), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted Alkyl group), SR (R is a hydrogen atom or a substituted or unsubstit
  • ⁇ 23> The GPR35 agonist according to any one of ⁇ 14> to ⁇ 22>, which has activity against at least one of human GPR35 and non-human animal GPR35.
  • ⁇ 24> The GPR35 agonist according to any one of ⁇ 14> to ⁇ 23>, which has activity against both human GPR35 and non-human animal GPR35.
  • ⁇ 25> The GPR35 agonist according to ⁇ 23> or ⁇ 24>, wherein the non-human animal is a rodent.
  • ⁇ 26> The GPR35 agonist according to any one of ⁇ 14> to ⁇ 25>, for use in the treatment of a condition or disease involving GPR35.
  • heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions are provided.
  • a first embodiment of the present disclosure is a heterocyclic compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
  • examples of the aryl group represented by R 1 include a phenyl group, a naphthyl group and the like, preferably a phenyl group.
  • the aromatic heterocyclic group represented by R 1 includes an aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a pyridyl group, a furanyl group, a thienyl group or a pyrrolyl group.
  • the type of the substituent is not particularly limited.
  • it can be selected from the substituents represented by R 2 in the general formula (I).
  • examples of the alkyl group represented by R 2 or R 4 include alkyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkyl group of 1 to 5, more preferably an alkyl group having 1 to 4 carbon atoms (excluding substituents), and still more preferably a methyl group, an ethyl group, a propyl group or a butyl group.
  • the alkyl group may be linear or branched.
  • examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the same applies to the following.
  • examples of the cycloalkyl group represented by R 2 or R 4 include cycloalkyl groups having 3 to 10 carbon atoms (excluding substituents), preferably carbon atoms (substituted groups And 3) is a cycloalkyl group of 3 to 6).
  • examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • Examples of the alkenyl group represented by R 2 or R 4 in the general formula (I) include alkenyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkenyl group of 1 to 5, and more preferably an alkenyl group having 1 to 3 carbon atoms (excluding substituents).
  • examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • examples of the alkynyl group represented by R 2 or R 4 include alkynyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkynyl group of 1 to 5, and more preferably an alkynyl group having 1 to 3 carbon atoms (excluding substituents).
  • examples of the substituent include a trialkylsilyl group (wherein the alkyl group has the same meaning as the above alkyl group).
  • Examples of the alicyclic heterocyclic group represented by R 2 or R 4 in the general formula (I) include an alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom, And an alicyclic heterocyclic group having 2 to 6 carbon atoms (excluding substituents) containing an oxygen atom or a sulfur atom.
  • an alkyl group is synonymous with the said alkyl group
  • an alkoxy group an alkyl group in an alkoxy group is synonymous with the said alkyl group
  • examples of the aryl group represented by R 2 or R 4 include a phenyl group and a naphthyl group, preferably a phenyl group.
  • examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • Examples of the aromatic heterocyclic group represented by R 2 or R 4 in the general formula (I) include aromatic heterocyclic groups containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom or an oxygen atom Or an aromatic heterocyclic group having 2 to 9 carbon atoms (excluding substituents) containing a sulfur atom.
  • examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group) and an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group) And a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
  • an aromatic heterocyclic alkyl group represented by R 2 or R 4 an aromatic group in which one carbon atom of an alkyl group having 1 to 6 carbon atoms (excluding substituents) is mentioned above
  • heteroaromatic alkyl groups substituted with a heterocycle As a substituent when the aromatic heterocyclic alkyl group has a substituent, an alkyl group (an alkyl group has the same meaning as the above alkyl group) and an alkoxy group (an alkyl group in an alkoxy group has the same meaning as the above alkyl group) And nitro, cyano, halogen, hydroxyl, carboxy, methyl ester, amino and the like.
  • R 1 is an aryl group having a substituent or an aromatic heterocyclic group
  • the number of the substituent is not particularly limited, but may be 1 to 3, or 1 Alternatively, it may be two or one.
  • R 1 is an aryl group or aromatic heterocyclic group having a substituent
  • R 1 is a substituted or unsubstituted alkyl group as a substituent
  • COOR R is a hydrogen atom or a substituted or unsubstituted alkyl group
  • OCH 2 COOR R is a hydrogen atom or a substituted or unsubstituted alkyl group
  • OR R is a hydrogen atom, a substituted or unsubstituted alkyl group
  • NRR R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group
  • COR R Is a hydrogen atom or a substituted or unsubstituted alkyl group
  • CONRR R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group
  • SO 2 R R is a substituted or unsubstituted alkyl group
  • SO 2 NRR R is Each independently a hydrogen atom or a substitute
  • R 1 is a substituted or unsubstituted alkyl group
  • COOR R is a hydrogen atom or a substituted or unsubstituted alkyl group
  • OCH 2 COOR R is a hydrogen atom or a substituted or unsubstituted alkyl group
  • OR R Is more preferably a hydrogen atom, a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom.
  • R 2 is preferably one or two, and more preferably one.
  • R 2 is NR 5 R 6 or NR 7 COR 8, more preferably NH 2 or NHCOR 8, and more preferably NH 2 or NHCOAr (Ar is a substituted or unsubstituted aryl group) .
  • Ar is a substituted or unsubstituted aryl group
  • a phenyl group and a naphthyl group are mentioned, Preferably it is a phenyl group.
  • the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, an amino group and the like. Among them, an alkoxy group and a halogen atom are preferable, and a methoxy group and a chloro group are more preferable.
  • R 2 is NHCOAr and Ar is an aryl group having a substituent
  • Ar preferably has a substituent at the para position.
  • R 3 is preferably COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), more preferably COOH.
  • X is O
  • R 1 is a substituted or unsubstituted aryl group
  • R 2 is NR 5 R 6 or NR 7 COR 8 It may be a certain heterocyclic compound.
  • R 1 further has no substituent, is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom, or substitution or Unsubstituted alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted Alkyl group), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substitution or Unsubstituted alkyl group), SR (R is a hydrogen atom or substituted or unsubstituted alkyl group,
  • the heterocyclic compound represented by the general formula (I) may be a heterocyclic compound represented by the following general formula (I-1).
  • the definitions of X, R 1 to R 3 and n in the general formula (I-1) are the same as in the general formula (I), and preferred examples are also the same.
  • the heterocyclic compound represented by the general formula (I) may be a heterocyclic compound represented by the following general formula (II).
  • the definitions of X and R 1 to R 3 in the general formula (I-2) are the same as in the general formula (I), and preferred examples are also the same.
  • any of them or a mixture thereof is also represented by the general formula (I)
  • the pharmacologically acceptable salt of the heterocyclic compound represented by the general formula (I) may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.
  • the pharmacologically acceptable salts of the heterocyclic compounds represented by the general formula (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. Can be mentioned.
  • acid addition salts inorganic acid salts such as hydrochloride, sulfate and phosphate, acetates, maleates, fumarate, tartrate, citrate, organic acid salts such as methanesulfonate and the like
  • the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • Ammonium salts include salts such as ammonium and tetramethyl ammonium.
  • Organic amine addition salts include addition salts of morpholine, piperidine and the like.
  • Examples of amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.
  • the heterocyclic compound when it is desired to obtain a salt of the heterocyclic compound represented by the general formula (I), when the heterocyclic compound is obtained in the form of a salt, it may be purified as it is, and when it is obtained in the free form, The heterocyclic compound may be dissolved or suspended in a suitable organic solvent, an acid or a base may be added, and a salt may be formed by a conventional method.
  • the heterocyclic compound represented by the general formula (I) may exhibit an activity as an agonist of GPR35.
  • the heterocyclic compound represented by the general formula (I) may have activity against at least one of human GPR35 and non-human animal GPR35, and human GPR35 and human GPR35 It may have activity against both GPR35 of other animals.
  • non-human animals include, but are not limited to, rodents such as mice and rats.
  • a second embodiment of the present disclosure is a GPR35 agonist which is the heterocyclic compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
  • the GPR35 agonist is a human GPR35 and a non-human animal (for example, a rodent such as a mouse or a rat) GPR35 It is preferable to show activity against both of
  • the use of the GPR35 agonist is not particularly limited and is directed to the treatment of any condition and disease in which the GPR35 is involved.
  • Symptoms and diseases in which GPR35 is involved include, but are not limited to, allergic diseases, inflammatory bowel diseases, diabetes, arteriosclerosis and the like.
  • GPR35 agonists may be used as anti-allergic agents.
  • GPR35 is known to suppress the secretion of IL-4 from iNKT cells upon activation. Therefore, when GPR35 agonist is applied to GPR35, it is considered that the induction of differentiation from Th0 cells to Th2 cells is suppressed. As a result, the chemical mediator released from Th2 cells can be expected to have the effect of suppressing the allergic reaction caused by binding to the receptor.
  • Anti-allergic agents using GPR35 agonists are means of achieving alleviation or elimination of symptoms more fundamentally than existing anti-allergic agents targeting binding of chemical mediators and receptors released from Th2 cells It is considered to be useful.
  • the GPR35 agonist may be used in the form of supplements, foods, beverages, etc. as well as pharmaceuticals, and may be used for purposes other than medical practice such as research.
  • GPR35 agonists can be administered alone as they are, it is usually preferable to provide them as various pharmaceutical preparations. Also, these pharmaceutical preparations are used for animals and humans. As the administration route, it is preferable to use one most effective in treatment, and oral or parenteral such as enteral, buccal, subcutaneous, intramuscular, intravenous and the like can be mentioned. Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.
  • the effective dose and frequency of administration of GPR35 agonist vary depending on the administration form, patient's age, body weight, nature of the condition to be treated, severity and the like, but the dosage is usually 0.01 to 1000 mg / day
  • the dose is preferably in the range of 5 to 500 mg / person, and the administration frequency is preferably once a day or in divided doses.
  • a third embodiment of the present disclosure is a pharmaceutical composition comprising the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment as an active ingredient. is there.
  • the ingredient when the pharmaceutical composition contains an ingredient other than the above active ingredient, the ingredient includes a medium and a formulation additive generally used for the preparation of a drug.
  • Media include solid media (eg, gelatin, lactose) and liquid media (eg, alcohol, water, saline).
  • pharmaceutical additives include excipients, disintegrants, binders, lubricants, surfactants, buffers, solubilizers, stabilizers, tonicity agents, and the like. If the compounding amount of these components is that the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound or the GPR35 agonist of the second embodiment can act as an active ingredient It is not particularly limited.
  • the form of the pharmaceutical composition is not particularly limited, and can be selected according to the use.
  • forms suitable for oral administration such as tablets, granules, powders, capsules, suspensions, syrups, emulsions, limonade agents etc.
  • forms suitable for parenteral administration such as suppositories, injections etc. can be mentioned.
  • Preparations suitable for oral administration for example, liquid preparations such as emulsions and syrups, water, sucrose, sorbit, saccharides such as fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, soybean oil etc. Oils, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint flavor.
  • Capsules, tablets, powders, granules and the like are excipients such as lactose, glucose, sucrose and mannitol, disintegrators such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl
  • the binder can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as a fatty acid ester, a plasticizer such as glycerin, or the like.
  • Formulations suitable for parenteral administration comprise sterile aqueous preparations which preferably contain the active compound isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising, for example, a salt solution, glucose solution or a mixture of saline and glucose solution.
  • Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohols and the like, or other bases used for topical pharmaceutical formulations.
  • Formulations for enteral administration are prepared as conventional suppositories using conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like.
  • glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified in oral preparations It is also possible to add one or more auxiliary components selected from plasticizers and the like.
  • the fourth embodiment of the present disclosure includes the step of contacting the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment with GPR35.
  • the method for bringing the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound or the GPR35 agonist of the second embodiment into contact with GPR 35 is not particularly limited, and oral administration, intravenous administration And surgical procedures such as indwelling.
  • the GPR 35 may be contacted in the state of the pharmaceutical composition of the third embodiment described above.
  • GPR35 to be contacted with the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment is human GPR35, but is not human It may be GPR35 of animals (laboratory animals, domestic animals, pets etc). Further, it may be GPR35 in vivo or GPR35 in vitro.
  • the GPR35 activation method may be for the purpose of treating a disease involving GPR35, or may be for the purpose of research, examination, etc. other than treatment.
  • the GPR35 activation method is for the treatment of a disease involving GPR35
  • the disease involving GPR35 to be treated includes allergic diseases, inflammatory bowel disease, diabetes, arteriosclerosis and the like However, it is not limited to these.
  • the reaction mixture was concentrated, saturated aqueous sodium chloride solution and chloroform were added to the residue, and the precipitated insoluble matter was separated by filtration, extracted with chloroform and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-1 (137 mg, 0.464 mmol) (yield 69%).
  • Methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate 200 mg, 0.671 mmol synthesized in CI-1 synthesis (2) and argon in 1,4-dioxane (8.0 mL)
  • PdCl 2 (dppf) 49 mg, 0.0671 mmol
  • K 3 PO 4 284 mg, 1.34 mmol
  • 4- (methoxycarbonyl) phenylboronic acid 181 mg, 1.01 mmol
  • Methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate synthesized by synthesis (1) of CI-2 (75 mg, 0.174 mmol) of 1,4-dioxane (5)
  • PdCl 2 (dppf) 13 mg, 0.0174 mmol
  • K 3 PO 4 74 mg, 0.347 mmol
  • 4- (methoxycarbonyl) phenylboronic acid 47 mg, 0.260 mmol
  • LiI (41 mg, 0.308 mmol) was added to a solution of CI-7 (50 mg, 0.103 mmol) in tetrahydrofuran (3.0 mL), and the mixture was heated under reflux for 7 hours. Further, LiI (41 mg, 0.308 mmol) is added, and the mixture is heated under reflux overnight. The reaction mixture is concentrated, 1 M hydrochloric acid is slowly added dropwise to the residue, and the precipitated crystals are collected by filtration, washed with water and dried under reduced pressure, (35 mg, 0.0739 mmol) were obtained (yield 72%).
  • LiI (44 mg, 0.329 mmol) was added to a solution of CI-11 (52 mg, 0.110 mmol) in tetrahydrofuran (4.0 mL), and the mixture was heated to reflux overnight. After adding LiI (44 mg, 0.329 mmol) and heating under reflux for 2 days, LiI (44 mg, 0.329 mmol) was further added, and the mixture was heated under reflux overnight. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure and recrystallized from methanol to give CI-17 (28 mg, 0.0610 mmol) (56% yield).
  • LiI (66 mg, 0.493 mmol) was added to a solution of CI-13 (71 mg, 0.164 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100 ° C. for 10 hours under microwave irradiation.
  • LiI (67 mg, 0.502 mmol) was added to a solution of CI-14 (80 mg, 0.167 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100 ° C. for 6 hours under microwave irradiation. Further, LiI (67 mg, 0.502 mmol) was added, and the mixture was stirred at 100 ° C. for 13 hours under microwave irradiation.
  • LiI (31 mg, 0.234 mmol) was added to a solution of CI-14 (19 mg, 0.0390 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred at 200 ° C. for 2 hours under microwave irradiation. After adding LiI (31 mg, 0.234 mmol) and stirring at 200 ° C. for 2.5 hours under microwave irradiation, LiI (31 mg, 0.234 mmol) was further added, and stirring was performed at 200 ° C. under microwave irradiation for 6 hours.
  • CI-32 was obtained in the same manner as in the synthesis of CI-31, using CI-29 instead of CI-28 (quantitative yield).
  • CI-33 was obtained in the same manner as in the synthesis of CI-31, using CI-30 instead of CI-28 (quantitative yield).
  • CI-85 was obtained in the same manner as in the synthesis of CI-7, using 2-methoxy-4-pyridylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid (yield 34%).
  • CI-87 was obtained (yield 30%) in the same manner as in the synthesis of CI-7, using 2-methylthio-5-pyridineboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid.
  • CI-88 was obtained (yield 7%) in the same manner as in the synthesis of CI-7, using 2-amino-5-pyridylboronic acid pinacol ester instead of 4- (Methoxycarbonyl) phenylboronic acid.
  • CII-7 was obtained in a similar manner to the synthesis of CII-6 (yield 91%).
  • CII-8 was obtained in a similar manner to the synthesis of CII-6 (yield 44%).
  • CII-10 was obtained in a similar manner to the synthesis of CII-6 (yield 94%).
  • ⁇ Evaluation using rat GPR35 expressing RBL-2H3 cells Using the rat mast cell line RBL-2H3, cells constitutively expressing a gene encoding rat GPR35 to which hemagglutinin (HA) epitope tag sequence was added at the N-terminal side were established and used for the following evaluation.
  • HA hemagglutinin
  • FIG. 1 shows the results of measurement of rat GPR35 mRNA expression by quantitative RT-PCR. It can be seen that RBL-2H3 cells (RBL) show substantially no expression of rat GPR35 as compared to rat peritoneal mast cells (pMC). In addition, it was confirmed from the results of flow cytometry using a fluorescently labeled anti-HA antibody that stable rat GPR35 expression was detected.
  • RBL-2H3 cells RBL-2H3 cells
  • pMC rat peritoneal mast cells
  • FIG. 2 is comparative experimental data of the degree of degranulation (Degranulation) by RBL-2H3 cells expressing rat GPR35 and RBL-2H3 cells not expressing rat GPR35.
  • RBL-2H3 cells stably expressing HA-tagged rat GPR35 were sensitized with 50 ng / ml anti-DNP IgE antibody (clone SPE-7) for 24 hours. Thereafter, washing was performed twice to remove free IgE antibodies.
  • the cells are then treated with dinitrophenol-human serum albumin (DNP-HSA) (30 ng / ml) in the presence of zaprinast (1 ⁇ M) as a positive control, or compound CI-18 or compound CI-26 at the concentrations shown in FIG.
  • DNP-HSA dinitrophenol-human serum albumin
  • FIG. 2 shows the results of performing the same treatment as above on RBL-2H3 cells (mock) not expressing rat GPR35.
  • Statistical processing was performed by one-way analysis of variance and Dunnett's test.
  • Rat peritoneal mast cells were used to investigate the effect of compounds on IgE-mediated antigen-induced degranulation responses.
  • Rat peritoneal cells collected from Wistar rats male, 7 weeks old were fractionated by density gradient centrifugation to obtain purified mast cells of 90-95% purity.
  • the resulting cells were sensitized to anti-DNP IgE antibody (clone SPE-7) (10 ⁇ g / ml) at 37 ° C. for 3 hours. Thereafter, washing was performed twice to remove free IgE antibodies.
  • Degranulation responses were then induced by stimulation with lysophosphatidylserine (2 ⁇ M) and dinitrophenol conjugated human serum albumin (DNP-HSA) (100 ng / ml).
  • zaprinast (1 ⁇ M) or compound CI-16, 18, 26 or 63 at the concentration shown in Table 3 was added simultaneously with DNP-HAS.
  • the degree of degranulation response was measured using ⁇ -hexosaminidase activity (%) as an index.
  • the results are shown in Table 3.
  • ⁇ -hexosaminidase activity was significantly reduced in the presence of CI-16, 18, 26, 63 in a dose-dependent manner. This result suggests that CI-16, 18, 26, 63 suppress the IgE-mediated antigen-induced degranulation response and exhibits an antiallergic action.
  • Formulation Example 1 Using the synthesized CI-16, a tablet having the following composition was prepared by a conventional method. CI-16 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar pigment trace amount
  • Formulation Example 3 A syrup having the following composition was prepared by a conventional method using CI-16 synthesized. CI-16 100 mg Refined white sugar 40 mg Ethyl p-hydroxybenzoate 40 mg Propyl p-hydroxybenzoate 10 mg Strawberry flavor 0.1cc Add water to the above materials to make a total volume of 100 cc.

Abstract

Provided is a heterocyclic compound represented by general formula (I), or a pharmacologically acceptable salt of the heterocyclic compound. In general formula (I): X represents O or NH; R1 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R2 represents a substituted or unsubstituted alkyl group, etc.; R3 represents COOR (where R is a hydrogen atom, an alkyl group, etc.); and the n appended to R2 represents the number of R2, and is an integer of 0-3.

Description

複素環化合物又はその塩、ＧＰＲ３５作動薬及び医薬組成物Heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions
　本発明は、複素環化合物又はその塩、ＧＰＲ３５作動薬及び医薬組成物に関する。 The present invention relates to heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions.
　Ｇタンパク質共役受容体（ＧＰＣＲ）のうち、ロドプシン様クラスＡＧＰＣＲに属するＧＰＲ３５は、免疫系、消化器系その他の内臓組織などに発現がみられるオーファン受容体である。ＧＰＲ３５の作用は多くは解明されていないものの、血圧、痛覚、免疫反応、炎症性腸疾患、糖尿病、動脈硬化等との関連性が報告されている。このため、ＧＰＲ３５の作動薬は種々の疾患の治療薬として期待され、候補化合物の模索がなされている。 Among G protein coupled receptors (GPCRs), GPR35, which belongs to rhodopsin-like class AGPCR, is an orphan receptor whose expression is seen in the immune system, digestive system and other visceral tissues. Although many of the effects of GPR35 have not been elucidated, their association with blood pressure, nociception, immune reaction, inflammatory bowel disease, diabetes, arteriosclerosis and the like has been reported. Therefore, agonists of GPR35 are expected as therapeutic agents for various diseases, and a search for candidate compounds is being made.
　ＧＰＲ３５作動薬としては、ザプリナスト、ジクマロール、クロモグリク酸二ナトリウム（ＤＳＣＧ）、パモ酸、ケルセチンといった化合物がこれまでに報告されている。また、非特許文献１には下記式又はこれに類似の構造を有する化合物がＧＰＲ３５作動薬としての活性を有すると報告されている。 As GPR35 agonists, compounds such as zaprinast, dicoumarol, disodium cromoglycate (DSCG), pamoic acid, quercetin have been reported so far. In addition, Non-Patent Document 1 reports that a compound having the following formula or a similar structure has activity as a GPR35 agonist.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　これまで報告されていないＧＰＲ３５作動薬の候補化合物を新たに見出すことは、ＧＰＲ３５の作用の解明、ＧＰＲ３５が関与する疾患の治療方法の発展等に資すると考えられる。
　さらに、ＧＰＲ３５は他のＧＰＣＲと比較してリガンド応答性に種差が大きいことが特徴である。たとえば、非特許文献１に記載の化合物は、ヒトＧＰＲ３５に対する活性が確認されているがラットＧＰＲ３５に対する活性は極めて弱く種差が存在する。 It is considered that finding new candidate compounds for GPR35 agonists that have not been reported so far will contribute to elucidation of the action of GPR35, development of treatment methods for diseases in which GPR35 is involved, and the like.
Furthermore, GPR35 is characterized by a large species difference in ligand responsiveness as compared to other GPCRs. For example, the compound described in Non-patent Document 1 has been confirmed to have activity against human GPR35, but its activity against rat GPR35 is extremely weak and there are species differences.
　医薬品開発の過程では動物試験を経ることが必須であることを考慮すると、ヒト以外の動物においても活性を示すＧＰＲ３５作動薬としての候補化合物を見出すことは、医薬品としての実用化を視野に入れると大きな利点であると考えられる。
　本発明は上記事情を鑑みてなされたものであり、本発明のある実施形態の目的は、複素環化合物又はその塩、ＧＰＲ３５作動薬及び医薬組成物を提供することである。 Considering that it is essential to go through animal studies in the process of drug development, finding candidate compounds as GPR35 agonists that show activity in non-human animals is a practical application as a drug. It is considered to be a great advantage.
The present invention has been made in view of the above-mentioned circumstances, and an object of an embodiment of the present invention is to provide a heterocyclic compound or a salt thereof, a GPR35 agonist and a pharmaceutical composition.
　上記課題を解決するための手段には、以下の実施形態が含まれる。
＜１＞　下記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 Means for solving the above problems include the following embodiments.
<1> A heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
［一般式（Ｉ）において、ＸはＯ又はＮＨを表し、Ｒ１は置換もしくは非置換アリール基又は置換もしくは非置換芳香族複素環基を表し、Ｒ２は置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、置換もしくは非置換芳香族複素環アルキル基、ＯＲ４（Ｒ４は水素原子、置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、又は置換もしくは非置換芳香族複素環アルキル基である）、ＮＲ５Ｒ６（Ｒ５及びＲ６はそれぞれ独立にＲ４と同義であり、一緒になって環を形成してもよい）、ＮＲ７ＣＯＲ８（Ｒ７及びＲ８はそれぞれ独立にＲ４と同義である）、ＮＲ９ＳＯ２Ｒ１０（Ｒ９及びＲ１０はそれぞれ独立にＲ４と同義である）、Ｓ（Ｏ）ｎＲ１１（ｎは０、１もしくは２であり、Ｒ１１はＲ４と同義である）、ＣＯＲ１２（Ｒ１２はＲ４と同義である）、ＣＯＯＲ１３（Ｒ１３はＲ４と同義である）、ＯＣＯＲ１４（Ｒ１４はＲ４と同義である）、ＣＯＮＲ１５Ｒ１６（Ｒ１５及びＲ１６はそれぞれ独立にＲ４と同義である）、ＳＯ２ＮＲ１７Ｒ１８（Ｒ１７及びＲ１８はそれぞれ独立にＲ４と同義である）、ＯＣＨ２ＣＯＯＲ１９（Ｒ１９はＲ４と同義である）、ＯＳＯ２Ｒ２０（Ｒ２０はＲ４と同義である）、ＳＲ２１（Ｒ２１はＲ４と同義である）、ニトロ基、シアノ基又はハロゲン原子を表し、Ｒ３はＣＯＯＲ２２（Ｒ２２はＲ４と同義である）を表す。Ｒ２に付されたｎはＲ２の個数を表し、０～３の整数である。］
＜２＞　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－１）で表される、＜１＞に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 [In general formula (I), X represents O or NH, R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted Substituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or substituted Substituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 5 R 6 (R 5 and R 6 have the same meanings as R 4 each independently, NR 7 COR 8 (R 7 and R 8 each independently have the same meaning as R 4 ), NR 9 SO 2 R 10 (R 9 and R 10 each independently may form a ring) the same meaning as R 4), S (O) n R 11 (n is 0, 1 or 2, R 11 has the same meaning as R 4), COR 12 (R 12 has the same meaning as R 4 ), COOR 13 (R 13 is the same as R 4 ), OCOR 14 (R 14 is the same as R 4 ), CONR 15 R 16 (R 15 and R 16 are each independently the same as R 4 ) ), SO 2 NR 17 R 18 (R 1 And R 18 is synonymous with R 4 each independently), OCH 2 COOR 19 (R 19 has the same meaning as R 4), OSO 2 R 20 (R 20 has the same meaning as R 4), SR 21 ( R 21 represents the same as R 4 ), a nitro group, a cyano group or a halogen atom, and R 3 represents COOR 22 (R 22 has the same meaning as R 4 ). N attached to R 2 represents the number of R 2, is an integer of 0-3. ]
<2> The heterocyclic compound represented by the general formula (I) or the heterocyclic compound is a heterocyclic compound described in <1> or the heterocyclic compound represented by the following general formula (I-1) Pharmacologically acceptable salt.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
［一般式（Ｉ－１）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］
＜３＞　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－２）で表される、＜１＞に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 [In the general formula (I-1), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
<3> The heterocyclic compound represented by the general formula (I) or the heterocyclic compound is a heterocyclic compound described in <1> or the heterocyclic compound represented by the following general formula (I-2) Pharmacologically acceptable salt.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
［一般式（Ｉ－２）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］
＜４＞　ＸがＯである、＜１＞～＜３＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜５＞　Ｒ２がＮＲ５Ｒ６又はＮＲ７ＣＯＲ８である、＜１＞～＜４＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜６＞　Ｒ１が置換基を有していないか、置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を置換基として有する、＜１＞～＜５＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜７＞　Ｒ３がＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）である、＜１＞～＜６＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜８＞　Ｒ２がＮＨ２又はＮＨＣＯＲ８である、＜１＞～＜７＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜９＞　Ｒ２がＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）である、＜１＞～＜８＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜１０＞　ＧＰＲ３５作動薬としての活性を有する、＜１＞～＜９＞のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜１１＞　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の少なくとも一方に対する活性を有する、＜１０＞に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜１２＞　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の両方に対する活性を有する、＜１０＞又は＜１１＞に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜１３＞　前記ヒト以外の動物がげっ歯類である、＜１１＞又は＜１２＞に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
＜１４＞　下記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩である、ＧＰＲ３５作動薬。 [In the general formula (I-2), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
<4> The heterocyclic compound according to any one of <1> to <3>, wherein X is O, or a pharmacologically acceptable salt of the heterocyclic compound.
<5> The heterocyclic compound according to any one of <1> to <4>, wherein R 2 is NR 5 R 6 or NR 7 COR 8 or a pharmacologically acceptable salt of the heterocyclic compound. .
<6> R 1 has no substituent, or is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom, or a substituted or unsubstituted group Alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted alkyl group) ), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted Alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom And having associated, <1> to pharmacologically acceptable salts of heterocyclic compounds or the heterocyclic compound according to any one of <5>.
<7> The heterocyclic compound according to any one of <1> to <6>, wherein R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), or a pharmacological of the heterocyclic compound Acceptable salt.
<8> The heterocyclic compound according to any one of <1> to <7>, wherein R 2 is NH 2 or NHCOR 8 or a pharmacologically acceptable salt of the heterocyclic compound.
<9> The heterocyclic compound according to any one of <1> to <8>, wherein R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group), or a pharmacologically acceptable of the heterocyclic compound. Salt.
<10> The heterocyclic compound according to any one of <1> to <9> or a pharmacologically acceptable salt of the heterocyclic compound, which has an activity as a GPR35 agonist.
<11> The heterocyclic compound according to <10> or a pharmacologically acceptable salt of the heterocyclic compound having activity against at least one of human GPR35 and non-human animal GPR35.
<12> The heterocyclic compound according to <10> or <11> or a pharmacologically acceptable salt of the heterocyclic compound, which has activity against both human GPR35 and non-human animal GPR35.
<13> The heterocyclic compound according to <11> or <12>, wherein the non-human animal is a rodent, or a pharmacologically acceptable salt of the heterocyclic compound.
<14> A GPR35 agonist which is a heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
［一般式（Ｉ）において、ＸはＯ又はＮＨを表し、Ｒ１は置換もしくは非置換アリール基又は置換もしくは非置換芳香族複素環基を表し、Ｒ２は置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、置換もしくは非置換芳香族複素環アルキル基、ＯＲ４（Ｒ４は水素原子、置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、又は置換もしくは非置換芳香族複素環アルキル基である）、ＮＲ５Ｒ６（Ｒ５及びＲ６はそれぞれ独立にＲ４と同義であり、一緒になって環を形成してもよい）、ＮＲ７ＣＯＲ８（Ｒ７及びＲ８はそれぞれ独立にＲ４と同義である）、ＮＲ９ＳＯ２Ｒ１０（Ｒ９及びＲ１０はそれぞれ独立にＲ４と同義である）、Ｓ（Ｏ）ｎＲ１１（ｎは０、１もしくは２であり、Ｒ１１はＲ４と同義である）、ＣＯＲ１２（Ｒ１２はＲ４と同義である）、ＣＯＯＲ１３（Ｒ１３はＲ４と同義である）、ＯＣＯＲ１４（Ｒ１４はＲ４と同義である）、ＣＯＮＲ１５Ｒ１６（Ｒ１５及びＲ１６はそれぞれ独立にＲ４と同義である）、ＳＯ２ＮＲ１７Ｒ１８（Ｒ１７及びＲ１８はそれぞれ独立にＲ４と同義である）、ＯＣＨ２ＣＯＯＲ１９（Ｒ１９はＲ４と同義である）、ＯＳＯ２Ｒ２０（Ｒ２０はＲ４と同義である）、ＳＲ２１（Ｒ２１はＲ４と同義である）、ニトロ基、シアノ基又はハロゲン原子を表し、Ｒ３はＣＯＯＲ２２（Ｒ２２はＲ４と同義である）を表す。Ｒ２に付されたｎはＲ２の個数を表し、０～３の整数である。］
＜１５＞　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－１）で表される、＜１４＞に記載のＧＰＲ３５作動薬。 [In general formula (I), X represents O or NH, R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted Substituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or substituted Substituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 5 R 6 (R 5 and R 6 have the same meanings as R 4 each independently, NR 7 COR 8 (R 7 and R 8 each independently have the same meaning as R 4 ), NR 9 SO 2 R 10 (R 9 and R 10 each independently may form a ring) the same meaning as R 4), S (O) n R 11 (n is 0, 1 or 2, R 11 has the same meaning as R 4), COR 12 (R 12 has the same meaning as R 4 ), COOR 13 (R 13 is the same as R 4 ), OCOR 14 (R 14 is the same as R 4 ), CONR 15 R 16 (R 15 and R 16 are each independently the same as R 4 ) ), SO 2 NR 17 R 18 (R 1 And R 18 is synonymous with R 4 each independently), OCH 2 COOR 19 (R 19 has the same meaning as R 4), OSO 2 R 20 (R 20 has the same meaning as R 4), SR 21 ( R 21 represents the same as R 4 ), a nitro group, a cyano group or a halogen atom, and R 3 represents COOR 22 (R 22 has the same meaning as R 4 ). N attached to R 2 represents the number of R 2, is an integer of 0-3. ]
<15> The GPR35 agonist according to <14>, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-1).
Figure JPOXMLDOC01-appb-C000012
［一般式（Ｉ－１）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］
＜１６＞　前記一般式（Ｉ－１）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－２）で表される、＜１４＞に記載のＧＰＲ３５作動薬。
Figure JPOXMLDOC01-appb-C000012
[In the general formula (I-1), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
<16> The GPR35 agonist according to <14>, wherein the heterocyclic compound represented by the general formula (I-1) or the heterocyclic compound is represented by the following general formula (I-2).
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［一般式（Ｉ－２）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］
＜１７＞　ＸがＯである、＜１４＞～＜１６＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜１８＞　Ｒ２がＮＲ５Ｒ６又はＮＲ７ＣＯＲ８である、＜１４＞～＜１７＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜１９＞　Ｒ１が置換基を有していないか、置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を置換基として有する、＜１４＞～＜１８＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２０＞　Ｒ３がＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）である、＜１４＞～＜１９＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２１＞　Ｒ２がＮＨ２又はＮＨＣＯＲ８である、＜１４＞～＜２０＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２２＞　Ｒ２がＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）である、＜１４＞～＜２１＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２３＞　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の少なくとも一方に対する活性を有する、＜１４＞～＜２２＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２４＞　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の両方に対する活性を有する、＜１４＞～＜２３＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２５＞　前記ヒト以外の動物がげっ歯類である、＜２３＞又は＜２４＞に記載のＧＰＲ３５作動薬。
＜２６＞　ＧＰＲ３５が関与する症状又は疾患の治療に用いるための、＜１４＞～＜２５＞のいずれか１項に記載のＧＰＲ３５作動薬。
＜２７＞　＜１＞～＜１３＞のいずれか１項に記載の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は＜１４＞～＜２６＞のいずれか１項に記載のＧＰＲ３５作動薬を有効成分として含む、医薬組成物。 [In the general formula (I-2), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
<17> The GPR35 agonist according to any one of <14> to <16>, wherein X is O.
<18> The GPR35 agonist according to any one of <14> to <17>, wherein R 2 is NR 5 R 6 or NR 7 COR 8 .
<19> R 1 has no substituent, or is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted Alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted alkyl group) ), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted Alkyl group), SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom Having a, <14> ~ GPR35 agonist according to any one of <18>.
<20> The GPR35 agonist according to any one of <14> to <19>, wherein R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group).
<21> The GPR35 agonist according to any one of <14> to <20>, wherein R 2 is NH 2 or NHCOR 8 .
<22> The GPR35 agonist according to any one of <14> to <21>, wherein R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group).
<23> The GPR35 agonist according to any one of <14> to <22>, which has activity against at least one of human GPR35 and non-human animal GPR35.
<24> The GPR35 agonist according to any one of <14> to <23>, which has activity against both human GPR35 and non-human animal GPR35.
<25> The GPR35 agonist according to <23> or <24>, wherein the non-human animal is a rodent.
<26> The GPR35 agonist according to any one of <14> to <25>, for use in the treatment of a condition or disease involving GPR35.
<27> The heterocyclic compound according to any one of <1> to <13>, or a pharmacologically acceptable salt of the heterocyclic compound, or any one of <14> to <26>. Pharmaceutical composition which contains the GPR35 agonist of a statement as an active ingredient.
　本発明によれば、複素環化合物又はその塩、ＧＰＲ３５作動薬及び医薬組成物が提供される。 According to the present invention, heterocyclic compounds or salts thereof, GPR35 agonists and pharmaceutical compositions are provided.
ラットＧＰＲ３５のｍＲＮＡの発現を定量ＲＴ－ＰＣＲにより測定した結果である。It is the result of measuring the expression of rat GPR35 mRNA by quantitative RT-PCR. ラットＧＰＲ３５を発現しているＲＢＬ－２Ｈ３細胞とラットＧＰＲ３５を発現していないＲＢＬ－２Ｈ３細胞の脱顆粒応答を比較するデータである。Data comparing RBL-2H3 cells expressing rat GPR35 and RBL-2H3 cells not expressing rat GPR35.
＜第１実施形態＞
　本開示の第１実施形態は、上述した一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩である。 First Embodiment
A first embodiment of the present disclosure is a heterocyclic compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
　一般式（Ｉ）において、Ｒ１で表されるアリール基としてはフェニル基、ナフチル基等が挙げられ、好ましくはフェニル基である。Ｒ１で表される芳香族複素環基としては窒素原子、酸素原子又は硫黄原子を含む芳香族複素環基が挙げられ、好ましくはピリジル基、フラニル基、チエニル基又はピロリル基である。 In the general formula (I), examples of the aryl group represented by R 1 include a phenyl group, a naphthyl group and the like, preferably a phenyl group. The aromatic heterocyclic group represented by R 1 includes an aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a pyridyl group, a furanyl group, a thienyl group or a pyrrolyl group.
　Ｒ１で表されるアリール基又は芳香族複素環基が置換基を有する場合、その置換基の種類は特に制限されない。例えば、一般式（Ｉ）においてＲ２で表される置換基から選択することができる。 When the aryl group or aromatic heterocyclic group represented by R 1 has a substituent, the type of the substituent is not particularly limited. For example, it can be selected from the substituents represented by R 2 in the general formula (I).
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるアルキル基としては、炭素数（置換基を除く）が１～１０のアルキル基が挙げられ、好ましくは炭素数（置換基を除く）が１～５のアルキル基であり、より好ましくは炭素数（置換基を除く）が１～４のアルキル基であり、さらに好ましくはメチル基、エチル基、プロピル基、ブチル基である。アルキル基は直鎖状であっても分岐していてもよい。アルキル基が置換基を有する場合の置換基としてはニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。ハロゲン原子としてはフッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられ、以下も同様である。 In the general formula (I), examples of the alkyl group represented by R 2 or R 4 include alkyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkyl group of 1 to 5, more preferably an alkyl group having 1 to 4 carbon atoms (excluding substituents), and still more preferably a methyl group, an ethyl group, a propyl group or a butyl group. The alkyl group may be linear or branched. When the alkyl group has a substituent, examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the same applies to the following.
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるシクロアルキル基としては、炭素数（置換基を除く）が３～１０のシクロアルキル基が挙げられ、好ましくは炭素数（置換基を除く）が３～６のシクロアルキル基である。シクロアルキル基が置換基を有する場合の置換基としてはニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 In the general formula (I), examples of the cycloalkyl group represented by R 2 or R 4 include cycloalkyl groups having 3 to 10 carbon atoms (excluding substituents), preferably carbon atoms (substituted groups And 3) is a cycloalkyl group of 3 to 6). When the cycloalkyl group has a substituent, examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるアルケニル基としては、炭素数（置換基を除く）が１～１０のアルケニル基が挙げられ、好ましくは炭素数（置換基を除く）が１～５のアルケニル基であり、より好ましくは炭素数（置換基を除く）が１～３のアルケニル基である。アルケニル基が置換基を有する場合の置換基としてはニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 Examples of the alkenyl group represented by R 2 or R 4 in the general formula (I) include alkenyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkenyl group of 1 to 5, and more preferably an alkenyl group having 1 to 3 carbon atoms (excluding substituents). When the alkenyl group has a substituent, examples of the substituent include a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるアルキニル基としては、炭素数（置換基を除く）が１～１０のアルキニル基が挙げられ、好ましくは炭素数（置換基を除く）が１～５のアルキニル基であり、より好ましくは炭素数（置換基を除く）が１～３のアルキニル基である。アルキニル基が置換基を有する場合の置換基としてはトリアルキルシリル基（アルキル基は前記アルキル基と同義である）等が挙げられる。 In the general formula (I), examples of the alkynyl group represented by R 2 or R 4 include alkynyl groups having 1 to 10 carbon atoms (excluding substituents), preferably carbon atoms (excluding substituents) Is an alkynyl group of 1 to 5, and more preferably an alkynyl group having 1 to 3 carbon atoms (excluding substituents). When the alkynyl group has a substituent, examples of the substituent include a trialkylsilyl group (wherein the alkyl group has the same meaning as the above alkyl group).
　一般式（Ｉ）において、Ｒ２又はＲ４で表される脂環式複素環基としては、窒素原子、酸素原子又は硫黄原子を含む脂環式複素環基が挙げられ、好ましくは窒素原子、酸素原子又は硫黄原子を含む炭素数（置換基を除く）が２～６の脂環式複素環基である。脂環式複素環基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 Examples of the alicyclic heterocyclic group represented by R 2 or R 4 in the general formula (I) include an alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom, And an alicyclic heterocyclic group having 2 to 6 carbon atoms (excluding substituents) containing an oxygen atom or a sulfur atom. As a substituent in case an alicyclic heterocyclic group has a substituent, an alkyl group (an alkyl group is synonymous with the said alkyl group) and an alkoxy group (an alkyl group in an alkoxy group is synonymous with the said alkyl group) And nitro, cyano, halogen, hydroxyl, carboxy, methyl ester, amino and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるアリール基としてはフェニル基及びナフチル基が挙げられ、好ましくはフェニル基である。アリール基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 In the general formula (I), examples of the aryl group represented by R 2 or R 4 include a phenyl group and a naphthyl group, preferably a phenyl group. When the aryl group has a substituent, examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表されるアラルキル基としては、炭素数（置換基を除く）が１～６のアルキル基の炭素原子のひとつが上述したアリール基で置換したアラルキル基が挙げられる。アラルキル基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 In the general formula (I), as the aralkyl group represented by R 2 or R 4 , an aralkyl wherein one carbon atom of an alkyl group having 1 to 6 carbon atoms (excluding substituents) is substituted by the above-mentioned aryl group Groups are mentioned. When the aralkyl group has a substituent, examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表される芳香族複素環基としては、窒素原子、酸素原子又は硫黄原子を含む芳香族複素環基が挙げられ、好ましくは窒素原子、酸素原子又は硫黄原子を含む炭素数（置換基を除く）が２～９の芳香族複素環基である。芳香族複素環基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 Examples of the aromatic heterocyclic group represented by R 2 or R 4 in the general formula (I) include aromatic heterocyclic groups containing a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom or an oxygen atom Or an aromatic heterocyclic group having 2 to 9 carbon atoms (excluding substituents) containing a sulfur atom. When the aromatic heterocyclic group has a substituent, examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group) and an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group) And a nitro group, a cyano group, a halogen atom, a hydroxyl group, a carboxy group, a methyl ester group, an amino group and the like.
　一般式（Ｉ）において、Ｒ２又はＲ４で表される芳香族複素環アルキル基としては、炭素数（置換基を除く）が１～６のアルキル基の炭素原子のひとつが上述した芳香族複素環で置換した芳香族複素環アルキル基が挙げられる。芳香族複素環アルキル基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、メチルエステル基、アミノ基等が挙げられる。 In the general formula (I), as the aromatic heterocyclic alkyl group represented by R 2 or R 4 , an aromatic group in which one carbon atom of an alkyl group having 1 to 6 carbon atoms (excluding substituents) is mentioned above There may be mentioned heteroaromatic alkyl groups substituted with a heterocycle. As a substituent when the aromatic heterocyclic alkyl group has a substituent, an alkyl group (an alkyl group has the same meaning as the above alkyl group) and an alkoxy group (an alkyl group in an alkoxy group has the same meaning as the above alkyl group) And nitro, cyano, halogen, hydroxyl, carboxy, methyl ester, amino and the like.
　一般式（Ｉ）において、Ｒ１が置換基を有するアリール基又は芳香族複素環基である場合、その置換基の数は特に制限されないが、１個～３個であってもよく、１個又は２個であってもよく、１個であってもよい。 In the general formula (I), when R 1 is an aryl group having a substituent or an aromatic heterocyclic group, the number of the substituent is not particularly limited, but may be 1 to 3, or 1 Alternatively, it may be two or one.
　Ｒ１が置換基を有するアリール基又は芳香族複素環基である場合、Ｒ１は置換基として置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を有することが好ましい。さらに、Ｒ１は置換基として置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を有することがより好ましい。 When R 1 is an aryl group or aromatic heterocyclic group having a substituent, R 1 is a substituted or unsubstituted alkyl group as a substituent, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R is a hydrogen atom, a substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R Is a hydrogen atom or a substituted or unsubstituted alkyl group, CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is Each independently a hydrogen atom or a substituted or unsubstituted alkyl group, SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), Toromoto preferably has a cyano group or a halogen atom. Furthermore, R 1 is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group) as a substituent, OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OR (R Is more preferably a hydrogen atom, a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom.
　一般式（Ｉ）において、Ｒ２の数は１個又は２個であることが好ましく、１個であることがさらに好ましい。
　Ｒ２はＮＲ５Ｒ６又はＮＲ７ＣＯＲ８であることが好ましく、ＮＨ２又はＮＨＣＯＲ８であることがより好ましく、ＮＨ２又はＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）であることがさらに好ましい。
　Ａｒとしてはフェニル基及びナフチル基が挙げられ、好ましくはフェニル基である。アリール基が置換基を有する場合の置換基としては、アルキル基（アルキル基は前記アルキル基と同義である）、アルコキシ基（アルコキシ基中のアルキル基は前記アルキル基と同義である）、ニトロ基、シアノ基、ハロゲン原子、水酸基、カルボキシ基、アミノ基等が挙げられる。中でもアルコキシ基およびハロゲン原子が好ましく、メトキシ基およびクロロ基がより好ましい。
　Ｒ２がＮＨＣＯＡｒであり、Ａｒが置換基を有するアリール基である場合、Ａｒはパラ位に置換基を有することが好ましい。 In the general formula (I), the number of R 2 is preferably one or two, and more preferably one.
Preferably R 2 is NR 5 R 6 or NR 7 COR 8, more preferably NH 2 or NHCOR 8, and more preferably NH 2 or NHCOAr (Ar is a substituted or unsubstituted aryl group) .
As Ar, a phenyl group and a naphthyl group are mentioned, Preferably it is a phenyl group. When the aryl group has a substituent, examples of the substituent include an alkyl group (the alkyl group has the same meaning as the alkyl group), an alkoxy group (the alkyl group in the alkoxy group has the same meaning as the alkyl group), and a nitro group And a cyano group, a halogen atom, a hydroxyl group, a carboxy group, an amino group and the like. Among them, an alkoxy group and a halogen atom are preferable, and a methoxy group and a chloro group are more preferable.
When R 2 is NHCOAr and Ar is an aryl group having a substituent, Ar preferably has a substituent at the para position.
　Ｒ３はＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）であることが好ましく、ＣＯＯＨであることがより好ましい。 R 3 is preferably COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), more preferably COOH.
　ある実施形態では、一般式（Ｉ）で表される複素環化合物は、ＸがＯであり、Ｒ１が置換又は非置換アリール基であり、Ｒ２がＮＲ５Ｒ６又はＮＲ７ＣＯＲ８である複素環化合物であってもよい。
　上記複素環化合物は、さらにＲ１が置換基を有しないか、置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を置換基として有するアリール基又は芳香族複素環基であり、Ｒ２がＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）であり、Ｒ３がＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）であり、ｎが１である複素環化合物であってもよい。 In one embodiment, in the heterocyclic compound represented by the general formula (I), X is O, R 1 is a substituted or unsubstituted aryl group, and R 2 is NR 5 R 6 or NR 7 COR 8 It may be a certain heterocyclic compound.
In the above heterocyclic compounds, R 1 further has no substituent, is a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom, or substitution or Unsubstituted alkyl group), OR (R is hydrogen atom, substituted or unsubstituted alkyl group), NRR (R is each independently hydrogen atom or substituted or unsubstituted alkyl group), COR (R is hydrogen atom or substituted or unsubstituted Alkyl group), CONRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substitution or Unsubstituted alkyl group), SR (R is a hydrogen atom or substituted or unsubstituted alkyl group), nitro group, cyano group or halogen An aryl group or aromatic heterocyclic group having a carbon atom as a substituent, R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group), R 3 is COOR (R is a hydrogen atom or substituted or unsubstituted alkyl Group), and may be a heterocyclic compound in which n is 1.
　ある実施形態では、一般式（Ｉ）で表される複素環化合物は、下記一般式（Ｉ－１）で表される複素環化合物であってもよい。一般式（Ｉ－１）におけるＸ、Ｒ１～Ｒ３及びｎの定義は一般式（Ｉ）と同様であり、好ましい例も同様である。 In one embodiment, the heterocyclic compound represented by the general formula (I) may be a heterocyclic compound represented by the following general formula (I-1). The definitions of X, R 1 to R 3 and n in the general formula (I-1) are the same as in the general formula (I), and preferred examples are also the same.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　ある実施形態では、一般式（Ｉ）で表される複素環化合物は、下記一般式（ＩＩ）で表される複素環化合物であってもよい。一般式（Ｉ－２）におけるＸ及びＲ１～Ｒ３の定義は一般式（Ｉ）と同様であり、好ましい例も同様である。 In one embodiment, the heterocyclic compound represented by the general formula (I) may be a heterocyclic compound represented by the following general formula (II). The definitions of X and R 1 to R 3 in the general formula (I-2) are the same as in the general formula (I), and preferred examples are also the same.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　一般式（Ｉ）で表される複素環化合物に位置異性体、幾何異性体、光学異性体又は互変異性体が存在する場合、これらのいずれも又はこれらの混合物も一般式（Ｉ）で表される複素環化合物に包含される。
　一般式（Ｉ）で表される複素環化合物の薬理学的に許容される塩は、水あるいは各種溶媒との付加物の形で存在することもあるが、これら付加物も本発明に包含される。 When positional isomers, geometric isomers, optical isomers or tautomers exist in the heterocyclic compound represented by the general formula (I), any of them or a mixture thereof is also represented by the general formula (I) Are included in the heterocyclic compounds.
The pharmacologically acceptable salt of the heterocyclic compound represented by the general formula (I) may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Ru.
　一般式（Ｉ）で表される複素環化合物の薬理学的に許容される塩としては、薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等が挙げられる。酸付加塩としては、塩酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩等の有機酸塩などが挙げられる。金属塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩などが挙げられる。アンモニウム塩としては、アンモニウム、テトラメチルアンモニウム等の塩が挙げられる。有機アミン付加塩としては、モルホリン、ピペリジン等の付加塩が挙げられる。アミノ酸付加塩としては、リジン、グリシン、フェニルアラニン等の付加塩が挙げられる。 The pharmacologically acceptable salts of the heterocyclic compounds represented by the general formula (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. Can be mentioned. As acid addition salts, inorganic acid salts such as hydrochloride, sulfate and phosphate, acetates, maleates, fumarate, tartrate, citrate, organic acid salts such as methanesulfonate and the like It can be mentioned. Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Ammonium salts include salts such as ammonium and tetramethyl ammonium. Organic amine addition salts include addition salts of morpholine, piperidine and the like. Examples of amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.
一般式（Ｉ）で表される複素環化合物の塩を取得したいとき、当該複素環化合物が塩の形で得られる場合には、そのまま精製すればよく、遊離の形で得られる場合には、当該複素環化合物を適当な有機溶媒に溶解もしくは懸濁させ、酸又は塩基を加えて通常の方法により塩を形成させればよい。 When it is desired to obtain a salt of the heterocyclic compound represented by the general formula (I), when the heterocyclic compound is obtained in the form of a salt, it may be purified as it is, and when it is obtained in the free form, The heterocyclic compound may be dissolved or suspended in a suitable organic solvent, an acid or a base may be added, and a salt may be formed by a conventional method.
　一般式（Ｉ）で表される複素環化合物は、ＧＰＲ３５の作動薬としての活性を示すものであってもよい。ある実施形態では、一般式（Ｉ）で表される複素環化合物は、ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の少なくとも一方に対する活性を有するものであってもよく、ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の両方に対する活性を有するものであってもよい。ヒト以外の動物としてはマウス、ラット等のげっ歯類が挙げられるが、これらに限定されない。 The heterocyclic compound represented by the general formula (I) may exhibit an activity as an agonist of GPR35. In one embodiment, the heterocyclic compound represented by the general formula (I) may have activity against at least one of human GPR35 and non-human animal GPR35, and human GPR35 and human GPR35 It may have activity against both GPR35 of other animals. Examples of non-human animals include, but are not limited to, rodents such as mice and rats.
　以下に一般式（Ｉ）で表される複素環化合物であってＸがＯである化合物の具体例（ＣＩ－１～ＣＩ－１２７）の構造を示すが、一般式（Ｉ）で表される複素環化合物はこれらに制限されるものではない。
  The structures of specific examples (CI-1 to CI-127) of the heterocyclic compound represented by the general formula (I) where X is O are shown below, but are represented by the general formula (I) Heterocyclic compounds are not limited to these.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
 
Figure JPOXMLDOC01-appb-C000020
 
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
 　
Figure JPOXMLDOC01-appb-C000027
 　
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　以下に一般式（Ｉ）で表される複素環化合物であってＸがＮＨである化合物の具体例（ＣＩＩ－１～ＣＩＩ－２２）の構造を示すが、一般式（Ｉ）で表される複素環化合物はこれらに制限されるものではない。 The structures of specific examples (CII-1 to CII-22) of the heterocyclic compound represented by the general formula (I) where X is NH are shown below, but are represented by the general formula (I) Heterocyclic compounds are not limited to these.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
 
 
Figure JPOXMLDOC01-appb-C000030
 
 
＜第２実施形態＞
　本開示の第２実施形態は、上述した一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩である、ＧＰＲ３５作動薬である。 Second Embodiment
A second embodiment of the present disclosure is a GPR35 agonist which is the heterocyclic compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
　ＧＰＲ３５作動薬を医薬品のように実用化にあたって動物試験を行う必要のある目的に用いる場合は、ＧＰＲ３５作動薬はヒトのＧＰＲ３５とヒト以外の動物（例えば、マウス、ラット等のげっ歯類）のＧＰＲ３５の両方に対して活性を示すことが好ましい。 When a GPR35 agonist is used for the purpose of conducting an animal test for practical use as a pharmaceutical, the GPR35 agonist is a human GPR35 and a non-human animal (for example, a rodent such as a mouse or a rat) GPR35 It is preferable to show activity against both of
　ＧＰＲ３５作動薬の用途は特に制限されず、ＧＰＲ３５が関与するあらゆる症状及び疾患の治療が対象となる。
　ＧＰＲ３５が関与する症状及び疾患としては、アレルギー疾患、炎症性腸疾患、糖尿病、動脈硬化等が挙げられるが、これらに限定されるものではない。 The use of the GPR35 agonist is not particularly limited and is directed to the treatment of any condition and disease in which the GPR35 is involved.
Symptoms and diseases in which GPR35 is involved include, but are not limited to, allergic diseases, inflammatory bowel diseases, diabetes, arteriosclerosis and the like.
　ＧＰＲ３５作動薬は、抗アレルギー剤として用いられるものであってもよい。
　ＧＰＲ３５は、活性化によりｉＮＫＴ細胞からのＩＬ－４の分泌を抑制することが知られている。このため、ＧＰＲ３５作動薬をＧＰＲ３５に適用すると、Ｔｈ０細胞からＴｈ２細胞への分化誘導が抑制されると考えられる。その結果、Ｔｈ２細胞から放出されるケミカルメディエーターが受容体に結合して引き起こされるアレルギー反応を抑制する効果が期待できる。ＧＰＲ３５作動薬を用いた抗アレルギー剤は、Ｔｈ２細胞から放出されるケミカルメディエーターと受容体との結合を標的とする既存の抗アレルギー剤に比べてより根本的な症状の緩和や解消を実現する手段として有用であると考えられる。 GPR35 agonists may be used as anti-allergic agents.
GPR35 is known to suppress the secretion of IL-4 from iNKT cells upon activation. Therefore, when GPR35 agonist is applied to GPR35, it is considered that the induction of differentiation from Th0 cells to Th2 cells is suppressed. As a result, the chemical mediator released from Th2 cells can be expected to have the effect of suppressing the allergic reaction caused by binding to the receptor. Anti-allergic agents using GPR35 agonists are means of achieving alleviation or elimination of symptoms more fundamentally than existing anti-allergic agents targeting binding of chemical mediators and receptors released from Th2 cells It is considered to be useful.
　ＧＰＲ３５作動薬は、医薬品に限らずサプリメント、食品、飲料等の形態で用いるものであってもよく、研究等の医療行為以外の目的に用いるものであってもよい。 The GPR35 agonist may be used in the form of supplements, foods, beverages, etc. as well as pharmaceuticals, and may be used for purposes other than medical practice such as research.
　ＧＰＲ３５作動薬は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが好ましい。また、それら医薬製剤は、動物及び人に使用されるものである。 
　投与経路としては、治療に際し最も効果的なものを使用するのが好ましく、経口、又は例えば腸内、口腔内、皮下、筋肉内、静脈内等の非経口をあげることができる。
投与形態としては、カプセル剤、錠剤、顆粒剤、散剤、シロップ剤、乳剤、座剤、注射剤等がある。
　ＧＰＲ３５作動薬の有効用量及び投与回数は、投与形態、患者の年令、体重、治療すべき症状の性質、重篤度等により異なるが、通常、投与量は、１日当たり０．０１～１０００ｍｇ／人、好ましくは５～５００ｍｇ／人であり、投与回数は、１日１回又は分割して投与するのが好ましい。 Although GPR35 agonists can be administered alone as they are, it is usually preferable to provide them as various pharmaceutical preparations. Also, these pharmaceutical preparations are used for animals and humans.
As the administration route, it is preferable to use one most effective in treatment, and oral or parenteral such as enteral, buccal, subcutaneous, intramuscular, intravenous and the like can be mentioned.
Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.
The effective dose and frequency of administration of GPR35 agonist vary depending on the administration form, patient's age, body weight, nature of the condition to be treated, severity and the like, but the dosage is usually 0.01 to 1000 mg / day The dose is preferably in the range of 5 to 500 mg / person, and the administration frequency is preferably once a day or in divided doses.
＜第３実施形態＞
　本開示の第３実施形態は、第１実施形態の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は第２実施形態のＧＰＲ３５作動薬を有効成分として含む医薬組成物である。 Third Embodiment
A third embodiment of the present disclosure is a pharmaceutical composition comprising the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment as an active ingredient. is there.
　医薬組成物が上記有効成分以外の成分を含む場合、当該成分としては、薬剤の調製に一般に用いられる媒質及び製剤用添加物が挙げられる。媒質としては、固体媒質（例えば、ゼラチン、乳糖）及び液体媒質（例えば、アルコール、水、生理食塩水）が挙げられる。製剤用添加物としては、賦形剤、崩壊剤、結合剤、滑沢剤、界面活性剤、緩衝剤、溶解補助剤、安定化剤、等張化剤などが挙げられる。これらの成分の配合量は、第１実施形態の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は第２実施形態のＧＰＲ３５作動薬が有効成分として作用しうるのであれば特に制限されない。 When the pharmaceutical composition contains an ingredient other than the above active ingredient, the ingredient includes a medium and a formulation additive generally used for the preparation of a drug. Media include solid media (eg, gelatin, lactose) and liquid media (eg, alcohol, water, saline). Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants, surfactants, buffers, solubilizers, stabilizers, tonicity agents, and the like. If the compounding amount of these components is that the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound or the GPR35 agonist of the second embodiment can act as an active ingredient It is not particularly limited.
　医薬組成物の形態は特に制限されず、用途に応じて選択できる。例えば、錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、シロップ、乳剤、リモナーデ剤等の経口投与に適した形態、座剤、注射剤等の非経口投与に適した形態などが挙げられる。 The form of the pharmaceutical composition is not particularly limited, and can be selected according to the use. For example, forms suitable for oral administration such as tablets, granules, powders, capsules, suspensions, syrups, emulsions, limonade agents etc., forms suitable for parenteral administration such as suppositories, injections etc. can be mentioned.
　経口投与に適した形態の製剤、例えば乳剤、シロップ剤等の液体調製物は、水、ショ糖、ソルビット、果糖等の糖類、ポリエチレングリコール、プロピレングリコール等のグリコール類、ゴマ油、オリーブ油、大豆油等の油類、ｐ－ヒドロキシ安息香酸エステル類等の防腐剤、ストロベリーフレーバー、ペパーミントフレーバー等のフレーバー類等を使用して製造できる。また、カプセル剤、錠剤、散剤、顆粒剤等は、乳糖、ブドウ糖、ショ糖、マンニット等の賦形剤、澱粉、アルギン酸ソーダ等の崩壊剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ポリビニルアルコール、ヒドロキシプロピルセルロース、ゼラチン等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤などを用いて製造できる。
　非経口投与に適した形態の製剤は、好ましくは受容者の血液と等張である活性化合物を含む滅菌水性製剤からなる。例えば注射剤の場合、塩溶液、ブドウ糖溶液又は塩水とブドウ糖溶液の混合物からなる担体等を用いて注射用の溶液を調製する。
　局所製剤は、活性化合物を、１種もしくはそれ以上の媒質、例えば鉱油、石油、多価アルコール等又は局所医薬製剤に使用される他の基剤中に溶解又は懸濁させて調製する。
腸内投与のための製剤は、通常の担体、例えばカカオ脂、水素化脂肪、水素化脂肪カルボン酸等を用いて調製し、座剤として提供される。
　また、これら非経口剤においても、経口剤で例示したグリコール類、油類、フレーバー類、防腐剤（抗酸化剤を含む）、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤等から選択される１種もしくはそれ以上の補助成分を添加することもできる。 Preparations suitable for oral administration, for example, liquid preparations such as emulsions and syrups, water, sucrose, sorbit, saccharides such as fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, soybean oil etc. Oils, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint flavor. Capsules, tablets, powders, granules and the like are excipients such as lactose, glucose, sucrose and mannitol, disintegrators such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl The binder can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as a fatty acid ester, a plasticizer such as glycerin, or the like.
Formulations suitable for parenteral administration comprise sterile aqueous preparations which preferably contain the active compound isotonic with the blood of the recipient. For example, in the case of injection, a solution for injection is prepared using a carrier comprising, for example, a salt solution, glucose solution or a mixture of saline and glucose solution.
Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohols and the like, or other bases used for topical pharmaceutical formulations.
Formulations for enteral administration are prepared as conventional suppositories using conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like.
Also in these parenteral preparations, glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified in oral preparations. It is also possible to add one or more auxiliary components selected from plasticizers and the like.
＜第４実施形態＞
　本開示の第４実施形態は、第１実施形態の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は第２実施形態のＧＰＲ３５作動薬をＧＰＲ３５に接触させる工程を含む、ＧＰＲ３５活性化方法、又はＧＰＲ３５が関与する疾患の治療方法である。 Fourth Embodiment
The fourth embodiment of the present disclosure includes the step of contacting the heterocyclic compound of the first embodiment or a pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment with GPR35. A method for activating GPR35 or a method for treating a disease involving GPR35.
　第１実施形態の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は第２実施形態のＧＰＲ３５作動薬をＧＰＲ３５に接触させる方法は特に制限されず、経口投与、静脈内投与、留置等の外科的処置等を挙げることができる。また、上述した第３実施形態の医薬組成物の状態でＧＰＲ３５に接触させてもよい。 The method for bringing the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound or the GPR35 agonist of the second embodiment into contact with GPR 35 is not particularly limited, and oral administration, intravenous administration And surgical procedures such as indwelling. Alternatively, the GPR 35 may be contacted in the state of the pharmaceutical composition of the third embodiment described above.
　第１実施形態の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は第２実施形態のＧＰＲ３５作動薬を接触させる対象のＧＰＲ３５は、ヒトのＧＰＲ３５であってもヒト以外の動物（実験動物、家畜動物、愛玩動物等）のＧＰＲ３５であってもよい。また、生体内のＧＰＲ３５であっても生体外のＧＰＲ３５であってもよい。 GPR35 to be contacted with the heterocyclic compound of the first embodiment or the pharmacologically acceptable salt of the heterocyclic compound, or the GPR35 agonist of the second embodiment is human GPR35, but is not human It may be GPR35 of animals (laboratory animals, domestic animals, pets etc). Further, it may be GPR35 in vivo or GPR35 in vitro.
　ＧＰＲ３５活性化方法は、ＧＰＲ３５が関与する疾患の治療を目的とするものであっても、治療以外の試験研究、検査等を目的とするものであってもよい。 The GPR35 activation method may be for the purpose of treating a disease involving GPR35, or may be for the purpose of research, examination, etc. other than treatment.
　ＧＰＲ３５活性化方法が、ＧＰＲ３５が関与する疾患の治療を目的とするものである場合、治療対象となるＧＰＲ３５が関与する疾患としては、アレルギー疾患、炎症性腸疾患、糖尿病、動脈硬化等が挙げられるが、これらに制限されるものではない。 When the GPR35 activation method is for the treatment of a disease involving GPR35, the disease involving GPR35 to be treated includes allergic diseases, inflammatory bowel disease, diabetes, arteriosclerosis and the like However, it is not limited to these.
　以下、本開示の実施形態を複素環化合物の合成例及び同定データ、ＧＰＲ３５作動薬としての活性の評価、並びに製剤例に基づいて具体的に説明するが、本開示はこれらの制限されるものではない。
　本開示の複素環化合物であって上述した複素環化合物の具体例に含まれていない化合物、又は上述した具体例のうち下記に合成例の記載がない化合物は、後述する合成例を参照して当業者の通常の技術知識の範囲内で合成することができる。 Hereinafter, embodiments of the present disclosure will be specifically described based on synthesis examples and identification data of heterocyclic compounds, evaluation of activity as a GPR35 agonist, and formulation examples, but the present disclosure is not limited thereto. Absent.
The compound which is a heterocyclic compound of the present disclosure and is not contained in the above-mentioned specific examples of the heterocyclic compound, or a compound which is not described in the synthesis example below among the above-mentioned specific examples, is referred to the synthesis examples described later. It can be synthesized within the ordinary technical knowledge of the person skilled in the art.
　Methyl 8-amino-6-phenyl-4-oxo-4H-chromene-2-carboxylate（ＣＩ－１）の合成 Synthesis of Methyl 8-amino-6-phenyl-4-oxo-4H-chromene-2-carboxylate (CI-1)
（１）市販の3-bromo-6-hydroxy-5-nitroacetophenone (2.50 g, 9.61 mmol)のジメチルホルムアミド (60 mL)溶液に (COOEt)2 (3.21 mL, 23.6 mmol)を加えた後、氷冷下でtBuOK (4.32 g, 38.5 mmol)をゆっくり加え、終夜攪拌した。反応液に0.4 M 塩酸をゆっくり加え、析出した結晶を濾取、水洗、減圧乾燥した。次いでメタノール(100 mL)に溶解させ、氷冷下で濃硫酸(7.00 mL)をゆっくり加え、終夜加熱還流した。反応液を濃縮し、残渣を飽和炭酸水素ナトリウム水溶液中にゆっくり滴下した。析出した結晶を、濾取、水洗、減圧乾燥し、methyl 6-bromo-8-nitro-4-oxo-4H-chromene-2-carboxylate (2.90 g, 8.85 mmol)を得た（収率９２％）。 (1) After adding (COOEt) 2 (3.21 mL, 23.6 mmol) to a solution of commercially available 3-bromo-6-hydroxy-5-nitroacetophenone (2.50 g, 9.61 mmol) in dimethylformamide (60 mL), ice cooling down in t BuOK (4.32 g, 38.5 mmol ) was added slowly and stirred overnight. 0.4 M hydrochloric acid was slowly added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure. Then, it was dissolved in methanol (100 mL), concentrated sulfuric acid (7.00 mL) was slowly added under ice-cooling, and the mixture was heated to reflux overnight. The reaction solution was concentrated and the residue was slowly dropped into a saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give methyl 6-bromo-8-nitro-4-oxo-4H-chromene-2-carboxylate (2.90 g, 8.85 mmol) (yield 92%) .
　1H-NMR (400 MHz, CDCl3)δ: 8.57 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 2.8 Hz), 7.20 (1H, s), 4.03 (3H, s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.57 (1 H, d, J = 2.4 Hz), 8. 46 (1 H, d, J = 2.8 Hz), 7. 20 (1 H, s), 4.03 (3 H, s) .
（２）上記（１）で得られたmethyl 6-bromo-8-nitro-4-oxo-4H-chromene-2-carboxylate (2.60 g, 7.93 mmol)のメタノール (21.8 mL)溶液にSnCl2(6.01 g, 31.7 mmol)及び4 M 塩酸(21.8 mL)を加え、65℃で4時間加熱攪拌した。反応液を濃縮し、残渣を飽和炭酸水素ナトリウム水溶液中にゆっくり滴下し、クロロホルムを加え室温で終夜攪拌した。反応液にセライトを加え、不溶物を濾別し、クロロホルム層を単離、無水硫酸ナトリウムで乾燥し、溶媒留去することでmethyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (1.67 g, 5.61 mmol)を得た（収率７１％）。 (2) SnCl 2 (6.01) in a solution of methyl 6-bromo-8-nitro-4-oxo-4H-chromene-2-carboxylate (2.60 g, 7.93 mmol) obtained in (1) above in methanol (21.8 mL) g, 31.7 mmol) and 4 M hydrochloric acid (21.8 mL) were added, and the mixture was heated and stirred at 65 ° C. for 4 hours. The reaction solution was concentrated, the residue was slowly dropped into a saturated aqueous sodium hydrogen carbonate solution, chloroform was added, and the mixture was stirred overnight at room temperature. Celite is added to the reaction solution, the insoluble matter is separated by filtration, the chloroform layer is isolated, dried over anhydrous sodium sulfate, and the solvent is distilled off to give methyl 8-amino-6-bromo-4-oxo-4H-chromene- 2-carboxylate (1.67 g, 5.61 mmol) was obtained (yield 71%).
　1H-NMR (400 MHz, CDCl3) δ: 7.63 (1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 2.0 Hz), 7.09 (1H, s), 4.41 (2H, br), 4.02 (3H, s). 1H-NMR (400 MHz, DMSO-d6) δ: 7.22 (1H, d, J = 2.0 Hz), 7.20 (1H, d, J = 2.4 Hz), 6.92 (1H, s), 5.92 (2H, brs), 3.94 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ: 177.30, 160.76, 151.13, 143.50, 138.18, 125.73, 120.63, 119.82, 116.00, 114.73, 53.60. 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.63 (1 H, d, J = 2.4 Hz), 7.16 (1 H, d, J = 2.0 Hz), 7.09 (1 H, s), 4.41 (2 H, br) , 4.02 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.22 (1 H, d, J = 2.0 Hz), 7.20 (1 H, d, J = 2.4 Hz), 6.92 (1 H) , s), 5.92 (2H, brs), 3.94 (3H, s). 13 C-NMR (100 MHz, DMSO-d 6 ) δ: 177.30, 160.76, 151.13, 143.50, 138.18, 125.73, 120.63, 119.82, 116.00 , 114.73, 53.60.
（３）上記（２）で得られたmethyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.671 mmol)の1,4-dioxane (5.0 mL)及びジメチルホルムアミド (2.0 mL)の混合溶液にアルゴン雰囲気下でPdCl2(dppf) (49 mg, 0.0671 mmol)、K3PO4(284 mg, 1.34 mmol)、phenylboronic acid (123 mg, 1.01 mmol)を加え、終夜加熱還流した。反応液を濃縮し、残渣に飽和食塩水溶液及びクロロホルムを加え、析出した不溶物を濾別した後、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－１(137 mg, 0.464 mmol)を得た（収率６９％）。 (3) Methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.671 mmol) obtained in the above (2), 1,4-dioxane (5.0 mL) and dimethyl To a mixed solution of formamide (2.0 mL) is added PdCl 2 (dppf) (49 mg, 0.0671 mmol), K 3 PO 4 (284 mg, 1.34 mmol), and phenylboronic acid (123 mg, 1.01 mmol) under argon atmosphere, Heated to reflux overnight. The reaction mixture was concentrated, saturated aqueous sodium chloride solution and chloroform were added to the residue, and the precipitated insoluble matter was separated by filtration, extracted with chloroform and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-1 (137 mg, 0.464 mmol) (yield 69%).
　1H-NMR (400 MHz, DMSO-d6) δ: 7.64 (2H, d, J = 7.5 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.42-7.39 (3H, m), 6.92 (1H, s), 5.70 (2H, brs), 3.96 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.64 (2 H, d, J = 7.5 Hz), 7.49 (2 H, t, J = 7.5 Hz), 7.42-7.39 (3 H, m), 6.92 (6 1H, s), 5.70 (2H, brs), 3.96 (3H, s).
　Methyl 8-(4-methoxybenzamido)-4-oxo-6-phenyl-4H-chromene-2-carboxylate（ＣＩ－２）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -4-oxo-6-phenyl-4H-chromene-2-carboxylate (CI-2)
（１）ＣＩ－１の合成の際に合成したmethyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (100 mg, 0.335 mmol)のCH2Cl2 (1.68 mL)及びテトラヒドロフラン (0.56 mL)の混合溶液に、N,N-ジイソプロピルエチルアミン (0.080 mL, 0.446 mmol)及び4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol)のCH2Cl2(1.12 mL)溶液を氷冷下でゆっくり加え、室温で4日間攪拌した。さらにN,N-ジイソプロピルエチルアミン(0.080 mL, 0.446 mmol)及び4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol)のCH2Cl2(1.12 mL)溶液を氷冷下でゆっくり加え、室温で終夜攪拌した。反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (144 mg, 0.332 mmol)を得た（収率９９％）。 (1) methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (100 mg, 0.335 mmol) synthesized in the synthesis of CI-1 (1.68 mL) and CH 2 Cl 2 In a mixed solution of tetrahydrofuran (0.56 mL), a solution of N, N-diisopropylethylamine (0.080 mL, 0.446 mmol) and 4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol) in CH 2 Cl 2 (1.12 mL) under ice-cooling Slowly add and stir at room temperature for 4 days. Furthermore, a solution of N, N-diisopropylethylamine (0.080 mL, 0.446 mmol) and 4-methoxybenzoyl chloride (0.060 mL, 0.446 mmol) in CH 2 Cl 2 (1.12 mL) was slowly added under ice-cooling and stirred overnight at room temperature. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent is purified by silica gel column chromatography to obtain methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (144 mg, 0.332 mmol) Obtained (yield 99%).
　1H-NMR (400 MHz, CDCl3) δ: 9.16 (1H, d, J = 2.4 Hz), 8.76 (1H, brs), 8.03 (1H, d, J = 2.8 Hz), 7.98 (2H, d, J = 9.1 Hz), 7.16 (1H, s), 7.08 (2H, d, J = 9.1 Hz), 4.08 (3H, s), 3.93 (3H, s).  1 H-NMR (400 MHz, CDCl 3 ) δ: 9.16 (1 H, d, J = 2.4 Hz), 8. 76 (1 H, brs), 8.03 (1 H, d, J = 2.8 Hz), 7. 98 (2 H, d, J = 9.1 Hz), 7.16 (1 H, s), 7.08 (2 H, d, J = 9.1 Hz), 4.08 (3 H, s), 3.93 (3 H, s).
（２）上記（１）で得られたmethyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.463 mmol)の1,4-dioxane (13 mL)及びジメチルホルムアミド (7 mL)の混合溶液に、アルゴン雰囲気下でPdCl2(dppf) (13 mg, 0.0174 mmol)、K3PO4 (74 mg, 0.347 mmol)、phenylboronic acid (85 mg, 0.694 mmol)を加え、85 ℃で終夜加熱攪拌した。さらにphenylboronic acid (85 mg, 0.694 mmol)を加え、85 ℃で終夜加熱攪拌した。反応液を濃縮し、残渣に飽和食塩水溶液及びクロロホルムを加え、析出した不溶物を濾別した後、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－２(143 mg, 0.333 mmol)を得た（収率７２％）。 (2) methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (200 mg, 0.463 mmol) of 1,4-dioxane (13) obtained in the above (1) In a mixed solution of mL) and dimethylformamide (7 mL) under argon atmosphere PdCl 2 (dppf) (13 mg, 0.0174 mmol), K 3 PO 4 (74 mg, 0.347 mmol), phenylboronic acid (85 mg, 0.694) mmol) was added, and the mixture was heated and stirred at 85 ° C. overnight. Furthermore, phenylboronic acid (85 mg, 0.694 mmol) was added, and the mixture was heated and stirred at 85 ° C. overnight. The reaction mixture was concentrated, saturated aqueous sodium chloride solution and chloroform were added to the residue, and the precipitated insoluble matter was separated by filtration, extracted with chloroform and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-2 (143 mg, 0.333 mmol) (yield 72%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.42 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.78 (2H, d, J = 7.9 Hz), 7.54 (2H, t, J = 7.5 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.93 (3H, s), 3.89 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8.42 (1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.78 (2 H, d, J = 7.9 Hz), 7.54 (2 H, t, J = 7.5 Hz), 7.45 (1 H, t, J = 7.5 Hz), 7.14 (2 H, d, J = 9.1 Hz), 7.04 (1 H, s), 3.93 (3 H, s), 3. 89 (3 H, s).
　8-(4-Methoxybenzamido)-4-oxo-6-phenyl-4H-chromene-2-carboxylic acid（ＣＩ－３）の合成 Synthesis of 8- (4-Methoxybenzamido) -4-oxo-6-phenyl-4H-chromene-2-carboxylic acid (CI-3)
　ＣＩ－２(50 mg, 0.116 mmol)の1,4-dioxane (5 mL)溶液に、4 M NaOH 水溶液(0.146 mL)を加え、室温で2.5時間攪拌した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、ＣＩ－３(44 mg, 0.106 mmol)を得た（収率９１％）。 To a solution of CI-2 (50 mg, 0.116 mmol) in 1,4-dioxane (5 mL) was added 4 M aqueous NaOH solution (0.146 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CI-3 (44 mg, 0.106 mmol) (yield 91%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, brs), 8.43 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.0 Hz ), 8.05 (2H, d, J = 8.7 Hz), 7.77 (2H, d, J = 7.5 Hz), 7.54 (2H, t, J = 7.5 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.97 (1H, s), 3.87 (3H, s). EI-MS (m/z): 416 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.19 (1 H, brs), 8.43 (1 H, d, J = 2.4 Hz), 8.09 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d, J = 8.7 Hz), 7.77 (2 H, d, J = 7.5 Hz), 7.54 (2 H, t, J = 7.5 Hz), 7.45 (1 H, t, J = 7.5 Hz), 7.12 (2 H, d, J = 8.7 Hz), 6.97 (1 H, s), 3. 87 (3 H, s). EI-MS (m / z): 416 [M] + .
　Methyl 8-amino-6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４）の合成 Synthesis of Methyl 8-amino-6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate (CI-4)
　ＣＩ－１の合成（２）で合成したmethyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.671 mmol)の1,4-dioxane (8.0 mL)にアルゴン雰囲気下でPdCl2(dppf) (49 mg, 0.0671 mmol)、K3PO4(284 mg, 1.34 mmol)、4-(methoxycarbonyl)phenylboronic acid (181 mg, 1.01 mmol)を加え、80 ℃で終夜加熱攪拌した。さらにPdCl2(dppf) (49 mg, 0.0671 mmol)及び4-(methoxycarbonyl)phenylboronic acid (181 mg, 1.01 mmol)を加え、80℃で終夜加熱攪拌した。さらにジメチルホルムアミド (2.0 mL)を加え7時間加熱還流した後、濃縮し、反応液を濃縮し、残渣に飽和食塩水溶液及びクロロホルムを加え、析出した不溶物を濾別した。その後、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－４(193 mg, 0.546 mmol)を得た（収率８１％）。 Methyl 8-amino-6-bromo-4-oxo-4H-chromene-2-carboxylate (200 mg, 0.671 mmol) synthesized in CI-1 synthesis (2) and argon in 1,4-dioxane (8.0 mL) Add PdCl 2 (dppf) (49 mg, 0.0671 mmol), K 3 PO 4 (284 mg, 1.34 mmol), 4- (methoxycarbonyl) phenylboronic acid (181 mg, 1.01 mmol) under atmosphere and heat overnight at 80 ° C. It stirred. Further, PdCl 2 (dppf) (49 mg, 0.0671 mmol) and 4- (methoxycarbonyl) phenylboronic acid (181 mg, 1.01 mmol) were added, and the mixture was heated and stirred at 80 ° C. overnight. Further, dimethylformamide (2.0 mL) was added and the mixture was heated under reflux for 7 hours and concentrated. The reaction solution was concentrated, saturated aqueous sodium chloride solution and chloroform were added to the residue, and the precipitated insolubles were separated by filtration. Thereafter, it was extracted with chloroform and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-4 (193 mg, 0.546 mmol) (yield 81%).
　1H-NMR (400 MHz, DMSO-d6) δ: 8.06 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.47 (1H, d, J = 2.4 Hz), 6.94 (1H, s), 5.76 (2H, brs), 3.96 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.06 (2 H, d, J = 8.7 Hz), 7.80 (2 H, d, J = 8.3 Hz), 7.47 (1 H, d, J = 2.4 Hz) , 7.47 (1 H, d, J = 2.4 Hz), 6.94 (1 H, s), 5. 76 (2 H, brs), 3. 96 (3 H, s), 3. 88 (3 H, s).
　Methyl 8-amino-6-(3-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５）の合成 Synthesis of Methyl 8-amino-6- (3-methoxycarbonylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-5)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-(methoxycarbonyl)phenylboronic acid を用い、ＣＩ－４の合成と同様の方法でＣＩ－５を得た（収率６４％）。 Using 3- (methoxycarbonyl) phenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-5 was obtained in the same manner as in the synthesis of CI-4 (yield: 64%).
　1H-NMR (400 MHz, DMSO-d6) δ: 8.18 (1H, t, J = 2.0 Hz), 8.00-7.94 (2H, m), 7.65 (1H, t, J = 7.5 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 6.94 (1H, s), 5.76 (2H, brs), 3.96 (3H, s), 3.91 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.18 (1 H, t, J = 2.0 Hz), 8.00-7.94 (2 H, m), 7.65 (1 H, t, J = 7.5 Hz), 7.47 ( 1H, d, J = 2.0 Hz), 7.42 (1 H, d, J = 2.0 Hz), 6.94 (1 H, s), 5. 76 (2 H, brs), 3. 96 (3 H, s), 3.91 (3 H, s).
　Methyl 8-amino-6-(2-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－６）の合成 Synthesis of Methyl 8-amino-6- (2-methoxycarbonylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-6)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-(methoxycarbonyl)phenylboronic acid を用い、ＣＩ－４の合成と同様の方法でＣＩ－５を得た（収率３８％）。 Using 2- (methoxycarbonyl) phenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-5 was obtained in the same manner as in the synthesis of CI-4 (yield: 38%).
　1H-NMR (400 MHz, DMSO-d6) δ: 7.75 (1H, dd, J = 7.5 Hz, 1.2 Hz), 7.64 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.45 (1H, dd, J = 7.9 Hz, 0.8 Hz), 7.06-7.04 (2H, m), 6.92 (1H, s), 5.69 (2H, d, J = 7.5 Hz), 3.96 (3H, s), 3.60 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.75 (1 H, dd, J = 7.5 Hz, 1.2 Hz), 7.64 (1 H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1 H, dt , J = 7.5 Hz, 1.2 Hz), 7.45 (1 H, dd, J = 7.9 Hz, 0.8 Hz), 7.06-7.04 (2 H, m), 6. 92 (1 H, s), 5. 69 (2 H, d, J = 7.5) Hz), 3.96 (3H, s), 3.60 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate（ＣＩ－７）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6-methoxycarbonylphenyl-4-oxo-4H-chromene-2-carboxylate (CI-7)
　ＣＩ－２の合成（１）で合成したmethyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate (75 mg, 0.174 mmol)の1,4-dioxane (5 mL)及びジメチルホルムアミド (3 mL)の混合溶液に、アルゴン雰囲気下でPdCl2(dppf) (13 mg, 0.0174 mmol)、K3PO4 (74 mg, 0.347 mmol)、4-(methoxycarbonyl)phenylboronic acid (47 mg, 0.260 mmol)を加え、85 ℃で2日間加熱攪拌した。反応液を濃縮し、残渣に飽和食塩水溶液及びクロロホルムを加え、析出した不溶物を濾別した後、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－７(16 mg, 0.0373 mmol)を得た（収率２１％）。 Methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate synthesized by synthesis (1) of CI-2 (75 mg, 0.174 mmol) of 1,4-dioxane (5) In a mixed solution of mL) and dimethylformamide (3 mL) under argon atmosphere PdCl 2 (dppf) (13 mg, 0.0174 mmol), K 3 PO 4 (74 mg, 0.347 mmol), 4- (methoxycarbonyl) phenylboronic acid (47 mg, 0.260 mmol) was added, and the mixture was heated and stirred at 85 ° C. for 2 days. The reaction mixture was concentrated, saturated aqueous sodium chloride solution and chloroform were added to the residue, and the precipitated insoluble matter was separated by filtration, extracted with chloroform and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-7 (16 mg, 0.0373 mmol) (yield 21%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.50 (1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 2.4 Hz ), 8.10 (2H, d, J = 8.7 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.96 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s). EI-MS (m/z): 487 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8. 50 (1 H, d, J = 2.0 Hz), 8. 19 (1 H, d, J = 2.4 Hz), 8. 10 (2 H, 2 H, d, J = 8.7 Hz), 8.05 (2 H, d, J = 8.7 Hz), 7. 96 (2 H, d, J = 8.3 Hz), 7. 15 (2 H, d, J = 8.7 Hz), 7.06 (1 H, s) , 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s). EI-MS (m / z): 487 [M] + .
　Methyl 8-(4-methoxybenzamido)-6-(3-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methoxycarbonylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-8)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-(methoxycarbonyl)phenylboronic acid を用い、ＣＩ－７の合成と同様の方法でＣＩ－８を得た（収率４６％）。 Using 3- (methoxycarbonyl) phenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-8 was obtained in the same manner as in the synthesis of CI-7 (yield 46%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.47 (1H, d, J = 2.4 Hz), 8.27 (1H, s), 8.13 (1H, d, J = 2.0 Hz), 8.11-8.03 (4H, m), 7.70 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 487[M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8.47 (1 H, d, J = 2.4 Hz), 8.27 (1 H, s), 8.13 (1 H, d, J = 2.0 Hz), 8.11-8.03 (4H, m), 7.70 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m / z): 487 [M] + .
　Methyl 8-(4-methoxybenzamido)-6-(2-methoxycarbonylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－９）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (2-methoxycarbonylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-9)
　ＣＩ－６ (87 mg, 0.246 mmol)のCH2Cl2　(2.0 mL)及びテトラヒドロフラン (1.0 mL)の混合溶液に、N,N-ジイソプロピルエチルアミン(0.057 mL, 0.327 mmol)及び4-methoxybenzoyl chloride (0.044 mL, 0.327 mmol)のCH2Cl2　(0.5 mL)溶液を氷冷下でゆっくり加え、室温で4日間攪拌した。反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－９(100 mg, 0.233 mmol)を得た（収率９５％）。 CI-6 (87 mg, 0.246 mmol) in a mixed solution of CH 2 Cl 2 (2.0 mL) and tetrahydrofuran (1.0 mL) in, N, N- diisopropylethylamine (0.057 mL, 0.327 mmol) and 4-methoxybenzoyl chloride (0.044 A solution of mL, 0.327 mmol) in CH 2 Cl 2 (0.5 mL) was slowly added under ice-cooling and stirred at room temperature for 4 days. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-9 (100 mg, 0.233 mmol) (yield 95%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, brs), 8.07 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.86 (1H, dd, J = 7.9 Hz, J = 1.2 Hz), 7.75 (1H, d, J = 2.4 Hz), 7.70 (1H, dt, J = 7.5 Hz, J =1.2 Hz), 7.60-7.55 (2H, m), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.94 (3H, s), 3.87 (3H, s), 3.64 (3H, s). EI-MS (m/z): 487 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.18 (1 H, brs), 8.07 (1 H, d, J = 2.0 Hz), 8.03 (2 H, d, J = 8.7 Hz), 7.86 (1 H, 1 H, dd, J = 7.9 Hz, J = 1.2 Hz), 7.75 (1 H, d, J = 2.4 Hz), 7. 70 (1 H, dt, J = 7.5 Hz, J = 1.2 Hz), 7.60-7.55 (2 H, m) , 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.94 (3H, s), 3.87 (3H, s), 3.64 (3H, s). EI-MS (m / z): 487 [M] + .
　Methyl 8-amino-6-carboxyphenyl-4-oxo-4H-chromene-2-carboxylate（ＣＩ－１０）の合成 Synthesis of Methyl 8-amino-6-carboxyphenyl-4-oxo-4H-chromene-2-carboxylate (CI-10)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに4-carboxyphenylboronic acidを用い、ＣＩ－４の合成と同様の方法でＣＩ－１０を得た（収率３２％）。 Using 4-carboxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-10 was obtained in the same manner as in the synthesis of CI-4 (yield 32%).
　1H-NMR (400 MHz, DMSO-d6) δ: 8.05 (2H, J = 7.9 Hz), 7.77 (2H, m), 7.47 (1H, d, J = 2.0 Hz), 7.45 (1H, J = 1.6 Hz), 6.93 (1H, s), 5.74 (2H, brs), 3.96 (3H, s). EI-MS (m/z): 339 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.05 (2 H, J = 7.9 Hz), 7.77 (2 H, m), 7.47 (1 H, d, J = 2.0 Hz), 7.45 (1 H, J = 1.6 Hz), 6.93 (1 H, s), 5. 74 (2 H, brs), 3. 96 (3 H, s). EI-MS (m / z): 339 [M] + .
　4-[8-(4-Methoxybenzamide)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid（ＣＩ－１１）の合成 Synthesis of 4- [8- (4-Methoxybenzamide) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] benzoic acid (CI-11)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに4-carboxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－１１を得た（収率７４％）。 Using 4-carboxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-11 was obtained in the same manner as in the synthesis of CI-7 (yield 74%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.49 (1H, s), 8.18 (1H, s), 8.08 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 473 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8.49 (1 H, s), 8.18 (1 H, s), 8.08 (2 H, d, J = 8.3 Hz), 8.05 ( 2H, d, J = 8.3 Hz), 7. 92 (2 H, d, J = 8.3 Hz), 7. 15 (2 H, d, J = 8.7 Hz), 7.05 (1 H, s), 3. 93 (3 H, s), 3. 88 ( 3H, s). EI-MS (m / z): 473 [M] + .
　4-[2-Ethoxycarbonyl-8-(4-methoxybenzamide)-4-oxo-4H-chromen-6-yl]benzoic acid（ＣＩ－１２）の合成 Synthesis of 4- [2-Ethoxycarbonyl-8- (4-methoxybenzamide) -4-oxo-4H-chromen-6-yl] benzoic acid (CI-12)
　Methyl 8-(4-Methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateのかわりにJ. Med. Chem. 2013, 56, 5182-5197に記載の方法で合成できるethyl 8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateを用い、ＣＩ－１１の合成と同様の方法でＣＩ－１２を得た（収率５９％）。 Instead of Methyl 8- (4-Methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate, methyl 8- (4-methoxybenzamido) can be synthesized by the method described in J. Med. Chem. 2013, 56, 5182-5197. CI-12 was obtained in the same manner as in the synthesis of CI-11, using 4-oxo-4H-chromene-2-carboxylate (yield 59%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.0 Hz), 8.08 (2H, d, J = 7.9 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.13 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 4.36 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.27 (3H, t, J = 7.1 Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8.49 (1 H, d, J = 2.0 Hz), 8.17 (1 H, d, J = 2.0 Hz), 8.08 (2 H, 2 H, d, J = 7.9 Hz), 8.06 (2 H, d, J = 9.1 Hz), 7. 92 (2 H, d, J = 8.3 Hz), 7. 13 (2 H, d, J = 9.1 Hz), 7.05 (1 H, s) , 4.36 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.27 (3H, t, J = 7.1 Hz).
　3-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid（ＣＩ－１３）の合成 Synthesis of 3- [8- (4-Methoxybenzamido) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] benzoic acid (CI-13)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-carboxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－１３を得た（収率４８％）。 Using 3-carboxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-13 was obtained in the same manner as in the synthesis of CI-7 (yield 48%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.24 (1H, brs), 8.48 (1H, d, J = 2.4 Hz), 8.27 (1H, s), 8.13 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 7.9 Hz), 7.95 (1H, d, J = 8.3 Hz), 7.67 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.80 (3H, s). EI-MS (m/z): 473 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.24 (1 H, brs), 8.48 (1 H, d, J = 2.4 Hz), 8.27 (1 H, s), 8.13 (1 H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 7.9 Hz), 7.95 (1H, d, J = 8.3 Hz), 7.67 (1 H, t, J = 7.9 Hz) , 7.15 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.80 (3H, s). EI-MS (m / z): 473 [M] + .
　2-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]benzoic acid（ＣＩ－１４）の合成 Synthesis of 2- [8- (4-Methoxybenzamido) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] benzoic acid (CI-14)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-carboxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－１４を得た（収率４％）。 Using 2-carboxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-14 was obtained in the same manner as in the synthesis of CI-7 (yield 4%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 8.13 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.85 (1H, d, J = 8.7 Hz), 7.77 (1H, d, J = 2.4 Hz), 7.65 (1H, m), 7.58-7.46 (2H, m), 7.13 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.94 (3H, s), 3.87 (3H, s). EI-MS (m/z): 473 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 8.13 (1 H, d, J = 2.4 Hz), 8.03 (2 H, d, J = 8.7 Hz), 7.85 (1 H, d, J = 8.7 Hz), 7. 77 (1 H, d, J = 2.4 Hz), 7. 65 (1 H, m), 7.58-7.46 (2 H, m), 7. 13 (2 H, d, J = 9.1 Hz), 7.04 (7 1 H, s), 3.94 (3 H, s), 3. 87 (3 H, s). EI-MS (m / z): 473 [M] + .
　6-(4-Methoxycarbonylphenyl)-8-(4-methoxybenzamide)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１５）の合成 Synthesis of 6- (4-Methoxycarbonylphenyl) -8- (4-methoxybenzamide) -4-oxo-4H-chromene-2-carboxylic acid (CI-15)
　ＣＩ－７ (50 mg, 0.103 mmol)のテトラヒドロフラン (3.0 mL)溶液にLiI (41 mg, 0.308 mmol)を加え、7時間加熱還流した。さらにLiI (41 mg, 0.308 mmol)を加え、終夜加熱還流した後、反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、ＣＩ－１５ (35 mg, 0.0739 mmol)を得た（収率７２％）。 LiI (41 mg, 0.308 mmol) was added to a solution of CI-7 (50 mg, 0.103 mmol) in tetrahydrofuran (3.0 mL), and the mixture was heated under reflux for 7 hours. Further, LiI (41 mg, 0.308 mmol) is added, and the mixture is heated under reflux overnight. The reaction mixture is concentrated, 1 M hydrochloric acid is slowly added dropwise to the residue, and the precipitated crystals are collected by filtration, washed with water and dried under reduced pressure, (35 mg, 0.0739 mmol) were obtained (yield 72%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.16 (1H, d, J = 2.4 Hz), 8.10 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz), 7.95 (2H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 6.93 (1H, s), 3.90 (3H, s), 3.87 (3H, s). EI-MS (m/z): 473[M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8.51 (1 H, d, J = 2.0 Hz), 8.16 (1 H, d, J = 2.4 Hz), 8. 10 (2 H, 2 H, d, J = 8.3 Hz), 8.05 (2 H, d, J = 8.3 Hz), 7. 95 (2 H, d, J = 8.7 Hz), 7.11 (2 H, d, J = 8.7 Hz), 6. 93 (1 H, s) , 3.90 (3H, s), 3.87 (3H, s). EI-MS (m / z): 473 [M] + .
　6-(3-Methoxycarbonylphenyl)-8-(4-methoxybenzamide)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１６）の合成 Synthesis of 6- (3-Methoxycarbonylphenyl) -8- (4-methoxybenzamide) -4-oxo-4H-chromene-2-carboxylic acid (CI-16)
　ＣＩ－８(50 mg, 0.116 mmol)の1,4-dioxane (2.5 mL)溶液に、4 M NaOH水溶液(0.058 mL, 0.233 mmol)を加え、室温で4.5時間攪拌した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、ＣＩ－１６(51 mg, 0.108 mmol)を得た（収率９３％）。なお加水分解されたカルボン酸の位置は、HMBC相関により決定した。 To a solution of CI-8 (50 mg, 0.116 mmol) in 1,4-dioxane (2.5 mL) was added 4 M aqueous NaOH solution (0.058 mL, 0.233 mmol), and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CI-16 (51 mg, 0.108 mmol) (yield 93%). The position of the hydrolyzed carboxylic acid was determined by HMBC correlation.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.21 (1H, brs), 8.48 (1H, d, J = 2.0 Hz), 8.27 (1H, s), 8.11 (1H, d, J = 2.0 Hz), 8.10-8.02 (4H, m), 7.70 (1H, m), 7.11 (2H, d, J = 9.1 Hz), 6.96 (1H, s), 3.92 (3H, s), 3.87 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ: 177.52, 166.00, 164.95, 162.29, 161.17, 154.18, 148.81, 138.75, 136.05, 131.69, 130.57, 129.87, 129.72, 129.31, 128.81, 128.37, 127.21, 125.93, 124.56, 118.40, 113.83, 112.95, 55.49, 52.36. EI-MS (m/z): 473 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.21 (1 H, brs), 8.48 (1 H, d, J = 2.0 Hz), 8.27 (1 H, s), 8.11 (1 H, d, J = 2.0 Hz), 8.10-8.02 (4H, m), 7.70 (1H, m), 7.11 (2H, d, J = 9.1 Hz), 6.96 (1H, s), 3.92 (3H, s), 3.87 (3H, s) 13 C-NMR (100 MHz, DMSO-d 6 ) δ: 177.52, 166.00, 164.95, 162.17, 154.18, 148.81, 138.75, 136.59, 130.57, 129.87, 129.72, 129.31, 128.81, 128.37, 127.21. , 125.93, 124.56, 118.40, 113.83, 112.95, 55.49, 52.36. EI-MS (m / z): 473 [M] + .
　6-Carboxyphenyl-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１７）の合成 Synthesis of 6-Carboxyphenyl-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-17)
　ＣＩ－１１ (52 mg, 0.110 mmol)のテトラヒドロフラン (4.0 mL)溶液にLiI (44 mg, 0.329 mmol)を加え、終夜加熱還流した。LiI (44 mg, 0.329 mmol)を加え2日間加熱還流した後、さらにLiI (44 mg, 0.329 mmol)を加え、終夜加熱還流した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥した後、メタノールから再結晶して、ＣＩ－１７(28 mg, 0.0610 mmol)を得た（収率５６％）。 LiI (44 mg, 0.329 mmol) was added to a solution of CI-11 (52 mg, 0.110 mmol) in tetrahydrofuran (4.0 mL), and the mixture was heated to reflux overnight. After adding LiI (44 mg, 0.329 mmol) and heating under reflux for 2 days, LiI (44 mg, 0.329 mmol) was further added, and the mixture was heated under reflux overnight. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure and recrystallized from methanol to give CI-17 (28 mg, 0.0610 mmol) (56% yield).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.06 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.8 Hz), 6.99 (1H, s), 3.87 (3H, s). EI-MS (m/z): 459 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 8. 49 (1 H, d, J = 2.0 Hz), 8. 17 (1 H, d, J = 2.4 Hz), 8.08 (2 H, 2 H, d d, J = 8.4 Hz), 8.06 (2 H, d, J = 8.8 Hz), 7. 92 (2 H, d, J = 8.0 Hz), 7.12 (2 H, d, J = 8.8 Hz), 6.99 (1 H, s) , 3.87 (3H, s). EI-MS (m / z): 459 [M] + .
　6-(3-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１８）の合成 Synthesis of 6- (3-Carboxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-18)
　ＣＩ－１３(71 mg, 0.164 mmol)のテトラヒドロフラン (3.5 mL)溶液に、LiI (66 mg, 0.493 mmol)を加え、マイクロウェーブ照射下100 ℃で10時間攪拌した。LiI (66 mg, 0.493 mmol)を加え、マイクロウェーブ照射下100 ℃で10時間攪拌した後、さらにLiI (66 mg, 0.493 mmol)を加え、マイクロウェーブ照射下100 ℃で6時間攪拌し、さらにLiI (44 mg, 0.329 mmol)を加え、マイクロウェーブ照射下100 ℃で2時間攪拌した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、メタノールから再結晶して、ＣＩ－１８(41 mg, 0.0950 mmol)を得た（収率５８％）。 LiI (66 mg, 0.493 mmol) was added to a solution of CI-13 (71 mg, 0.164 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100 ° C. for 10 hours under microwave irradiation. Add LiI (66 mg, 0.493 mmol) and stir at 100 ° C for 10 hours under microwave irradiation, then add LiI (66 mg, 0.493 mmol) and stir for 6 hours at 100 ° C under microwave irradiation, then add LiI (44 mg, 0.329 mmol) was added and stirred at 100 ° C. for 2 hours under microwave irradiation. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure and recrystallized from methanol to give CI-18 (41 mg, 0.0950 mmol) ( Yield 58%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 9.65 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.84 (1H, m), 3.87 (3H, s). EI-MS (m/z): 459 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 9.65 (1 H, brs), 8.38 (1 H, d, J = 2.4 Hz), 8.05 (2 H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, 2H, s) d, J = 9.1 Hz), 6.97 (1 H, s), 6. 84 (1 H, m), 3. 87 (3 H, s). EI-MS (m / z): 459 [M] + .
　6-(2-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１９）の合成 Synthesis of 6- (2-Carboxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-19)
　ＣＩ－１４(80 mg, 0.167 mmol)のテトラヒドロフラン(3.5 mL)溶液に、LiI (67 mg, 0.502 mmol)を加え、マイクロウェーブ照射下100 ℃で6時間攪拌した。さらにLiI (67 mg, 0.502 mmol)を加え、マイクロウェーブ照射下100 ℃で13時間攪拌した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥して得られた固体をメタノールから再結晶して、ＣＩ－１９(42 mg, 0.0914 mmol)を得た（収率５５％）。 LiI (67 mg, 0.502 mmol) was added to a solution of CI-14 (80 mg, 0.167 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 100 ° C. for 6 hours under microwave irradiation. Further, LiI (67 mg, 0.502 mmol) was added, and the mixture was stirred at 100 ° C. for 13 hours under microwave irradiation. The reaction solution is concentrated, 1 M hydrochloric acid is slowly added dropwise to the residue, and the precipitated crystals are collected by filtration, washed with water and dried under reduced pressure to give a solid, which is recrystallized from methanol to give CI-19 (42 mg, 0.0914 mmol) ) (Yield 55%).
　　1H-NMR (400 MHz, DMSO-d6) δ: 10.04 (1H, brs), 8.21 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.79 (1H, d, J = 7.1 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.65 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1H, m), 7.48 (1H, d, J = 7.5 Hz), 7.09 (2H, d, J = 8.3 Hz), 6.69 (1H, s), 3.86 (3H, s). EI-MS (m/z): 459 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.04 (1 H, brs), 8.21 (1 H, d, J = 2.0 Hz), 8.03 (2 H, d, J = 8.7 Hz), 7.79 (1 H, d, J = 7.1 Hz, 7. 70 (1 H, d, J = 2.0 Hz), 7. 65 (1 H, dt, J = 7.5 Hz, 1.2 Hz), 7.52 (1 H, m), 7. 48 (1 H, d, J = 7.5 Hz), 7.09 (2 H, d, J = 8.3 Hz), 6.69 (1 H, s), 3. 86 (3 H, s). EI-MS (m / z): 459 [M] + .
　6-(2-Carboxyphenyl)-8-(4-hydroxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－２０）の合成 Synthesis of 6- (2-Carboxyphenyl) -8- (4-hydroxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-20)
　ＣＩ－１４(19 mg, 0.0390 mmol)のテトラヒドロフラン (2.0 mL)溶液に、LiI (31 mg, 0.234 mmol)を加え、マイクロウェーブ照射下200 ℃で2時間攪拌した。LiI (31 mg, 0.234 mmol)を加え、マイクロウェーブ照射下200 ℃で2.5時間攪拌した後、さらにLiI (31 mg, 0.234 mmol)を加え、マイクロウェーブ照射下200 ℃で6時間攪拌した。反応液を濃縮し、残渣に1 M塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、ＣＩ－２０(4 mg, 0.00898 mmol)を得た（収率２３％）。 LiI (31 mg, 0.234 mmol) was added to a solution of CI-14 (19 mg, 0.0390 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred at 200 ° C. for 2 hours under microwave irradiation. After adding LiI (31 mg, 0.234 mmol) and stirring at 200 ° C. for 2.5 hours under microwave irradiation, LiI (31 mg, 0.234 mmol) was further added, and stirring was performed at 200 ° C. under microwave irradiation for 6 hours. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise to the residue, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CI-20 (4 mg, 0.00898 mmol) (yield 23%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.27 (1H, br), 10.01 (1H, brs), 8.14 (1H, d, J = 2.4 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.84 (1H, dd, J = 7.5 Hz, 1.2 Hz), 7.75 (1H, d, J = 2.0 Hz), 7.65 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.54 (1H, dt, J = 7.5 Hz, 1.2 Hz), 7.48 (1H, d, J = 7.1 Hz), 6.98 (1H, s), 6.91 (2H, d, J = 8.7 Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.27 (1 H, br), 1 0.01 (1 H, brs), 8. 14 (1 H, d, J = 2.4 Hz), 7. 92 (2 H, d, J = 8.3 Hz), 7.84 (1H, dd, J = 7.5 Hz, 1.2 Hz), 7.75 (1 H, d, J = 2.0 Hz), 7.65 (1 H, dt, J = 7.5 Hz, 1.2 Hz), 7.54 (1 H, dt , J = 7.5 Hz, 1.2 Hz), 7.48 (1 H, d, J = 7.1 Hz), 6. 98 (1 H, s), 6. 91 (2 H, d, J = 8.7 Hz).
　Methyl 6-(4-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２１）の合成 Synthesis of Methyl 6- (4-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-21)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに4-hydroxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－２１を得た（収率７２％）。 Using 4-hydroxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-21 was obtained in the same manner as in the synthesis of CI-7 (yield: 72%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, brs), 9.73 (1H, brs), 8.33 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.01 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 445 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.18 (1 H, brs), 9. 73 (1 H, brs), 8.33 (1 H, d, J = 2.0 Hz), 8.04 (2 H, d, J = 9.1 Hz), 8.00 (1 H, d, J = 2.4 Hz), 7. 60 (2 H, d, J = 8.7 Hz), 7. 14 (2 H, d, J = 9.1 Hz), 7.01 (1 H, s), 6. 91 (2 H, d, J = 8.7 Hz), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m / z): 445 [M] + .
　Ethyl 6-hydroxyphenyl-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２２）の合成 Synthesis of Ethyl 6-hydroxyphenyl-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-22)
　Methyl 8-(4-Methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateのかわりにJ. Med. Chem. 2013, 56, 5182-5197に記載の方法で合成できるethyl 8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateを用い、ＣＩ－２１の合成と同様の方法でＣＩ－２２を得た（収率２５％）。 Instead of Methyl 8- (4-Methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate, methyl 8- (4-methoxybenzamido) can be synthesized by the method described in J. Med. Chem. 2013, 56, 5182-5197. CI-22 was obtained in the same manner as in the synthesis of CI-21 using 4-oxo-4H-chromene-2-carboxylate (yield 25%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 9.73 (1H, brs), 8.33 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.01 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 4.35 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.26 (3H, m). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 9. 73 (1 H, brs), 8.33 (1 H, d, J = 2.0 Hz), 8.04 (2 H, d, J = 9.1 Hz), 8.00 (1 H, d, J = 2.4 Hz), 7. 60 (2 H, d, J = 8.7 Hz), 7.12 (2 H, d, J = 9.1 Hz), 7.01 (1 H, s), 6. 91 (2 H, d, J = 8.7 Hz), 4.35 (2 H, q, J = 7.1 Hz), 3. 87 (3 H, s), 1. 26 (3 H, m).
　Methyl 6-(3-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２３）の合成 Synthesis of Methyl 6- (3-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-23)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-hydroxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－２３を得た（収率５１％）。 Using 3-hydroxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-23 was obtained in the same manner as in the synthesis of CI-7 (yield 51%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, brs), 9.67 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 9.1 Hz), 8.03 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.13 (1H, s), 7.03 (1H, s), 6.84 (1H, m), 3.94 (3H, s), 3.88 (3H, s). EI-MS (m/z): 445 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.20 (1 H, brs), 9.67 (1 H, brs), 8.38 (1 H, d, J = 2.4 Hz), 8.04 (2 H, d, J = 9.1 Hz), 8.03 (1 H, d, J = 2.4 Hz), 7.33 (1 H, t, J = 7.9 Hz), 7.18 (1 H, d, J = 7.9 Hz), 7.14 (2 H, d, J = 9.1 Hz) , 7.13 (1H, s), 7.03 (1H, s), 6.84 (1H, m), 3.94 (3H, s), 3.88 (3H, s). EI-MS (m / z): 445 [M] + .
　Methyl 6-(2-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２４）の合成 Synthesis of Methyl 6- (2-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-24)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-hydroxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－２４を得た（収率６４％）。 Using 2-hydroxyphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-24 was obtained in the same manner as in the synthesis of CI-7 (yield: 64%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, brs), 9.85 (1H, s), 8.26 (1H, d, J = 1.6 Hz), 8.07 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.38 (1H, dd, J = 7.9 Hz, 1.6 Hz), 7.32 (1H, m), 7.13 (2H, d, J = 9.1 Hz), 7.02 (1H, s), 7.01 (1H, m), 6.95 (1H, m), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 445 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.20 (1 H, brs), 9. 85 (1 H, s), 8. 26 (1 H, d, J = 1.6 Hz), 8.07 (1 H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.38 (1 H, dd, J = 7.9 Hz, 1.6 Hz), 7.32 (1 H, m), 7.13 (2 H, d, J = 9.1 Hz), 7.02 (1H, s), 7.01 (1H, m), 6.95 (1H, m), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m / z): 445 [M] + .
　6-(4-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－２５）の合成 Synthesis of 6- (4-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-25)
　ＣＩ－１３のかわりにＣＩ－２１を用い、ＣＩ－１８の合成と同様の方法でＣＩ－２５を得た（収率５１％）。 Using CI-21 instead of CI-13, CI-25 was obtained in a similar manner to the synthesis of CI-18 (yield 51%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, brs), 9.74 (1H, brs), 8.32 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.7 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 3.87 (3H, s). EI-MS (m/z): 431 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.19 (1 H, brs), 9.74 (1 H, brs), 8.32 (1 H, d, J = 2.0 Hz), 8.05 (2 H, d, J = 8.7 Hz), 8.00 (1 H, d, J = 2.4 Hz), 7. 60 (2 H, d, J = 8.7 Hz), 7.12 (2 H, d, J = 9.1 Hz), 6. 97 (1 H, s), 6. 91 (2 H, s) d, J = 8.7 Hz), 3.87 (3 H, s). EI-MS (m / z): 431 [M] + .
　6-(3-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－２６）の合成 Synthesis of 6- (3-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-26)
　ＣＩ－１３のかわりにＣＩ－２３を用い、ＣＩ－１８の合成と同様の方法でＣＩ－２６を得た（収率５８％）。 Using CI-23 instead of CI-13, CI-26 was obtained in a similar manner to the synthesis of CI-18 (yield: 58%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 9.65 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, d, J = 9.1 Hz), 6.97 (1H, s), 6.84 (1H, m), 3.87 (3H, s). EI-MS (m/z): 431 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 9.65 (1 H, brs), 8.38 (1 H, d, J = 2.4 Hz), 8.05 (2 H, d, J = 9.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz), 7.13 (1H, s), 7.12 (2H, 2H, s) d, J = 9.1 Hz), 6.97 (1 H, s), 6. 84 (1 H, m), 3. 87 (3 H, s). EI-MS (m / z): 431 [M] + .
　6-(2-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－２７）の合成 Synthesis of 6- (2-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-27)
　ＣＩ－１３のかわりにＣＩ－２４を用い、ＣＩ－１８の合成と同様の方法でＣＩ－２７を得た（収率８６％）。 Using CI-24 instead of CI-13, CI-27 was obtained in a similar manner to the synthesis of CI-18 (yield 86%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, brs), 9.82 (1H, brs), 8.28 (1H, d, J = 2.0 Hz), 8.07 (1H, d, J= 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.37 (1H, m), 7.24 (1H, m), 7.11 (2H, d, J= 8.7 Hz), 7.01 (1H, d, J = 7.1 Hz), 6.97 (1H, s), 6.94 (1H, t, J = 7.5 Hz), 3.87 (3H, s). EI-MS (m/z): 431 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.51 (1 H, brs), 9. 82 (1 H, brs), 8. 28 (1 H, d, J = 2.0 Hz), 8.07 (1 H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.37 (1 H, m), 7.24 (1 H, m), 7.11 (2 H, d, J = 8.7 Hz), 7.01 (1 H, d, J = 7.1 Hz), 6.97 (1 H, s), 6.94 (1 H, t, J = 7.5 Hz), 3. 87 (3 H, s). EI-MS (m / z): 431 [M] + .
　Methyl 6-(4-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２８）の合成 Synthesis of Methyl 6- (4-tert-butylcarbonylmethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-28)
　ＣＩ－２１(233 mg, 0.523 mmol)のジメチルホルムアミド(3.5 mL)溶液に、アルゴン雰囲気下でK2CO3(94 mg, 0.680 mmol)及びtert-butyl 2-bromoacetate (0.092 mL, 0.628 mmol)を加え、2日間室温で攪拌した。反応液を濃縮し、残渣に飽和食塩水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ＣＩ－２８(211 mg, 0.377 mmol)を得た（収率７２％）。 To a solution of CI-21 (233 mg, 0.523 mmol) in dimethylformamide (3.5 mL) under argon atmosphere K 2 CO 3 (94 mg, 0.680 mmol) and tert-butyl 2-bromoacetate (0.092 mL, 0.628 mmol) In addition, it was stirred at room temperature for 2 days. The reaction mixture was concentrated, saturated brine was added to the residue, extracted with chloroform, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography to obtain CI-28 (211 mg, 0.377 mmol) (yield 72%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, brs), 8.38 (1H, d, J = 2.4 Hz), 8.05 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.05 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 4.73 (2H, s), 3.92 (3H, s), 3.88 (3H, s), 1.45 (9H, s). EI-MS (m/z): 559 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.20 (1 H, brs), 8.38 (1 H, d, J = 2.4 Hz), 8.05 (1 H, d, J = 2.4 Hz), 8.04 (2 H, 2 H, d, J = 8.7 Hz), 7.72 (2 H, d, J = 8.7 Hz), 7. 14 (2 H, d, J = 8.3 Hz), 7.05 (2 H, d, J = 9.1 Hz), 7.05 (1 H, s) , 4.73 (2H, s), 3.92 (3H, s), 3.88 (3H, s), 1.45 (9H, s). EI-MS (m / z): 559 [M] + .
　Methyl 6-(3-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－２９）の合成 Synthesis of Methyl 6- (3-tert-butylcarbonylmethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-29)
　ＣＩ－２１のかわりにＣＩ－２３を用い、ＣＩ－２８の合成と同様の方法でＣＩ－２９を得た（収率４８％）。 Using CI-23 instead of CI-21, CI-29 was obtained in a similar manner to the synthesis of CI-28 (yield 48%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.23 (1H, brs), 8.40 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.46 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.25 (1H, s), 7.14 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 7.00 (1H, dd, J = 7.9 Hz, 2.0 Hz), 4.79 (2H, s), 3.92 (3H, s), 3.88 (3H, s), 1.46 (9H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8. 40 ( 1 H, d, J = 2.0 Hz), 8. 10 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.46 (1 H, m), 7. 36 (1 H, d, J = 7.9 Hz), 7. 25 (1 H, s), 7. 14 (2 H, d, J = 8.7 Hz), 7.04 (1 H, s), 7.00 (1 H, dd, J = 7.9 Hz, 2.0 Hz), 4.79 (2 H, s), 3.92 (3 H, s), 3. 88 (3 H, s), 1.46 (9 H, s).
　Methyl 6-(2-tert-butoxycarbonylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate （ＣＩ－３０）の合成 Synthesis of Methyl 6- (2-tert-butylcarbonylmethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-30)
　ＣＩ－２１のかわりにＣＩ－２４を用い、ＣＩ－２８の合成と同様の方法でＣＩ－３０を得た（収率６３％）。 Using CI-24 instead of CI-21, CI-30 was obtained in a similar manner to the synthesis of CI-28 (yield 63%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 8.28 (1H, d, J = 1.6 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.42 (1H, m), 7.39 (1H, t, J = 7.9 Hz), 7.13 (2H, J = 9.1 Hz), 7.14-7.02 (2H, m), 7.02 (1H, s), 4.74 (2H, s), 3.92 (3H, s), 3.87 (3H, s), 1.38 (9H, s). EI-MS (m/z): 559 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 8.28 (1 H, d, J = 1.6 Hz), 8.04 (1 H, d, J = 2.0 Hz), 8.03 (2 H, 2 H, d, J = 8.7 Hz), 7.42 (1 H, m), 7. 39 (1 H, t, J = 7.9 Hz), 7. 13 (2 H, J = 9.1 Hz), 7.14-7.02 (2 H, m), 7.02 (1 H, s), 4.74 (2H, s), 3.92 (3H, s), 3.87 (3H, s), 1.38 (9H, s). EI-MS (m / z): 559 [M] + .
　4-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid（ＣＩ－３１）の合成 Synthesis of 4- [8- (4-Methoxybenzamido) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] phenoxyacetic acid (CI-31)
　ＣＩ－２８(191 mg, 0.341 mmol)に、4 M HClを含むdioxane (6.4 mL, 25.6 mmol)を加え、室温で終夜攪拌した。反応液を濃縮し、ＣＩ－３１(165 mg, 0.328 mmol)を得た （収率９６％）。 Dioxane (6.4 mL, 25.6 mmol) containing 4 M HCl was added to CI-28 (191 mg, 0.341 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated to give CI-31 (165 mg, 0.328 mmol) (yield 96%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.37 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.3 Hz), 8.04 (1H, d, J = 2.0 Hz), 7.72 (2H, d, J = 9.1 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 4.76 (2H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 503 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10. 22 (1 H, brs), 8. 37 (1 H, d, J = 2.4 Hz), 8.05 (2 H, d, J = 8.3 Hz), 8.04 (1 H, 1 H, d, J = 2.0 Hz), 7.72 (2 H, d, J = 9.1 Hz), 7. 14 (2 H, d, J = 8.7 Hz), 7.06 (2 H, d, J = 8.7 Hz), 7.03 (1 H, s) , 4.76 (2H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m / z): 503 [M] + .
　3-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid（ＣＩ－３２）の合成 Synthesis of 3- [8- (4-Methoxybenzamido) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] phenoxyacetic acid (CI-32)
　ＣＩ－２８のかわりにＣＩ－２９を用い、ＣＩ－３１の合成と同様の方法でＣＩ－３２を得た（定量的収率）。 CI-32 was obtained in the same manner as in the synthesis of CI-31, using CI-29 instead of CI-28 (quantitative yield).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.23 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.45 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 7.00 (1H, dd, J = 7.9 Hz, 2.4 Hz), 4.82 (2H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 503 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8. 40 ( 1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7. 45 (1 H, t, J = 7.9 Hz), 7. 35 (1 H, d, J = 8.3 Hz), 7. 28 (1 H, d, J = 2.0 Hz), 7. 14 (2 H, d, J) EI (9.1 H), 7.04 (1 H, s), 7.00 (1 H, dd, J = 7.9 Hz, 2.4 Hz), 4.82 (2 H, s), 3.92 (3 H, s), 3.88 (3 H, s). -MS (m / z): 503 [M] + .
　2-[8-(4-Methoxybenzamido)-2-methoxycarbonyl-4-oxo-4H-chromen-6-yl]phenoxyacetic acid（ＣＩ－３３）の合成 Synthesis of 2- [8- (4-Methoxybenzamido) -2-methoxycarbonyl-4-oxo-4H-chromen-6-yl] phenoxyacetic acid (CI-33)
　ＣＩ－２８のかわりにＣＩ－３０を用い、ＣＩ－３１の合成と同様の方法でＣＩ－３３を得た（定量的収率）。 CI-33 was obtained in the same manner as in the synthesis of CI-31, using CI-30 instead of CI-28 (quantitative yield).
　1H-NMR (400 MHz, DMSO-d6) δ:10.17 (1H, brs), 8.28 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 9.5 Hz), 7.42 (1H, m), 7.39 (1H, t, J = 8.3 Hz), 7.13 (2H, J = 9.1 Hz), 7.14-7.04 (2H, m), 7.02 (1H, s), 4.77 (2H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 503 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 8.28 (1 H, d, J = 2.0 Hz), 8.04 (1 H, d, J = 2.0 Hz), 8.03 (2 H, d, J = 9.5 Hz), 7.42 (1 H, m), 7. 39 (1 H, t, J = 8.3 Hz), 7. 13 (2 H, J = 9.1 Hz), 7.14-7.04 (2 H, m), 7.02 (1 H, s), 4.77 (2H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m / z): 503 [M] + .
　6-(4-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－３４）の合成 Synthesis of 6- (4-Carboxymethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-34)
　ＣＩ－１３のかわりにＣＩ－３１を用い、ＣＩ－１８の合成と同様の方法でＣＩ－３４を得た（収率６４％）。 Using CI-31 instead of CI-13, CI-34 was obtained (yield 64%) in the same manner as in the synthesis of CI-18.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, brs), 8.36 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.71 (2H, d, J = 9.1 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 9.1 Hz), 6.98 (1H, s), 4.76 (2H, s), 3.87 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.18 (1 H, brs), 8.36 (1 H, d, J = 2.4 Hz), 8.04 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.71 (2 H, d, J = 9.1 Hz), 7.12 (2 H, d, J = 8.7 Hz), 7.06 (2 H, d, J = 9.1 Hz), 6.98 (1 H, s) , 4.76 (2H, s), 3.87 (3H, s).
　6-(3-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－３５）の合成 Synthesis of 6- (3-Carboxymethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-35)
　ＣＩ－１３のかわりにＣＩ－３２を用い、ＣＩ－１８の合成と同様の方法でＣＩ－３５を得た(収率７３%)。 Using CI-32 instead of CI-13, CI-35 was obtained in a similar manner to the synthesis of CI-18 (yield 73%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.44 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.27 (1H, s), 7.12 (2H, d, J = 8.3 Hz), 7.00 (1H, m), 6.99 (1H, s), 4.82 (2H, s), 3.87 (3H, s). EI-MS (m/z): 489 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.20 (1 H, brs), 8. 40 ( 1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.44 (1 H, t, J = 7.9 Hz), 7. 35 (1 H, d, J = 8.3 Hz), 7.27 (1 H, s), 7.12 (2 H, d, J = 8.3 Hz) , 7.00 (1H, m), 6.99 (1H, s), 4.82 (2H, s), 3.87 (3H, s). EI-MS (m / z): 489 [M] + .
　6-(2-Carboxylmethoxyphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－３６）の合成 Synthesis of 6- (2-Carboxymethoxyphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-36)
　ＣＩ－１３のかわりにＣＩ－３３を用い、ＣＩ－１８の合成と同様の方法でＣＩ－３６を得た（収率８４％）。 Using CI-33 instead of CI-13, CI-36 was obtained in a similar manner to the synthesis of CI-18 (yield 84%).
　1H-NMR (400 MHz, DMSO-d6) δ:10.15 (1H, brs), 8.28 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.42 (1H, dd, J = 7.9 Hz, 2.0 Hz), 7.38 (1H, m), 7.11 (2H, d, J = 8.7 Hz), 7.11 (1H, m), 7.05 (1H, d, J = 8.7 Hz), 7.02 (1H, s), 4.77 (2H, s), 3.86 (3H, s). EI-MS (m/z): 489 [M]+. 
  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.15 (1 H, brs), 8.28 (1 H, d, J = 2.4 Hz), 8.04 (1 H, d, J = 2.0 Hz), 8.03 (2 H, 2 H, d d, J = 8.7 Hz), 7.42 (1 H, dd, J = 7.9 Hz, 2.0 Hz), 7.38 (1 H, m), 7.11 (2 H, d, J = 8.7 Hz), 7.11 (1 H, m), 7.05 (1H, d, J = 8.7 Hz), 7.02 (1H, s), 4.77 (2H, s), 3.86 (3H, s). EI-MS (m / z): 489 [M] + .
　Methyl 6-[4-(methoxycarbonylmethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－３７） の合成 Synthesis of Methyl 6- [4- (methoxycarbonylmethyl) phenyl] -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-37)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに4-(methoxycarbonylmethyl)phenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－３７を得た（収率２０％）。 Using 4- (methoxycarbonylmethyl) phenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-37 was obtained in the same manner as in the synthesis of CI-7 (yield 20%).
　1H-NMR (400 MHz, DMSO-d6) δ:10.23 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 3.77 (2H, s), 3.64 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8.41 (1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7. 75 (2 H, d, J = 8.7 Hz), 7.43 (2 H, d, J = 8.3 Hz), 7. 14 (2 H, d, J = 9.1 Hz), 7.04 (1 H, s) , 3.92 (3H, s), 3.88 (3H, s), 3.77 (2H, s), 3.64 (3H, s).
　Methyl 6-[3-(methoxycarbonylmethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－３８）の合成 Synthesis of Methyl 6- [3- (methoxycarbonylmethyl) phenyl] -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-38)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-(methoxycarbonylmethyl)phenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－３８を得た（収率４４％）。 Using 3- (methoxycarbonylmethyl) phenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-38 was obtained in the same manner as in the synthesis of CI-7 (yield 44%).
　1H-NMR (400 MHz, DMSO-d6) δ:10.24 (1H, brs), 8.41 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.71 (1H, s), 7.68 (1H, m), 7.49 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.87 (3H, s), 3.82 (2H, s), 3.38 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.24 (1 H, brs), 8.41 (1 H, d, J = 2.0 Hz), 8.11 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7. 71 (1 H, s), 7. 68 (1 H, m), 7. 49 (1 H, t, J = 7.9 Hz), 7. 35 (1 H, d, J = 7.5 Hz), 7. 14 (2 H, d, J = 9.1 Hz), 7.05 (1 H, s), 3.92 (3 H, s), 3. 87 (3 H, s), 3.82 (2 H, s), 3. 38 (3 H, s).
　6-[4-(Carboxymethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－３９）の合成 Synthesis of 6- [4- (Carboxymethyl) phenyl] -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-39)
　ＣＩ－１３のかわりにＣＩ－３７を用い、ＣＩ－１８の合成と同様の方法で得た（収率７５％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-37 instead of CI-13 (yield 75%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.24 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.06 (2H, d, J = 9.2 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 9.2 Hz), 6.98 (1H, s), 3.87 (3H, s), 3.77 (2H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.24 (1 H, brs), 8.41 (1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.8 Hz), 8.06 (2 H, 2 H, d, J = 9.2 Hz), 7.74 (2 H, d, J = 8.4 Hz), 7.43 (2 H, d, J = 8.8 Hz), 7.12 (2 H, d, J = 9.2 Hz), 6. 98 (1 H, s) , 3.87 (3H, s), 3.77 (2H, s).
　6-[3-(Carboxymethyl)phenyl]-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－４０）の合成 Synthesis of 6- [3- (Carboxymethyl) phenyl] -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-40)
　ＣＩ－１３のかわりにＣＩ－３８を用い、ＣＩ－１８の合成と同様の方法でＣＩ－４０を得た（収率７４％）。 Using CI-38 instead of CI-13, CI-40 was obtained in a similar manner to the synthesis of CI-18 (yield 74%).
　1H-NMR (400 MHz, DMSO-d6) δ:10.22 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.69 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.34 (1H, d, J = 7.5 Hz), 7.12 (2H, d, J = 9.1 Hz), 6.98 (1H, s), 3.87 (3H, s), 3.71 (2H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8.41 (1 H, d, J = 2.4 Hz), 8. 10 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.69 (1 H, s), 7. 66 (1 H, d, J = 7.5 Hz), 7. 48 (1 H, t, J = 7.5 Hz), 7.34 (1 H, d, J = 7.5 Hz) , 7.12 (2H, d, J = 9.1 Hz), 6.98 (1 H, s), 3.87 (3 H, s), 3.71 (2 H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４１）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methoxyphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-41)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率５２％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield: 52%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.40 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.45 (1H, m), 7.33 (1H, d, J = 7.9 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.14 (2H, m), 7.04 (1H, s), 7.03 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.86 (3H, s). EI-MS (m/z): 459 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8. 40 ( 1 H, d, J = 2.4 Hz), 8.09 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7. 45 (1 H, m), 7.33 (1 H, d, J = 7.9 Hz), 7. 28 (1 H, d, J = 1.6 Hz), 7. 14 (2 H, m), 7.04 (1 H, s), 7.03 (1 H, m), 3.92 (3 H, s), 3. 88 (3 H, s), 3. 86 (3 H, s). EI-MS (m / z): 459 [M] + .
　Methyl 8-(4-methoxybenzamido)-6-(4-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４２）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (4-methoxyphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-42)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率３２％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 32%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, brs), 8.37 (1H, d, J = 2.0 Hz), 8.04 (2H, d, J = 8.7 Hz), 8.04 (1H, m), 7.72 (2H, d, J = 9.1 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 7.02 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 3.83 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.18 (1 H, brs), 8.37 (1 H, d, J = 2.0 Hz), 8.04 (2 H, d, J = 8.7 Hz), 8.04 (1 H, m), 7.72 (2H, d, J = 9.1 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 7.02 (1H, s), 3.92 (3H, s) s), 3.88 (3H, s), 3.83 (3H, s).
　Methyl 6-(3-cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４３）の合成 Synthesis of Methyl 6- (3-cyanophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-43)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率４６％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 46%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.27 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.31 (1H, s), 8.19 (1H, d, J = 2.0 Hz), 8.14 (1H, m), 8.05 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.73 (1H, t, J = 7.9 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 454 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.27 (1 H, brs), 8. 49 (1 H, d, J = 2.0 Hz), 8.31 (1 H, s), 8. 19 (1 H, d, J = 2.0 Hz), 8.14 (1 H, m), 8.05 (2 H, d, J = 8.7 Hz), 7. 91 (1 H, d, J = 7.5 Hz), 7.73 (1 H, t, J = 7.9 Hz), 7.14 (2 H, d, J = 9.1 Hz), 7.05 (1 H, s), 3.93 (3 H, s), 3. 88 (3 H, s). EI-MS (m / z): 454 [M] + .
　Methyl 6-(4-cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４４）の合成 Synthesis of Methyl 6- (4-cyanophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-44)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率５４％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 54%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.27 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.00 (2H, d, J = 9.1 Hz), 7.98 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.27 (1 H, brs), 8. 49 (1 H, d, J = 2.4 Hz), 8. 17 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 8.00 (2 H, d, J = 9.1 Hz), 7. 98 (2 H, d, J = 8.7 Hz), 7. 15 (2 H, d, J = 9.1 Hz), 7.06 (1 H, s) , 3.93 (3H, s), 3.88 (3H, s).
　Methyl 6-(3-formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４５）の合成 Synthesis of Methyl 6- (3-formylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-45)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率５９％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield: 59%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.26 (1H, brs), 10.14 (1H, s), 8.52 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 8.20 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.06 (2H, d, J = 8.8 Hz), 7.98 (1H, d, J = 7.6 Hz), 7.76 (1H, t, J = 8.0 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.06 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 457 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 10.14 (1 H, s), 8.52 (1 H, d, J = 2.4 Hz), 8.33 (1 H, s), 8.20 ( 1 H, d, J = 2.0 Hz), 8. 15 (1 H, d, J = 8.0 Hz), 8.06 (2 H, d, J = 8.8 Hz), 7. 98 (1 H, d, J = 7.6 Hz), 7. 76 (1 H, t, J = 8.0 Hz), 7.15 (2 H, d, J = 8.4 Hz), 7.06 (1 H, s), 3. 93 (3 H, s), 3. 88 (3 H, s). EI-MS (m / z): 457 [M] + .
　Methyl 6-(4-formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４６）の合成 Synthesis of Methyl 6- (4-formylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-46)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率１６％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 16%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.30 (1H, brs), 10.09 (1H, s), 8.52 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 2.4 Hz), 8.06 (2H, d, J = 8.7 Hz), 8.07-8.05 (4H, m), 7.15 (2H, d, J = 8.7 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.30 (1 H, brs), 10.09 (1 H, s), 8.52 (1 H, d, J = 2.0 Hz), 8.21 (1 H, d, J = 2.4 Hz), 8.06 (2H, d, J = 8.7 Hz), 8.07-8.05 (4H, m), 7.15 (2H, d, J = 8.7 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s).
　Methyl 6-(3-fluorophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４７）の合成 Synthesis of Methyl 6- (3-fluorophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-47)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率２８％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield: 28%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.23 (1H, brs), 8.44 (1H, d, J = 2.0 Hz), 8.13 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.66-7.63 (2H, m), 7.57 (1H, m), 7.29 (1H, m), 7.14 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m/z): 447 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8.44 (1 H, d, J = 2.0 Hz), 8.13 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7.66-7.63 (2 H, m), 7.57 (1 H, m), 7. 29 (1 H, m), 7. 14 (2 H, d, J = 8.7 Hz), 7.05 (1 H, s), 3.92 (3H, s), 3.88 (3H, s). EI-MS (m / z): 447 [M] + .
　Methyl 8-(4-methoxybenzamido)-6-(3-trifluoromethoxyphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４８）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-trifluoromethoxyphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-48)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率６６％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield: 66%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.46 (1H, d, J = 2.0 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.78 (1H, s), 7.67 (1H, t, J = 8.0 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m/z): 513 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8.46 (1 H, d, J = 2.0 Hz), 8.14 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.8 Hz), 7. 85 (1 H, d, J = 8.0 Hz), 7. 78 (1 H, s), 7. 67 (1 H, t, J = 8.0 Hz), 7.46 (1 H, d, J = 8.4 Hz) , 7.14 (2H, d, J = 8.8 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.87 (3H, s). EI-MS (m / z): 513 [M] + .
　Methyl 8-(4-methoxybenzamido)-6-(3-nitrophenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－４９）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-nitrophenyl) -4-oxo-4H-chromene-2-carboxylate (CI-49)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率３％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 3%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.30 (1H, brs), 8.54 (1H, d, J = 2.4 Hz), 8.33-8.28 (3H, m), 8.22 (1H, d, J = 2.8 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.83 (1H, t, J = 7.9 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.30 (1 H, brs), 8.54 (1 H, d, J = 2.4 Hz), 8.33-8.28 (3 H, m), 8.22 (1 H, d, J = 2.8 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.83 (1 H, t, J = 7.9 Hz), 7.15 (2 H, d, J = 9.1 Hz), 7.07 (1 H, s), 3.93 ( 3H, s), 3.88 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(4-nitrophenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５０）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (4-nitrophenyl) -4-oxo-4H-chromene-2-carboxylate (CI-50)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率５％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 5%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.30 (1H, brs), 8.54 (1H, s), 8.36 (2H, d, J = 8.8 Hz), 8.23 (1H, s), 8.10 (2H, d, J = 8.8 Hz), 8.05 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.89 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.30 (1 H, brs), 8.54 (1 H, s), 8. 36 (2 H, d, J = 8.8 Hz), 8.23 (1 H, s), 8.10 (8 2H, d, J = 8.8 Hz, 8.05 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.07 (1 H, s), 3.93 (3 H, s), 3.89 (3 3H, s).
　Methyl 6-(3-acetylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate （ＣＩ－５１）の合成 Synthesis of Methyl 6- (3-acetylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-51)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率１４％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 14%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.27 (1H, brs), 8.48 (1H, d, J = 2.4 Hz), 8.28 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 8.0 Hz), 8.06 (1H, m), 8.06 (2H, d, J = 8.8 Hz), 7.70 (1H, t, J = 8.0 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.06 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.69 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.27 (1 H, brs), 8.48 (1 H, d, J = 2.4 Hz), 8.28 (1 H, d, J = 2.0 Hz), 8.18 (1 H, 1 H, d d, J = 2.4 Hz), 8.07 (1 H, d, J = 8.0 Hz), 8.06 (1 H, m), 8.06 (2 H, d, J = 8.8 Hz), 7.70 (1 H, t, J = 8.0 Hz) , 7.15 (2H, d, J = 8.8 Hz), 7.06 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.69 (3H, s).
　Methyl 6-(3-dimethylaminophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５２）の合成 Synthesis of Methyl 6- (3-dimethylaminophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-52)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率２６％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 26%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.36 (1H, d, J = 2.4 Hz), 8.06 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 8.8 Hz), 8.03 (1H, m), 7.33 (1H, t, J = 8.0 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.03 (1H, s), 7.00 (1H, d, J = 8.8 Hz), 6.81 (1H, d, J = 8.4 Hz), 3.91 (3H, s), 3.88 (3H, s), 2.99 (6H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8.36 (1 H, d, J = 2.4 Hz), 8.06 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d d, J = 8.8 Hz), 8.03 (1 H, m), 7.33 (1 H, t, J = 8.0 Hz), 7. 14 (2 H, d, J = 9.2 Hz), 7.03 (1 H, s), 7.00 (1 H, d, J = 8.8 Hz), 6.81 (1 H, d, J = 8.4 Hz), 3.91 (3 H, s), 3. 88 (3 H, s), 2.99 (6 H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-pyridyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５３）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-pyridinyl) -4-oxo-4H-chromene-2-carboxylate (CI-53)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率６％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 6%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.30 (1H, brs), 8.99 (1H, d, J = 2.0 Hz), 8.65 (1H, dd, J = 5.1 Hz, 1.6 Hz), 8.46 (1H, m), 8.30 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.98 (1H, dd, J = 8.3 Hz, 5.1 Hz), 7.11 (2H, d, J = 9.1 Hz), 7.06 (1H, s), 3.92 (3H, s), 3.88 (3H, s).  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.30 (1 H, brs), 8.99 (1 H, d, J = 2.0 Hz), 8.65 (1 H, dd, J = 5.1 Hz, 1.6 Hz), 8.46 (1H, m), 8.30 (1 H, d, J = 2.4 Hz), 8. 17 (1 H, d, J = 2.4 Hz), 8.05 (2 H, d, J = 9.1 Hz), 7. 98 (1 H, dd, J = 8.3 Hz, 5.1 Hz), 7.11 (2 H, d, J = 9.1 Hz), 7.06 (1 H, s), 3.92 (3 H, s), 3. 88 (3 H, s).
　Methyl 8-(4-methoxybenzamido)-6-(4-pyridyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５４）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (4-pyridinyl) -4-oxo-4H-chromene-2-carboxylate (CI-54)
　4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩ－７の合成と同様の方法で得た（収率１５％）。 The corresponding boronic acid was used instead of 4- (methoxycarbonyl) phenylboronic acid and obtained in the same manner as in the synthesis of CI-7 (yield 15%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.29 (1H, brs), 8.73 (2H, d, J = 4.4 Hz), 8.52 (1H, d, J = 2.4 Hz), 8.25 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.84 (2H, d, J = 4.4 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.29 (1 H, brs), 8. 73 (2 H, d, J = 4.4 Hz), 8.52 (1 H, d, J = 2.4 Hz), 8. 25 (1 H, 1 H, d d, J = 2.4 Hz), 8.05 (2 H, d, J = 9.1 Hz), 7.84 (2 H, d, J = 4.4 Hz), 7. 15 (2 H, d, J = 8.7 Hz), 7.07 (1 H, s) , 3.93 (3H, s), 3.88 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-methylphenyl)-4-oxo-4H-chromene-2-carboxylate （ＣＩ－５５）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-55)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-methylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－５５を得た（収率３４％）。 Using 3-methylphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-55 was obtained in a similar manner to the synthesis of CI-7 (yield: 34%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.23 (1H, brs), 8.41 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 2.8 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.60 (1H, s), 7.56 (1H, d, J = 7.9 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.27 (1H, d, J = 7.5 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.42 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8.41 (1 H, d, J = 2.4 Hz), 8.09 (1 H, d, J = 2.8 Hz), 8.05 (2 H, 2 H, d, J = 8.7 Hz), 7. 60 (1 H, s), 7.56 (1 H, d, J = 7.9 Hz), 7. 49 (1 H, t, J = 7.5 Hz), 7. 27 (1 H, d, J = 7.5 Hz) , 7.14 (2H, d, J = 9.1 Hz), 7.04 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.42 (3H, s).
　Methyl 6-(3-tert-butylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５７）の合成 Synthesis of Methyl 6- (3-tert-butylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-57)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-tert-butylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－５７を得た（収率５９％）。 Using 3-tert-butylphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-57 was obtained in a similar manner to the synthesis of CI-7 (yield: 59%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.21 (1H, brs), 8.39 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.71 (1H, s), 7.56 (1H, d, J = 6.7 Hz), 7.50 (1H, d, J = 6.3 Hz), 7.46 (1H, m), 7.14 (2H, d, J = 8.3 Hz), 7.03 (1H, s), 3.92 (3H, s), 3.87 (3H, s), 1.36 (9H, s). EI-MS (m/z): 485 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.21 (1 H, brs), 8. 39 (1 H, d, J = 2.4 Hz), 8.07 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7.71 (1 H, s), 7.56 (1 H, d, J = 6.7 Hz), 7.50 (1 H, d, J = 6.3 Hz), 7.46 (1 H, m), 7.14 (2 H, d, J = 8.3 Hz), 7.03 (1 H, s), 3.92 (3 H, s), 3. 87 (3 H, s), 1. 36 (9 H, s). EI-MS (m / z): 485 [M] + .
　Methyl 6-(3-carbamoylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５８）の合成 Synthesis of Methyl 6- (3-carbamoylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-58)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-carbamoylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－５８を得た（収率１８％）。 Using 3-carbamoylphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-58 was obtained in the same manner as in the synthesis of CI-7 (yield: 18%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.04 (1H, brs), 8.50 (1H, d, J = 2.4 Hz), 8.26 (1H, s), 8.19 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.7 Hz), 7.92 (1H, d, J = 8.3 Hz), 7.86 (1H, m), 7.60 (1H, t, J = 7.9 Hz), 7.29 (1H, br), 7.13 (2H, d, J = 9.1 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.04 (1 H, brs), 8. 50 (1 H, d, J = 2.4 Hz), 8.26 (1 H, s), 8. 19 (1 H, d, J = 2.4 Hz), 8.04 (2 H, d, J = 8.7 Hz), 7. 92 (1 H, d, J = 8.3 Hz), 7. 86 (1 H, m), 7. 60 (1 H, t, J = 7.9 Hz), 7. 29 (1 H, br), 7.13 (2H, d, J = 9.1 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.88 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-methylthiophenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－５９）の合成
4-(Methoxycarbonyl)phenylboronic acidのかわりに3-methylthiophenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－５９を得た（収率５２％）。 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methylthiophenyl) -4-oxo-4H-chromene-2-carboxylate (CI-59)
Using 3-methylthiophenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-59 was obtained by a method similar to the synthesis of CI-7 (yield: 52%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.00 (1H, brs), 8.44 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 8.7 Hz), 7.58 (1H, s), 7.51 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.01 (1H, s), 3.93 (3H, s), 3.88 (3H, s), 2.56 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.00 (1 H, brs), 8.44 (1 H, d, J = 2.4 Hz), 8.07 (1 H, d, J = 2.4 Hz), 8.03 (2 H, 2 H, d d, J = 8.7 Hz), 7.58 (1 H, s), 7.51 (1 H, d, J = 7.5 Hz), 7.46 (1 H, t, J = 7.5 Hz), 7. 35 (1 H, d, J = 7.5 Hz) , 7.12 (2H, d, J = 8.7 Hz), 7.01 (1H, s), 3.93 (3H, s), 3.88 (3H, s), 2.56 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-methylsulfonylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－６０）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methylsulfonylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-60)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-methylsulfonylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－６０を得た（収率２３％）。 Using 3-methylsulfonylphenylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-60 was obtained in the same manner as in the synthesis of CI-7 (yield 23%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.29 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.29 (1H, t, J = 2.0 Hz), 8.23 (1H, d, J = 2.8 Hz), 8.17 (1H, d, J = 8.3 Hz), 8.06 (2H, d, J = 9.1 Hz), 8.00 (1H, d, J = 7.5 Hz), 7.82 (1H, t, J = 7.5 Hz), 7.15 (2H, d, J = 9.1 Hz), 7.07 (1H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.29 (1 H, brs), 8.51 (1 H, d, J = 2.0 Hz), 8.29 (1 H, t, J = 2.0 Hz), 8.23 (1 H, d, J = 2.8 Hz), 8.17 (1 H, d, J = 8.3 Hz), 8.06 (2 H, d, J = 9.1 Hz), 8.00 (1 H, d, J = 7.5 Hz), 7.82 (1 H, t, J = 7.5 Hz), 7.15 (2 H, d, J = 9.1 Hz), 7.07 (1 H, s), 3.93 (3 H, s), 3. 88 (3 H, s).
　8-(4-Methoxybenzamido)-6-(3-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６１）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (3-methoxyphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-61)
　ＣＩ－１３のかわりにＣＩ－４１を用い、ＣＩ－１８の合成と同様の方法で得た（収率９１％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-41 instead of CI-13 (yield 91%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.18 (1H, brs), 8.40 (1H, d, J = 2.0 Hz), 8.09 (1H, d, J = 2.0 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.45 (1H, t, J = 8.3 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.27 (1H, t, J = 2.0 Hz), 7.12 (2H, m), 7.02 (1H, dd, J = 8.3 Hz, 1.6 Hz), 6.99 (1H, s), 3.87 (3H, s), 3.86 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ: 177.47, 164.96, 162.28, 161.21, 159.92, 152.94, 148.87, 139.76, 137.33, 130.35, 129.72, 129.21, 129.05, 125.96, 124.50, 119.23, 118.52, 114.06, 113.83, 113.38, 112.18, 55.50, 55.27. EI-MS (m/z): 445 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.18 (1 H, brs), 8. 40 ( 1 H, d, J = 2.0 Hz), 8.09 (1 H, d, J = 2.0 Hz), 8.05 (2 H, 2 H, d, J = 9.1 Hz), 7.45 (1 H, t, J = 8.3 Hz), 7.32 (1 H, d, J = 7.9 Hz), 7.27 (1 H, t, J = 2.0 Hz), 7.12 (2 H, m) , 7.02 (1H, dd, J = 8.3 Hz, 1.6 Hz), 6.99 (1 H, s), 3.87 (3 H, s), 3.86 (3 H, s). 13 C-NMR (100 MHz, DMSO-d 6 ) δ: 177.47, 164.96, 162.28, 161.21, 159.92, 152.94, 148.76, 137.33, 130.35, 129.72, 129.92, 129.05, 125.50, 124.23, 118.52, 114.06, 113.83, 113.38, 112.18, 55.50, 55.27. MS (m / z): 445 [M] + .
　8-(4-Methoxybenzamido)-6-(4-methoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６２）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (4-methoxyphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-62)
　ＣＩ－１３のかわりにＣＩ－４２を用い、ＣＩ－１８の合成と同様の方法で得た（収率７５％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-42 instead of CI-13 (yield 75%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.16 (1H, brs), 8.37 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.04 (1H, d, J = 2.8 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.08 (2H, d, J = 8.3 Hz), 6.97 (1H, s), 3.87 (3H, s), 3.83 (3H, s). EI-MS (m/z): 445 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.16 (1 H, brs), 8.37 (1 H, d, J = 2.4 Hz), 8.04 (2 H, d, J = 8.3 Hz), 8.04 (1 H, 1 H, d d, J = 2.8 Hz), 7.72 (2 H, d, J = 8.7 Hz), 7.12 (2 H, d, J = 9.1 Hz), 7.08 (2 H, d, J = 8.3 Hz), 6. 97 (1 H, s) , 3.87 (3H, s), 3.83 (3H, s). EI-MS (m / z): 445 [M] + .
　6-(3-Cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６３）の合成 Synthesis of 6- (3-Cyanophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-63)
　ＣＩ－１３のかわりにＣＩ－４３を用い、ＣＩ－１８の合成と同様の方法で得た（収率８９％）。 It obtained by the method similar to the synthesis | combination of CI-18 using CI-43 instead of CI-13 (yield 89%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.31 (1H, s), 8.19 (1H, d, J = 2.0 Hz), 8.14 (1H, m), 8.06 (2H, d, J = 9.1 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.73 (1H, t, J = 7.9 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 440 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 8. 49 (1 H, d, J = 2.4 Hz), 8.31 (1 H, s), 8. 19 (1 H, d, J = 2.0 Hz), 8.14 (1 H, m), 8.06 (2 H, d, J = 9.1 Hz), 7. 91 (1 H, d, J = 7.5 Hz), 7.73 (1 H, t, J = 7.9 Hz), 7.12 (2 H, 2 H, d, J = 8.7 Hz), 7.00 (1 H, s), 3. 87 (3 H, s). EI-MS (m / z): 440 [M] + .
　6-(4-Cyanophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６４）の合成 Synthesis of 6- (4-Cyanophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-64)
　ＣＩ－１３のかわりにＣＩ－４４を用い、ＣＩ－１８の合成と同様の方法で得た（収率８７％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-44 instead of CI-13 (yield 87%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.26 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 8.01 (2H, d, J = 9.1 Hz), 7.98 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 9.1 Hz), 6.99 (1H, s), 3.87 (3H, s). EI-MS (m/z): 440 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 8. 49 (1 H, d, J = 2.0 Hz), 8.18 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 8.01 (2 H, d, J = 9.1 Hz), 7. 98 (2 H, d, J = 8.7 Hz), 7.12 (2 H, d, J = 9.1 Hz), 6.99 (1 H, s) , 3.87 (3H, s). EI-MS (m / z): 440 [M] + .
　6-(3-Formylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６５）の合成 Synthesis of 6- (3-Formylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-65)
　ＣＩ－１３のかわりにＣＩ－４５を用い、ＣＩ－１８の合成と同様の方法で得た（収率７３％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-45 instead of CI-13 (yield 73%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.26 (1H, brs), 10.14 (1H, s), 8.51 (1H, d, J = 2.0 Hz), 8.33 (1H, s), 8.20 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 7.6 Hz), 8.06 (2H, d, J = 9.2 Hz), 7.96 (1H, d, J = 7.6 Hz), 7.76 (1H, t, J = 7.6 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.01 (1H, s), 3.87 (3H, s). EI-MS (m/z): 443 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 10.14 (1 H, s), 8.51 (1 H, d, J = 2.0 Hz), 8.33 (1 H, s), 8.20 (8 1 H, d, J = 2.0 Hz), 8. 15 (1 H, d, J = 7.6 Hz), 8.06 (2 H, d, J = 9.2 Hz), 7. 96 (1 H, d, J = 7.6 Hz), 7. 76 (1 H, 1 H, d t, J = 7.6 Hz), 7.12 (2 H, d, J = 8.8 Hz), 7.01 (1 H, s), 3.87 (3 H, s). EI-MS (m / z): 443 [M] + .
　6-(3-Fluorophenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６７）の合成 Synthesis of 6- (3-Fluorophenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-67)
　ＣＩ－１３のかわりにＣＩ－４７を用い、ＣＩ－１８の合成と同様の方法で得た（収率７２％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-47 instead of CI-13 (yield 72%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.23 (1H, brs), 8.43 (1H, d, J = 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.66-7.55 (3H, m), 7.28 (1H, m), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 433 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.23 (1 H, brs), 8.43 (1 H, d, J = 2.4 Hz), 8.13 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.7 Hz), 7.66-7.55 (3 H, m), 7. 28 (1 H, m), 7.12 (2 H, d, J = 8.7 Hz), 7.00 (1 H, s), 3. 87 (3 H, s). EI-MS (m / z): 433 [M] + .
　8-(4-Methoxybenzamido)-6-(3-trifluoromethoxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－６８）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (3-trifluoromethoxyphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-68)
　ＣＩ－１３のかわりにＣＩ－４８を用い、ＣＩ－１８の合成と同様の方法で得た（収率７０％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-48 instead of CI-13 (yield 70%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.24 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.8 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.67 (1H, t, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 499 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.24 (1 H, brs), 8.45 (1 H, d, J = 2.4 Hz), 8.14 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 8.8 Hz), 7.84 (1 H, d, J = 8.4 Hz), 7. 78 (1 H, s), 7. 67 (1 H, t, J = 8.4 Hz), 7.46 (1 H, d, J = 8.4 Hz) , 7.12 (2H, d, J = 8.8 Hz), 7.00 (1 H, s), 3.87 (3 H, s). EI-MS (m / z): 499 [M] + .
　8-(4-Methoxybenzamido)-6-(4-nitrophenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－７０）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (4-nitrophenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-70)
　ＣＩ－１３のかわりにＣＩ－５０を用い、ＣＩ－１８の合成と同様の方法で得た（収率５１％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-50 instead of CI-13 (yield 51%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.27 (1H, brs), 8.54 (1H, d, J = 2.4 Hz), 8.36 (2H, d, J = 8.3 Hz), 8.22 (1H, m), 8.09 (2H, d, J = 8.7 Hz), 8.06 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.27 (1 H, brs), 8.54 (1 H, d, J = 2.4 Hz), 8.36 (2 H, d, J = 8.3 Hz), 8.22 (1 H, m), 8.09 (2H, d, J = 8.7 Hz), 8.06 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, 3H, s) s).
　6-(3-Acetylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－７１）の合成 Synthesis of 6- (3-Acetylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-71)
　ＣＩ－１３のかわりにＣＩ－５１を用い、ＣＩ－１８の合成と同様の方法で得た（収率７６％）。 It obtained by the method similar to the synthesis | combination of CI-18, using CI-51 instead of CI-13 (yield 76%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, brs), 8.49 (1H, d, J = 2.0 Hz), 8.25 (1H, s), 8.09 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 9.1 Hz), 8.02 (1H, d, J = 7.5 Hz), 8.01 (1H, d, J = 7.5 Hz), 7.70 (1H, t, J = 7.9 Hz), 7.11 (2H, d, J = 8.7 Hz), 6.78 (1H, s), 3.87 (3H, s), 2.68 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.17 (1 H, brs), 8. 49 (1 H, d, J = 2.0 Hz), 8. 25 (1 H, s), 8.09 (1 H, d, J = 2.4 Hz), 8.07 (2H, d, J = 9.1 Hz), 8.02 (1 H, d, J = 7.5 Hz), 8.01 (1 H, d, J = 7.5 Hz), 7.70 (1 H, t, J = 7.9 Hz) , 7.11 (2H, d, J = 8.7 Hz), 6.78 (1H, s), 3.87 (3H, s), 2.68 (3H, s).
　8-(4-Methoxybenzamido)-6-(4-pyridyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－７４）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (4-pyridyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-74)
　ＣＩ－１３のかわりにＣＩ－５４を用い、ＣＩ－１８の合成と同様の方法で得た（収率３９％）。 It obtained by the method similar to the synthesis | combination of CI-18 using CI-54 instead of CI-13 (yield 39%).
　1H-NMR (400 MHz, DMSO-d6)δ: 10.30 (1H, brs), 9.07 (2H, d, J = 6.8 Hz), 8.66 (1H, d, J = 2.8 Hz), 8.54 (2H, d, J = 6.8 Hz), 8.28 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.07 (1H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.30 (1 H, brs), 9.07 (2 H, d, J = 6.8 Hz), 8.66 (1 H, d, J = 2.8 Hz), 8.54 (2 H, 2 H, d d, J = 6.8 Hz), 8. 28 (1 H, d, J = 2.4 Hz), 8.07 (2 H, d, J = 8.8 Hz), 7. 14 (2 H, d, J = 9.2 Hz), 7.07 (1 H, s) , 3.88 (3H, s).
　6-(3-tert-Butylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－７７）の合成 Synthesis of 6- (3-tert-Butylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-77)
　ＣＩ－１３のかわりにＣＩ－５７を用い、ＣＩ－１８の合成と同様の方法でＣＩ－７７を得た（収率８１％）。 Using CI-57 instead of CI-13, CI-77 was obtained in the same manner as in the synthesis of CI-18 (yield 81%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.40 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.08 (2H, d, J = 8.7 Hz), 7.98 (1H, d, J = 2.4 Hz), 7.68 (1H, s), 7.52 (1H, d, J = 6.3 Hz), 7.47 (1H, t, J = 6.7 Hz), 7.46 (1H, m), 7.09 (2H, d, J = 9.1 Hz), 6.73 (1H, s), 3.87 (3H, s), 1.37 (9H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.40 (1 H, brs), 8. 45 (1 H, d, J = 2.4 Hz), 8.08 (2 H, d, J = 8.7 Hz), 7.98 (1 H, 1 H, d, J = 2.4 Hz), 7. 68 (1 H, s), 7.52 (1 H, d, J = 6.3 Hz), 7. 47 (1 H, t, J = 6.7 Hz), 7.46 (1 H, m), 7.09 (2 H, d, J = 9.1 Hz), 6.73 (1 H, s), 3. 87 (3 H, s), 1. 37 (9 H, s).
　8-(4-Methoxybenzamido)-6-(3-methylsulfonylphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－８０）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (3-methylsulfonylphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-80)
　ＣＩ－１３のかわりにＣＩ－６０を用い、ＣＩ－１８の合成と同様の方法でＣＩ－８０を得た（収率８９％）。 Using CI-60 instead of CI-13, CI-80 was obtained in a similar manner to the synthesis of CI-18 (yield 89%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.29 (1H, brs), 8.51 (1H, d, J = 2.4 Hz), 8.28 (1H, s), 8.22 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 7.9 Hz), 8.06 (2H, d, J = 9.1 Hz), 7.99 (1H, d, J = 8.3 Hz), 7.81 (1H, t, J = 7.9 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.00 (1H, s), 3.87 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.29 (1 H, brs), 8.51 (1 H, d, J = 2.4 Hz), 8.28 (1 H, s), 8.22 (1 H, d, J = 2.4 Hz), 8.17 (1 H, d, J = 7.9 Hz), 8.06 (2 H, d, J = 9.1 Hz), 7.99 (1 H, d, J = 8.3 Hz), 7.81 (1 H, t, J = 7.9 Hz) , 7.12 (2H, d, J = 9.1 Hz), 7.00 (1 H, s), 3.87 (3 H, s).
　Methyl 6-(3-furyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８２）の合成 Synthesis of Methyl 6- (3-furyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-82)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-furylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－８２を得た（収率２４％）。 Using 3-furylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-82 was obtained in the same manner as in the synthesis of CI-7 (yield: 24%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.21 (1H, brs), 8.41 (1H, s), 8.30 (1H, d, J = 2.4 Hz), 8.08 (1H, d, J = 2.4 Hz), 8.04 (2H, dd, J = 9.1 Hz, 2.4 Hz), 7.81 (1H, m), 7.13 (1H, d, J = 2.0 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.01 (1H, s), 3.90 (3H, s), 3.87 (3H, d, J = 2.0 Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.21 (1 H, brs), 8.41 (1 H, s), 8.30 (1 H, d, J = 2.4 Hz), 8.08 (1 H, d, J = 2.4 Hz), 8.04 (2H, dd, J = 9.1 Hz, 2.4 Hz), 7.81 (1 H, m), 7.13 (1 H, d, J = 2.0 Hz), 7.13 (2 H, d, J = 8.7 Hz), 7.01 (1H, s), 3.90 (3H, s), 3.87 (3H, d, J = 2.0 Hz).
　Methyl 6-(5-acetyl-2-thienyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８３）の合成 Synthesis of Methyl 6- (5-acetyl-2-thienyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-83)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに5-acetyl-2-thienylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－８３を得た（収率３６％）。 Using 5-acetyl-2-thienylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-83 was obtained in a similar manner to the synthesis of CI-7 (yield: 36%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.02 (1H, brs), 8.53 (1H, d, J = 2.0 Hz), 8.13 (1H, d, J = 2.0 Hz), 8.03 (2H, d, J = 8.3 Hz), 7.95 (1H, d, J = 4.4 Hz), 7.76 (1H, d, J = 4.0 Hz), 7.13 (2H, m), 7.02 (1H, s), 3.93 (3H, s), 3.88 (3H, s), 2.56 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.02 (1 H, brs), 8.53 (1 H, d, J = 2.0 Hz), 8.13 (1 H, d, J = 2.0 Hz), 8.03 (2 H, 2 H, d d, J = 8.3 Hz), 7. 95 (1 H, d, J = 4.4 Hz), 7. 76 (1 H, d, J = 4.0 Hz), 7. 13 (2 H, m), 7.02 (1 H, s), 3. 93 (3 H, s), 3.88 (3H, s), 2.56 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(2-methoxy-4-pyridyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８５）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (2-methoxy-4-pyridinyl) -4-oxo-4H-chromene-2-carboxylate (CI-85)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-methoxy-4-pyridylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－８５を得た（収率３４％）。 CI-85 was obtained in the same manner as in the synthesis of CI-7, using 2-methoxy-4-pyridylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid (yield 34%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.06 (1H, brs), 8.50 (1H, d, J = 2.0 Hz), 8.29 (1H, d, J = 5.5 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.03 (2H, d, J = 9.1 Hz), 7.37 (1H, dd, J = 5.5 Hz, 1.6 Hz), 7.14 (1H, s), 7.13 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.06 (1 H, brs), 8. 50 (1 H, d, J = 2.0 Hz), 8. 29 (1 H, d, J = 5.5 Hz), 8. 17 (1 H, 1 H, d d, J = 2.4 Hz), 8.03 (2 H, d, J = 9.1 Hz), 7. 37 (1 H, dd, J = 5.5 Hz, 1.6 Hz), 7.14 (1 H, s), 7.13 (2 H, d, J = 8.7 Hz), 7.03 (1 H, s), 3.93 (3 H, s), 3. 93 (3 H, s), 3. 88 (3 H, s).
　Methyl 8-(4-methoxybenzamido)-6-(2-methylthio-5-pyridyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８７）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (2-methylthio-5-pyridine) -4-oxo-4H-chromene-2-carboxylate (CI-87)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-methylthio-5-pyridylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－８７を得た（収率３０％）。 CI-87 was obtained (yield 30%) in the same manner as in the synthesis of CI-7, using 2-methylthio-5-pyridineboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.26 (1H, brs), 8.85 (1H, d, J = 2.0 Hz), 8.42 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.08 (1H, dd, J = 8.4 Hz, 2.4 Hz), 8.05 (2H, d, J = 9.2 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.14 (2H, d, J = 9.2 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.88 (3H, s), 2.58 (3H, s).  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.26 (1 H, brs), 8. 85 (1 H, d, J = 2.0 Hz), 8.42 (1 H, d, J = 2.4 Hz), 8.14 (1 H, 1 H, d d, J = 2.4 Hz), 8.08 (1 H, dd, J = 8.4 Hz, 2.4 Hz), 8.05 (2 H, d, J = 9.2 Hz), 7.44 (1 H, d, J = 8.4 Hz), 7.14 (2 H) , d, J = 9.2 Hz), 7.05 (1 H, s), 3.92 (3 H, s), 3. 88 (3 H, s), 2.58 (3 H, s).
　Methyl 6-(2-amino-5-pyridyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８８）の合成 Synthesis of Methyl 6- (2-amino-5-pyridine) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-88)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに2-amino-5-pyridylboronic acid pinacol esterを用い、ＣＩ－７の合成と同様の方法でＣＩ－８８を得た（収率７％）。 CI-88 was obtained (yield 7%) in the same manner as in the synthesis of CI-7, using 2-amino-5-pyridylboronic acid pinacol ester instead of 4- (Methoxycarbonyl) phenylboronic acid.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.24 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.85-7.75 (2H, m), 7.71-7.50 (3H, m), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.92 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.24 (1 H, brs), 8. 45 (1 H, d, J = 2.4 Hz), 8.12 (1 H, d, J = 2.4 Hz), 8.05 (2 H, 2 H, d d, J = 9.1 Hz), 7.85-7.75 (2H, m), 7.71-7.50 (3H, m), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, s), 3.92 (3H, s) ), 3.88 (3H, s).
　Methyl 8-(4-methoxybenzamido)-6-(3-trifluoromethylphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－８９）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-trifluoromethylphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-89)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-trifluoromethylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－８９を得た（収率４８％）。 Using 3-trifluoromethylboronic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-89 was obtained by a method similar to the synthesis of CI-7 (yield: 48%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.06 (1H, brs), 8.51 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 7.1 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.04 (1H, s), 7.81 (1H, m), 7.77 (1H, t, J = 7.5 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 3.93 (3H, s), 3.88 (3H, s). EI-MS (m/z): 497 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.06 (1 H, brs), 8.51 (1 H, d, J = 2.0 Hz), 8.15 (1 H, d, J = 2.4 Hz), 8.09 (1 H, d, J = 7.1 Hz), 8.04 (2 H, d, J = 8.3 Hz), 8.04 (1 H, s), 7.81 (1 H, m), 7. 77 (1 H, t, J = 7.5 Hz), 7. 13 (2 H, 7 d, J = 8.7 Hz), 7.03 (1 H, s), 3. 93 (3 H, s), 3. 88 (3 H, s). EI-MS (m / z): 497 [M] + .
　Methyl 6-(3-hydroxymethylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－９１）の合成 Synthesis of Methyl 6- (3-hydroxymethylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-91)
　4-(Methoxycarbonyl)phenylboronic acidのかわりに3-hydroxymethylphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－９１を得た（収率３７％）。 Using 3-hydroxymethylphenylonic acid instead of 4- (Methoxycarbonyl) phenylboronic acid, CI-91 was obtained in the same manner as in the synthesis of CI-7 (yield: 37%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.22 (1H, brs), 8.43 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 1.6 Hz), 8.05 (2H, d, J = 9.1 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 7.9 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.39 (1H, d, J = 7.1 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 5.31 (1H, brm), 4.61 (2H, d, J = 5.9 Hz), 3.93 (3H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.22 (1 H, brs), 8.43 (1 H, d, J = 2.0 Hz), 8.11 (1 H, d, J = 1.6 Hz), 8.05 (2 H, 2 H, d, J = 9.1 Hz), 7.73 (1 H, s), 7. 64 (1 H, d, J = 7.9 Hz), 7. 49 (1 H, t, J = 7.5 Hz), 7. 39 (1 H, d, J = 7.1 Hz) , 7.14 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 5.31 (1H, brm), 4.61 (2H, d, J = 5.9 Hz), 3.93 (3H, s), 3.88 (3H, s).
　Methyl 8-(4-chlorobenzamido)-6-(3-hydroxyphenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－９６）の合成 Synthesis of Methyl 8- (4-chlorobenzamido) -6- (3-hydroxyphenyl) -4-oxo-4H-chromene-2-carboxylate (CI-96)
（１）4-Methoxybenzoyl chlorideのかわりに4-chlorobenzoyl chlorideを用い、ＣＩ－２の合成（１）と同様の方法でmethyl 6-bromo-8-(4-chlorobenzamido)-4-oxo-4H-chromene-2-carboxylateを得た（定量的収率）。 (1) Using 4-chlorobenzoyl chloride instead of 4-Methoxybenzoyl chloride, and in the same manner as in synthesis (1) of CI-2, methyl 6-bromo-8- (4-chlorobenzamido) -4-oxo-4H-chromene -2-carboxylate was obtained (quantitative yield).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.53 (1H, brs), 8.28 (1H, d, J = 2.4 Hz), 8.04 (2H, d, J = 8.3 Hz), 8.01 (1H, d, J = 2.4 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.05 (1H, s), 3.91 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.53 (1 H, brs), 8.28 (1 H, d, J = 2.4 Hz), 8.04 (2 H, d, J = 8.3 Hz), 8.01 (1 H, 1 H, d d, J = 2.4 Hz), 7.70 (2 H, d, J = 8.7 Hz), 7.05 (1 H, s), 3.91 (3 H, s).
（２）Methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateのかわりにmethyl 6-bromo-8-(4-chlorobenzamido)-4-oxo-4H-chromene-2-carboxylateを用い、4-(methoxycarbonyl)phenylboronic acidのかわりに3-hydroxyphenylboronic acidを用い、ＣＩ－７の合成と同様の方法でＣＩ－９６を得た（収率１７％）。 (2) Methyl 6-bromo-8- (4-chlorobenzamido) -4-oxo-4H-chromene instead of methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate CI-96 was obtained in the same manner as in the synthesis of CI-7 (yield: 17%) using -2-carboxylate, using 3-hydroxyphenylboronic acid instead of 4- (methoxycarbonyl) phenylboronic acid.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.52 (1H, brs), 9.68 (1H, brs), 8.32 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.7 Hz), 8.07 (1H, m), 7.70 (2H, d, J = 8.3 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.04 (1H, s), 6.85 (1H, dd, J = 8.3 Hz, 2.0 Hz), 3.94 (3H, s). 1 H-NMR (400 MHz, DMSO-d6) δ: 10.52 (1 H, brs), 9.68 (1 H, brs), 8.32 (1 H, d, J = 2.4 Hz), 8.07 (2 H, d, J = 8.7 Hz ), 8.07 (1H, m), 7.70 (2H, d, J = 8.3 Hz), 7.33 (1 H, t, J = 7.9 Hz), 7.18 (1 H, d, J = 8.3 Hz), 7.13 (1 H, t) , J = 2.0 Hz), 7.04 (1 H, s), 6. 85 (1 H, dd, J = 8.3 Hz, 2.0 Hz), 3.94 (3 H, s).
　Methyl 8-(4-chlorobenzamido)-6-(3-cyanophenyl)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－９８）の合成 Synthesis of Methyl 8- (4-chlorobenzamido) -6- (3-cyanophenyl) -4-oxo-4H-chromene-2-carboxylate (CI-98)
　3-Hydroxyphenylboronic acidのかわりに3-cyanophenylboronic acidを用い、ＣＩ－９６の合成と同様の方法でＣＩ－９８を得た（収率３０％）。 Using 3-cyanophenylboronic acid instead of 3-hydroxyphenylboronic acid, CI-98 was obtained in a similar manner to the synthesis of CI-96 (yield 30%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.58 (1H, brs), 8.45 (1H, d, J = 2.4 Hz), 8.32 (1H, t, J = 1.6 Hz), 8.24 (1H, d, J = 2.4 Hz), 8.15 (1H, dt, J = 8.7 Hz, 1.2 Hz), 8.08 (2H, d, J = 8.3 Hz), 7.91 (1H, dt, J = 7.9 Hz, 1.6 Hz), 7.73 (1H, m), 7.71 (2H, d, J = 8.3 Hz), 7.06 (1H, s), 3.92 (3H, s). 1 H-NMR (400 MHz, DMSO-d6) δ: 10.58 (1 H, brs), 8. 45 (1 H, d, J = 2.4 Hz), 8.32 (1 H, t, J = 1.6 Hz), 8.24 (1 H, d , J = 2.4 Hz), 8.15 (1 H, dt, J = 8.7 Hz, 1.2 Hz), 8.08 (2 H, d, J = 8.3 Hz), 7.91 (1 H, dt, J = 7.9 Hz, 1.6 Hz), 7.73 (1H, m), 7.71 (2H, d, J = 8.3 Hz), 7.06 (1 H, s), 3.92 (3 H, s).
　6-(3-Furyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylate（ＣＩ－１０５）の合成 Synthesis of 6- (3-Furyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate (CI-105)
　ＣＩ－１３のかわりにＣＩ－８２を用い、ＣＩ－１８の合成と同様の方法でＣＩ－１０５を得た（収率９４％）。 Using CI-82 instead of CI-13, CI-105 was obtained in a similar manner to the synthesis of CI-18 (yield: 94%).
　1H-NMR (400 MHz, DMSO-d6) 10.19 (1H, brs), 8.40 (1H, s), 8.29 (1H, d, J = 2.4 Hz), 8.08 (1H, m), 8.05 (2H, d, J = 9.1 Hz), 7.81 (1H, d, J = 2.0 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.11 (1H, m), 6.96 (1H, s), 3.87 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) 10.19 (1 H, brs), 8. 40 ( 1 H, s), 8. 29 (1 H, d, J = 2.4 Hz), 8.08 (1 H, m), 8.05 (2 H, d, J = 9.1 Hz), 7.81 (1 H, d, J = 2.0 Hz), 7.11 (2 H, d, J = 8.7 Hz), 7.11 (1 H, m), 6.96 (1 H, s), 3. 87 (3 H, s) s).
　8-(4-Methoxybenzamido)-6-(3-trifluoromethylphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１１２）の合成 Synthesis of 8- (4-Methoxybenzamido) -6- (3-trifluoromethylphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-112)
　ＣＩ－１３のかわりにＣＩ－８９を用い、ＣＩ－１８の合成と同様の方法でＣＩ－１１２を得た（収率９１％）。 Using CI-89 instead of CI-13, CI-112 was obtained (yield 91%) in the same manner as in the synthesis of CI-18.
　1H-NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, brs), 8.49 (1H, d, J = 2.4 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 7.1 Hz), 8.09 (1H, s), 8.06 (2H, d, J = 9.1 Hz), 7.82 (1H, d, J = 7.9 Hz), 7.77 (1H, t, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.00 (1H, s), 3.87 (3H, s). EI-MS (m/z): 483 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.25 (1 H, brs), 8. 49 (1 H, d, J = 2.4 Hz), 8. 18 (1 H, d, J = 2.4 Hz), 8.12 (1 H, 1 H, d d, J = 7.1 Hz), 8.09 (1 H, s), 8.06 (2 H, d, J = 9.1 Hz), 7.82 (1 H, d, J = 7.9 Hz), 7.77 (1 H, t, J = 7.5 Hz) , 7.12 (2H, d, J = 8.7 Hz), 7.00 (1 H, s), 3.87 (3 H, s). EI-MS (m / z): 483 [M] + .
　6-(3-Hydroxymethylphenyl)-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１１４）の合成 Synthesis of 6- (3-Hydroxymethylphenyl) -8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylic acid (CI-114)
　ＣＩ－１３のかわりにＣＩ－９１を用い、ＣＩ－１８の合成と同様の方法でＣＩ－１１４を得た（収率８９％）。 Using CI-91 instead of CI-13, CI-114 was obtained in a similar manner to the synthesis of CI-18 (yield 89%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, brs), 8.42 (1H, m), 8.11 (1H, d, J = 2.4 Hz), 8.05 (2H, d, J = 8.7 Hz), 7.73 (1H, s), 7.64 (1H, d, J = 7.5 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.38 (1H, d, J = 7.1 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.99 (1H, s), 5.29 (1H, br), 4.61 (2H, s), 3.87 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.20 (1 H, brs), 8.42 (1 H, m), 8.11 (1 H, d, J = 2.4 Hz), 8.05 (2 H, d, J = 8.7 Hz), 7.73 (1 H, s), 7. 64 (1 H, d, J = 7.5 Hz), 7. 48 (1 H, t, J = 7.5 Hz), 7. 38 (1 H, d, J = 7.1 Hz), 7.12 (2 H, 2 H, d, J = 8.7 Hz), 6.99 (1 H, s), 5. 29 (1 H, br), 4.61 (2 H, s), 3. 87 (3 H, s).
　8-(4-Chlorobenzamido)-6-(3-hydroxyphenyl)-4-oxo-4H-chromene-2-carboxylic acid（ＣＩ－１１９）の合成 Synthesis of 8- (4-Chlorobenzamido) -6- (3-hydroxyphenyl) -4-oxo-4H-chromene-2-carboxylic acid (CI-119)
　ＣＩ－１３のかわりにＣＩ－９６を用い、ＣＩ－１８の合成と同様の方法でＣＩ－１１９を得た（収率７５％）。 Using CI-96 instead of CI-13, CI-119 was obtained in a similar manner to the synthesis of CI-18 (yield 75%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.48 (1H, brs), 9.65 (1H, brs), 8.31 (1H, d, J = 2.4 Hz), 8.07 (2H, d, J = 8.7 Hz), 8.05 (1H, m), 7.67 (2H, d, J = 8.3 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.17 (1H, d, J = 7.9 Hz), 7.12 (1H, t, J = 2.0 Hz), 6.98 (1H, s), 6.84 (1H, dd, J = 7.5 Hz, J = 1.6 Hz). 1 H-NMR (400 MHz, DMSO-d6) δ: 10.48 (1 H, brs), 9.65 (1 H, brs), 8.31 (1 H, d, J = 2.4 Hz), 8.07 (2 H, d, J = 8.7 Hz ), 8.05 (1H, m), 7.67 (2H, d, J = 8.3 Hz), 7.32 (1 H, t, J = 7.9 Hz), 7.17 (1 H, d, J = 7.9 Hz), 7.12 (1 H, t) , J = 2.0 Hz), 6.98 (1 H, s), 6. 84 (1 H, dd, J = 7.5 Hz, J = 1.6 Hz).
　Methyl 8-(4-methoxybenzamido)-6-(4-methoxycarbonylphenyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate（ＣＩＩ－１）の合成 Synthesis of Methyl 8- (4-methoxybenzamido) -6- (4-methoxycarbonylphenyl) -4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-1)
（１）市販の5-bromo-2-nitroaniline（4.84 g, 22.3 mmol）のpyridine（30.0 mL）溶液に、4-methoxybenzoylchloride（3.62 mL, 26.8 mmol）をゆっくり滴下し、室温で40時間攪拌した。析出した結晶を濾取、メタノール洗浄、減圧乾燥し、N-(4-bromo-2-nitrophenyl)-4-methoxybenzamideを得た。また濾液を濃縮し、クロロホルム / メタノール = 1 / 1の混合溶媒で洗浄、減圧乾燥し、合わせてN-(4-bromo-2-nitrophenyl)-4-methoxybenzamide（7.65 g, 21.8 mmol）を得た（収率９８％）。 (1) To a solution of commercially available 5-bromo-2-nitroaniline (4.84 g, 22.3 mmol) in pyridine (30.0 mL), 4-methoxybenzoyl chloride (3.62 mL, 26.8 mmol) was slowly added dropwise and stirred at room temperature for 40 hours. The precipitated crystals were collected by filtration, washed with methanol and dried under reduced pressure to obtain N- (4-bromo-2-nitrophenyl) -4-methoxybenzamide. The filtrate was concentrated, washed with a mixed solvent of chloroform / methanol = 1/1, dried under reduced pressure, and combined to obtain N- (4-bromo-2-nitrophenyl) -4-methoxybenzamide (7.65 g, 21.8 mmol). (98% yield).
　1H-NMR (400 MHz, CDCl3) δ: 11.36 (1H, brs), 9.31 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 9.1 Hz), 7.96 (2H, d, J = 9.1 Hz), 7.33 (1H, dd, J = 9.1 Hz, 2.4 Hz), 7.03 (2H, d, J = 9.1 Hz), 3.90 (3H, s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.36 (1 H, brs), 9.31 (1 H, d, J = 2.4 Hz), 8. 14 (1 H, d, J = 9.1 Hz), 7. 96 (2 H, d, J) J = 9.1 Hz), 7.33 (1 H, dd, J = 9.1 Hz, 2.4 Hz), 7.03 (2 H, d, J = 9.1 Hz), 3.90 (3 H, s).
（２）上記で得られたN-(4-bromo-2-nitrophenyl)-4-methoxybenzamide（3.70 g, 10.5 mmol）のEtOH（50 mL）、THF（50 mL）およびH2O（5.0 mL）の混合溶液に、Na2S2O4（11.0 g, 105 mmol）を加え、アルゴン雰囲気下で22時間加熱還流した。反応液を濃縮し、残渣に飽和食塩水溶液を加え、酢酸エチルで抽出、無水硫酸ナトリウムで乾燥した。溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ヘキサン / 酢酸エチル = 1 / 1 画分よりN-(2-amino-4-bromophenyl)-4-methoxybenzamide（2.70 g, 8.40 mmol）を得た（収率８０％）。 (2) EtOH (50 mL), THF (50 mL) and H 2 O (5.0 mL) of N- (4-bromo-2-nitrophenyl) -4-methoxybenzamide (3.70 g, 10.5 mmol) obtained above To the mixture solution of the above, Na 2 S 2 O 4 (11.0 g, 105 mmol) was added, and the mixture was heated to reflux under an argon atmosphere for 22 hours. The reaction mixture was concentrated, saturated aqueous sodium chloride solution was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of solvent is purified by silica gel column chromatography, and N- (2-amino-4-bromophenyl) -4-methoxybenzamide (2.70 g, 8.40 mmol) from hexane / ethyl acetate = 1/1 fraction. ) (Yield 80%).
　1H-NMR (400 MHz, CDCl3) δ: 7.85 (2H, d, J = 8.7 Hz), 7.77 (1H, brs), 7.53 (1H, d, J = 2.4 Hz), 7.17 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.97 (2H, d, J = 9.1 Hz), 6.72 (1H, d, J = 8.7 Hz), 3.88 (3H, s), 3.85 (2H, br). 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.85 (2 H, d, J = 8.7 Hz), 7.77 (1 H, brs), 7.53 (1 H, d, J = 2.4 Hz), 7.17 (1 H, dd, J = 8.7 Hz, 2.4 Hz), 6.97 (2 H, d, J = 9.1 Hz), 6.72 (1 H, d, J = 8.7 Hz), 3. 88 (3 H, s), 3. 85 (2 H, br).
（３）上記で得られたN-(2-amino-4-bromophenyl)-4-methoxybenzamide（106 mg, 0.330 mmol）の1,4-dioxane（5.0 mL）溶液に、DMAD（0.0809 mL, 0.495 mmol）を加え、microwave照射下、140 ℃で90分間加熱攪拌した。反応液を濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、ヘキサン / 酢酸エチル = 4 / 1画分よりdimethyl 2-[4-bromo-2-(4-methoxybenzamido)anilino]-2-butenedioate（114 mg, 0.244 mmol）を得た（収率74%）。 (3) DMAD (0.0809 mL, 0.495 mmol) in a solution of N- (2-amino-4-bromophenyl) -4-methoxybenzamide (106 mg, 0.330 mmol) obtained above in 1,4-dioxane (5.0 mL) ) Was added and the mixture was heated and stirred at 140 ° C. for 90 minutes under microwave irradiation. The residue obtained by concentration of the reaction solution is purified by silica gel column chromatography, and hexane / ethyl acetate = 4/1 fraction to give dimethyl 2- [4-bromo-2- (4-methoxybenzamido) anilino] -2- Butenedioate (114 mg, 0.244 mmol) was obtained (yield 74%).
　1H-NMR (400 MHz, CDCl3) δ: 9.04 (1H, brs), 8.53 (1H, d, J = 2.4 Hz), 8.35 (1H, br), 7.86 (2H, d, J = 9.1 Hz), 7.17 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.99 (2H, d, J = 8.7 Hz), 6.81 (1H, d, J = 8.3 Hz), 5.69 (1H, s), 3.88 (3H, s), 3.77 (3H, s), 3.66 (3H, s) . 1 H-NMR (400 MHz, CDCl 3 ) δ: 9.04 (1 H, brs), 8.53 (1 H, d, J = 2.4 Hz), 8.35 (1 H, br), 7.86 (2 H, d, J = 9.1 Hz) , 7.17 (1 H, dd, J = 8.7 Hz, 2.4 Hz), 6.99 (2 H, d, J = 8.7 Hz), 6.81 (1 H, d, J = 8.3 Hz), 5.69 (1 H, s), 3.88 (3 H) , s), 3.77 (3H, s), 3.66 (3H, s)   .
（４）上記で得られたdimethyl 2-[4-bromo-2-(4-methoxybenzamido)anilino]-2-butenedioate（121 mg, 0.261 mmol）のxylene（5.0 mL）溶液を、microwave照射下、200 ℃で24時間加熱攪拌した。析出した結晶を濾取、xyleneによる洗浄、減圧乾燥し、シリカゲルカラムクロマトグラフィーで精製し、ヘキサン/ 酢酸エチル = 1 / 1 画分よりmethyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate（64 mg, 0.148 mmol）を得た（収率５７％）。 (4) A solution of dimethyl 2- [4-bromo-2- (4-methoxybenzamido) anilino] -2-butenedioate (121 mg, 0.261 mmol) obtained above in xylene (5.0 mL) was irradiated under microwave irradiation to 200 The mixture was heated and stirred at ° C for 24 hours. The precipitated crystals are collected by filtration, washed with xylene, dried under reduced pressure, purified by silica gel column chromatography, and methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo from hexane / ethyl acetate = 1/1 fraction. -1, 4-dihydroquinoline-2-carboxylate (64 mg, 0.148 mmol) was obtained (yield 57%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.67 (1H, brs), 8.82 (1H, brs), 7.99 (1H, m), 7.98 (2H, d, J = 8.6 Hz), 7.57 (1H, brs), 7.20 (2H, d, J = 8.6 Hz), 3.99 (3H, s), 3.89 (3H, s). EI-MS (m/z): 432 [81BrM]+, 430 [79BrM]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.67 (1 H, brs), 8.82 (1 H, brs), 7.99 (1 H, m), 7. 98 (2 H, d, J = 8.6 Hz), 7.57 ( 1 H, brs), 7.20 (2 H, d, J = 8.6 Hz), 3.99 (3 H, s), 3. 89 (3 H, s). EI-MS (m / z): 432 [ 81 BrM] + , 430 [ 79 BrM] + .
（５）Methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateのかわりに上記で得られたmethyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylateを用い、ＣＩ－７の合成と同様の方法でＣＩＩ－１を得た（収率４６％）。 (5) Methyl 6-bromo-8- (4-methoxybenzamido) -4-obtained as described above instead of Methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate Using oxo-1, 4-dihydroquinoline-2-carboxylate, CII-1 was obtained in the same manner as in the synthesis of CI-7 (yield 46%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.68 (1H, brs), 9.09 (1H, brs), 8.12 (2H, d, J = 8.3 Hz), 8.12 (1H, m), 8.00 (2H, d, J = 8.3 Hz), 7.94 (2H, d, J = 8.7 Hz), 7.59 (1H, brs), 7.19 (2H, d, J = 9.1 Hz), 4.00 (3H, s), 3.91 (3H, s), 3.89 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.68 (1 H, brs), 9.09 (1 H, brs), 8.12 (2 H, d, J = 8.3 Hz), 8.12 (1 H, m), 8.00 ( 2H, d, J = 8.3 Hz), 7.94 (2H, d, J = 8.7 Hz), 7.59 (1H, brs), 7.19 (2H, d, J = 9.1 Hz), 4.00 (3H, s), 3.91 ( 3H, s), 3.89 (3H, s).
　以下の化合物ＣＩＩ－２からＣＩＩ－５の合成においては、methyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-4H-chromene-2-carboxylateのかわりに上記で得られたmethyl 6-bromo-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylateを用い、4-(methoxycarbonyl)phenylboronic acidのかわりに対応するボロン酸を用い、ＣＩＩ－１の合成と同様の方法で得た。 In the synthesis of the following compounds CII-2 to CII-5, methyl 6-bromo-8- (4-methoxybenzamido) -4-oxo-4H-chromene-2-carboxylate is substituted for methyl 6- obtained above Similar to the synthesis of CII-1 using bromo-8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylate and using the corresponding boronic acid instead of 4- (methoxycarbonyl) phenylboronic acid It was obtained by the method of
　Methyl 8-(4-methoxybenzamido)-6-(3-methoxycarbonylphenyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate（ＣＩＩ－２）の合成（収率１８％） Synthesis of Methyl 8- (4-methoxybenzamido) -6- (3-methoxycarbonylphenyl) -4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-2) (yield 18%)
　1H-NMR (400 MHz, DMSO-d6) δ: 10.67 (1H, brs), 9.05 (1H, brs), 8.29 (1H, s), 8.06 (2H, d, J = 7.5 Hz), 8.06 (1H, m), 8.00 (2H, d, J = 7.9 Hz), 7.70 (1H, t, J = 7.9 Hz), 7.57 (1H, brs), 7.18 (2H, m), 4.00 (3H, s), 3.93 (3H, s), 3.89 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.67 (1 H, brs), 9.05 (1 H, brs), 8.29 (1 H, s), 8.06 (2 H, d, J = 7.5 Hz), 8.06 ( 1H, m), 8.00 (2H, d, J = 7.9 Hz), 7.70 (1 H, t, J = 7.9 Hz), 7.57 (1 H, brs), 7.18 (2 H, m), 4.00 (3 H, s), 3.93 (3H, s), 3.89 (3H, s).
　Methyl 6-(4-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate（ＣＩＩ－３）の合成（収率４％）。 Synthesis of Methyl 6- (4-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-3) (yield 4%).
　1H-NMR (400 MHz, DMSO-d6) δ: 12.19 (1H, br), 10.70 (1H, brs), 9.75 (1H, brs), 8.99 (1H, brs), 8.01 (2H, d, J = 8.7 Hz), 8.01 (1H, m), 7.64 (2H, d, J = 8.7 Hz), 7.54 (1H, brs), 7.21 (2H, d, J = 9.1 Hz), 6.95 (2H, d, J = 8.7 Hz), 3.99 (3H, s), 3.89 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.19 (1H, br), 10.70 (1H, brs), 9.75 (1H, brs), 8.99 (1H, brs), 8.01 (2H, d, J = 8.7 Hz), 8.01 (1 H, m), 7. 64 (2 H, d, J = 8.7 Hz), 7.54 (1 H, brs), 7.21 (2 H, d, J = 9.1 Hz), 6.95 (2 H, d, J = 8.7 Hz), 3.99 (3H, s), 3.89 (3H, s).
　Methyl 6-(3-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate（ＣＩＩ－４）の合成（収率５４％）。 Synthesis of Methyl 6- (3-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-4) (yield 54%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.71 (1H, brs), 9.69 (1H, brs), 9.07 (1H, brs), 8.02 (1H, brs), 8.02 (2H, d, J = 8.7 Hz), 7.60 (1H, brs), 7.36 (1H, t, J = 7.5 Hz), 7.23-7.20 (2H, m), 7.21 (2H, d, J = 8.7 Hz), 6.86 (1H, m), 4.00 (3H, s), 3.89 (3H, s). EI-MS (m/z): 444 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.71 (1 H, brs), 9.69 (1 H, brs), 9.07 (1 H, brs), 8.02 (1 H, brs), 8.02 (2 H, d, J = 8.7 Hz), 7.60 (1H, brs), 7.36 (1H, t, J = 7.5 Hz), 7.23-7.20 (2H, m), 7.21 (2H, d, J = 8.7 Hz), 6.86 (1H, m) ), 4.00 (3H, s), 3.89 (3H, s). EI-MS (m / z): 444 [M] + .
　Methyl 6-(2-hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylate（ＣＩＩ－５）の合成（収率２３％）。 Synthesis of Methyl 6- (2-hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylate (CII-5) (yield 23%).
　1H-NMR (400 MHz, DMSO-d6) δ: 12.17 (1H, br), 10.70 (1H, brs), 9.74 (1H, brs), 9.01 (1H, brs), 8.00 (1H, m), 8.00 (2H, d, J = 8.3 Hz), 7.60 (1H, brs), 7.40 (1H, d, J = 7.5 Hz), 7.26 (1H, t, J = 7.1 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.02 (1H, d, J = 7.9 Hz), 6.96 (1H, t, J = 7.5 Hz), 4.00 (3H, s), 3.89 (3H, s). EI-MS (m/z): 444 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.17 (1 H, br), 10.70 (1 H, brs), 9.74 (1 H, brs), 9.01 (1 H, brs), 8.00 (1 H, m), 8.00 (2 H, d, J = 8.3 Hz), 7. 60 (1 H, brs), 7. 40 (1 H, d, J = 7.5 Hz), 7. 26 (1 H, t, J = 7.1 Hz), 7. 20 (2 H, d, J EI-MS (m / z) = 8.7 Hz), 7.02 (1 H, d, J = 7.9 Hz), 6.96 (1 H, t, J = 7.5 Hz), 4.00 (3 H, s), 3. 89 (3 H, s). ): 444 [M] + .
　6-(4-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid（ＣＩＩ－６）の合成 Synthesis of 6- (4-Carboxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-6)
　ＣＩＩ－１（20 mg, 0.0411 mmol）の1,4-dioxane（2.0 mL）溶液に、4 M NaOH水溶液（0.153 mL, 0.603 mmol）を加え、室温で12時間攪拌した後、50 ℃で3日間加熱攪拌した。反応液を濃縮し、結晶が析出するまで1 M 塩酸をゆっくり滴下し、析出した結晶を濾取、水洗、減圧乾燥し、ＣIII－６（14 mg, 0.0305 mmol）を得た（収率７４％）。 To a solution of CII-1 (20 mg, 0.0411 mmol) in 1,4-dioxane (2.0 mL), 4 M aqueous NaOH solution (0.153 mL, 0.603 mmol) was added, and after stirring for 12 hours at room temperature, 3 days at 50 ° C. Heated and stirred. The reaction solution was concentrated, 1 M hydrochloric acid was slowly added dropwise until crystals were precipitated, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain CIII-6 (14 mg, 0.0305 mmol) (yield 74%) ).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.70 (1H, brs), 10.23 (1H, brs), 8.29 (1H, d, J = 2.4 Hz), 8.12 (2H, d, J = 8.3 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.01 (2H, d, J = 8.3 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.13 (2H, m), 6.55 (1H, s), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.70 (1 H, brs), 10.23 (1 H, brs), 8. 29 (1 H, d, J = 2.4 Hz), 8.12 (2 H, d, J = 8.3 Hz), 8.03 (1 H, d, J = 2.4 Hz), 8.01 (2 H, d, J = 8.3 Hz), 7.69 (2 H, d, J = 8.3 Hz), 7.13 (2 H, m), 6.55 (1 H, s), 3.88 (3H, s).
　6-(3-Carboxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid（ＣＩＩ－７）の合成 Synthesis of 6- (3-Carboxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-7)
　ＣＩＩ－１のかわりにＣＩＩ－２を用い、ＣＩＩ－６の合成と同様の方法でＣＩＩ－７を得た（収率９１％）。 Using CII-2 instead of CII-1, CII-7 was obtained in a similar manner to the synthesis of CII-6 (yield 91%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.77 (1H, brs), 10.28 (1H, brs), 8.31 (1H, s), 8.28 (1H, d, J = 2.0 Hz), 8.11 (2H, d, J = 8.3 Hz), 8.03 (1H, brs), 7.90 (1H, d, J = 7.5 Hz), 7.71 (1H, d, J = 7.5 Hz), 7.41 (1H, t, J = 7.5 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.54 (1H, s), 3.87 (3H, s). EI-MS (m/z): 458 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.77 (1 H, brs), 10.28 (1 H, brs), 8.31 (1 H, s), 8.28 (1 H, d, J = 2.0 Hz), 8.11 ( 2H, d, J = 8.3 Hz), 8.03 (1 H, brs), 7. 90 (1 H, d, J = 7.5 Hz), 7.71 (1 H, d, J = 7.5 Hz), 7.41 (1 H, t, J = 7.5) Hz), 7.12 (2H, d, J = 8.7 Hz), 6.54 (1 H, s), 3.87 (3 H, s). EI-MS (m / z): 458 [M] + .
　6-(4-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid（ＣＩＩ－８）の合成 Synthesis of 6- (4-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-8)
　ＣＩＩ－１のかわりにＣＩＩ－３を用い、ＣＩＩ－６の合成と同様の方法でＣＩＩ－８を得た（収率４４％）。 Using CII-3 instead of CII-1, CII-8 was obtained in a similar manner to the synthesis of CII-6 (yield 44%).
　1H-NMR (400 MHz, DMSO-d6) δ: 12.18 (1H, br), 10.75 (1H, br), 9.72 (1H, brs), 9.12 (1H, br), 8.01 (1H, brs), 8.01 (2H, d, J = 9.1 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.54 (1H, brs), 7.16 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 8.3 Hz), 3.88 (3H, s). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.18 (1 H, br), 10.75 (1 H, br), 9. 72 (1 H, brs), 9.12 (1 H, br), 8.01 (1 H, brs), 8.01 (2H, d, J = 9.1 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.54 (1H, brs), 7.16 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 8.3 Hz), 3.88 (3 H, s).
　6-(3-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid（ＣＩＩ－９）の合成 Synthesis of 6- (3-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-9)
　ＣＩＩ－１のかわりにＣＩＩ－４を用い、ＣＩＩ－６の合成と同様の方法でＣＩＩ－９を得た（収率７１％）。 Using CII-4 instead of CII-1, CII-9 was obtained in a similar manner to the synthesis of CII-6 (yield 71%).
　1H-NMR (400 MHz, DMSO-d6) δ: 10.68 (1H, brs), 9.63 (1H, brs), 8.20 (1H, d, J = 2.4 Hz), 8.09 (2H, d, J = 8.7 Hz), 8.02 (1H, brs), 7.30 (1H, t, J = 7.5 Hz), 7.17 (1H, brs), 7.13 (1H, m), 7.13 (2H, d, J = 9.1 Hz), 6.79 (1H, m), 6.58 (1H, brs), 3.87 (3H, s). EI-MS (m/z): 430 [M]+.  1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.68 (1 H, brs), 9.63 (1 H, brs), 8.20 (1 H, d, J = 2.4 Hz), 8.09 (2 H, d, J = 8.7 Hz), 8.02 (1H, brs), 7.30 (1H, t, J = 7.5 Hz), 7.17 (1 H, brs), 7.13 (1 H, m), 7.13 (2 H, d, J = 9.1 Hz), 6.79 ( 1 H, m), 6.58 (1 H, brs), 3. 87 (3 H, s). EI-MS (m / z): 430 [M] + .
　6-(2-Hydroxyphenyl)-8-(4-methoxybenzamido)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid（ＣＩＩ－１０）の合成 Synthesis of 6- (2-Hydroxyphenyl) -8- (4-methoxybenzamido) -4-oxo-1,4-dihydroquinoline-2-carboxylic acid (CII-10)
　ＣＩＩ－１のかわりにＣＩＩ－５を用い、ＣＩＩ－６の合成と同様の方法でＣＩＩ－１０を得た（収率９４％）。 Using CII-5 instead of CII-1, CII-10 was obtained in a similar manner to the synthesis of CII-6 (yield 94%).
　　1H-NMR (400 MHz, DMSO-d6) δ: 10.71 (1H, brs), 9.80 (1H, brs), 8.70 (1H, br), 8.09 (1H, brs), 8.02 (2H, d, J = 9.1 Hz), 7.38 (1H, dd, J = 7.9 Hz, 1.6 Hz), 7.23 (1H, t, J = 8.3 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.05 (1H, d, J = 7.9 Hz), 6.94 (1H, m), 3.87 (3H, s). EI-MS (m/z): 430 [M]+. 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.71 (1 H, brs), 9.80 (1 H, brs), 8.70 (1 H, br), 8.09 (1 H, brs), 8.02 (2 H, d, J = 9.1 Hz), 7.38 (1 H, dd, J = 7.9 Hz, 1.6 Hz), 7.23 (1 H, t, J = 8.3 Hz), 7.14 (2 H, d, J = 9.1 Hz), 7.05 (1 H, d, J = 7.9 Hz), 6.94 (1 H, m), 3.87 (3 H, s). EI-MS (m / z): 430 [M] + .
＜ＧＰＲ３５作動薬としての活性の評価＞
　下記の試験を行い、ＧＰＲ３５作動薬としての活性を評価した。試験は、表１及び表２に示す番号の化合物と、ポジティブコントロールとしてラットＧＰＲ３５に対する活性を有することが知られているザプリナスト及びＤＳＣＧに対して行った。 <Evaluation of activity as GPR35 agonist>
The following test was performed to evaluate the activity as a GPR35 agonist. The test was performed on the compounds of numbers shown in Tables 1 and 2 and zaprinast and DSCG which are known to have activity against rat GPR35 as a positive control.
（１）発現ベクターであるｐＣＡＧＧＳに、アルカリホスファターゼ融合ＴＧＦ－α遺伝子（詳細はＪ．Ｃｅｌｌ　Ｂｉｏｌ．１５１，２０９－２２０，２０００．を参照）と、三量体型Ｇタンパク質Ｇｉ１、Ｇｉ３、Ｇｏ、Ｇ１２、Ｇ１３、Ｇｚ、Ｇｓ、Ｇ１６のαサブユニットのそれぞれとＧαｑとの融合遺伝子（詳細はＮａｔ．Ｍｅｔｈｏｄｓ，９，１０２１－１０２９，２０１２．を参照）と、ヒトＧＰＲ３５又はラットＧＰＲ３５の遺伝子を組み込み、ｐｏｌｙｅｔｈｙｌｅｎｅｉｍｉｎｅ“Ｍａｘ”試薬（Ｐｏｌｙｓｃｉｅｎｃｅ，Ｉｎｃ．）を用いてＨＥＫ２９３細胞に遺伝子導入した。 (1) in an expression vector pCAGGS, a alkaline phosphatase fusion TGF-alpha gene (see details J.Cell Biol.151,209-220,2000.), Trimeric G protein G i1, G i3, G A fusion gene of each of the α subunits of o , G 12 , G 13 , G z , G s and G 16 with G αq (for details, see Nat. Methods, 9, 1021-1029, 2012.), and human The gene of GPR35 or rat GPR35 was incorporated and transfected into HEK293 cells using polyethyleneimine "Max" reagent (Polyscience, Inc.).
（２）遺伝子導入したＨＥＫ２９３細胞に対し、Ｈａｎｋ’ｓ緩衝液（５ｍＭ　ＨＥＰＥＳ－ＮａＯＨ，ｐＨ７．４，１３７ｍＭ　ＮａＣｌ，５．３ｍＭ　ＫＣｌ，１．２６ｍＭ　ＣａＣｌ２，０．４４ｍＭ　ＭｇＣｌ２，０．３４ｍＭ　ＮａＨ２ＰＯ４，　０．４１ｍＭ　ＭｇＳＯ４，５．６ｍＭ　ｇｌｕｃｏｓｅ）中で化合物又はポジティブコントロールを１０００ｎＭ、１００００ｎＭの濃度で添加し、３０分間３７℃でインキュベートした。 (2) Hank's buffer solution (5 mM HEPES-NaOH, pH 7.4, 137 mM NaCl, 5.3 mM KCl, 1.26 mM CaCl 2 , 0.44 mM MgCl 2 , 0.34 mM NaH) to the transfected HEK 293 cells Compounds or positive controls were added at a concentration of 1000 nM, 10000 nM in 2 PO 4, 0.41 mM MgSO 4 , 5.6 mM glucose) and incubated for 30 minutes at 37 ° C.
（３）インキュベート後、緩衝液及び細胞表面のアルカリホスファターゼ活性を、パラニトロフェニルリン酸溶液（４０ｍＭ　Ｔｒｉｓ－ＨＣｌ，ｐＨ９．５，４０ｍＭ　ＮａＣｌ，１０ｍＭ　ＭｇＣｌ２，１０ｍＭ　ｐ－ｎｉｔｒｏｐｈｅｎｏｌ）を用いて、遊離するｐ－ｎｉｔｒｏｐｈｅｎｏｌの濃度から算出した（詳細はＮａｔ．Ｍｅｔｈｏｄｓ，９，１０２１－１０２９，２０１２．を参照）。具体的には、両画分のアルカリホスファターゼ活性の和を総活性とし、ｓｈｅｄｄｉｎｇ率（％）は（緩衝液中の活性／総活性）×１００で示した。結果を表１（ヒトＧＰＲ３５）及び表２（ラットＧＰＲ３５）に示す（ｎ＝３）。 (3) After incubation, the buffer solution and cell surface alkaline phosphatase activity were released using para-nitrophenyl phosphate solution (40 mM Tris-HCl, pH 9.5, 40 mM NaCl, 10 mM MgCl 2 , 10 mM p-nitrophenol) The concentration was calculated from the concentration of p-nitrophenol (see Nat. Methods, 9, 1021-1029, 2012. for details). Specifically, the sum of the alkaline phosphatase activities of both fractions was taken as the total activity, and the shedding rate (%) was shown as (activity in buffer / total activity) × 100. The results are shown in Table 1 (human GPR35) and Table 2 (rat GPR35) (n = 3).
Figure JPOXMLDOC01-appb-T000031
 
Figure JPOXMLDOC01-appb-T000031
 
Figure JPOXMLDOC01-appb-T000032
 
Figure JPOXMLDOC01-appb-T000032
 
＜ラットＧＰＲ３５発現ＲＢＬ－２Ｈ３細胞を用いた評価＞
　ラットマスト細胞株ＲＢＬ－２Ｈ３を用いて、Ｎ－末端側にヘマグルチニン（ＨＡ）エピトープタグ配列を付加したラットＧＰＲ３５をコードする遺伝子を構成的に発現した細胞を樹立し、下記の評価に使用した。 <Evaluation using rat GPR35 expressing RBL-2H3 cells>
Using the rat mast cell line RBL-2H3, cells constitutively expressing a gene encoding rat GPR35 to which hemagglutinin (HA) epitope tag sequence was added at the N-terminal side were established and used for the following evaluation.
　図１は、ラットＧＰＲ３５のｍＲＮＡの発現を定量ＲＴ－ＰＣＲにより測定した結果である。ＲＢＬ－２Ｈ３細胞（ＲＢＬ）はラット腹腔マスト細胞（ｐＭＣ）と比較して実質的にラットＧＰＲ３５の発現が認められないことがわかる。あわせて、蛍光標識した抗ＨＡ抗体を用いたフローサイトメトリーの結果から、安定的なラットＧＰＲ３５の発現が検出されることを確認した。 FIG. 1 shows the results of measurement of rat GPR35 mRNA expression by quantitative RT-PCR. It can be seen that RBL-2H3 cells (RBL) show substantially no expression of rat GPR35 as compared to rat peritoneal mast cells (pMC). In addition, it was confirmed from the results of flow cytometry using a fluorescently labeled anti-HA antibody that stable rat GPR35 expression was detected.
　図２は、ラットＧＰＲ３５を発現しているＲＢＬ－２Ｈ３細胞とラットＧＰＲ３５を発現していないＲＢＬ－２Ｈ３細胞による脱顆粒（Ｄｅｇｒａｎｕｌａｔｉｏｎ）の度合いの比較実験データである。
　ＨＡタグを付加したラットＧＰＲ３５を安定的に発現しているＲＢＬ－２Ｈ３細胞を、５０ｎｇ／ｍｌの抗ＤＮＰＩｇＥ抗体（ｃｌｏｎｅ　ＳＰＥ－７）で２４時間感作した。その後、２回洗浄操作を行って遊離ＩｇＥ抗体を除いた。次いで、ポジティブコントロールとしてのザプリナスト（１μＭ）、又は図２に示す濃度の化合物ＣＩ－１８又は化合物ＣＩ－２６の存在下で、細胞をジニトロフェノール－ヒト血清アルブミン（ＤＮＰ－ＨＳＡ）（３０ｎｇ／ｍｌ）で刺激をして、細胞による脱顆粒の度合いの指標としてβ－ヘキソサミニダーゼ活性（％）を調べた。結果を図２に示す。比較のため、上記と同様の処理をラットＧＰＲ３５を発現していないＲＢＬ－２Ｈ３細胞（ｍｏｃｋ）に対して行った結果を図２に示す。
　図２において、エラーバーは標準誤差（ｎ＝３）を示し、＊ｐ　＜　０．０５　及び　＊＊ｐ　＜　０．０１　のときは有意差ありと判断する。統計的処理は一元配置分散分析及びダネット検定により行った。 FIG. 2 is comparative experimental data of the degree of degranulation (Degranulation) by RBL-2H3 cells expressing rat GPR35 and RBL-2H3 cells not expressing rat GPR35.
RBL-2H3 cells stably expressing HA-tagged rat GPR35 were sensitized with 50 ng / ml anti-DNP IgE antibody (clone SPE-7) for 24 hours. Thereafter, washing was performed twice to remove free IgE antibodies. The cells are then treated with dinitrophenol-human serum albumin (DNP-HSA) (30 ng / ml) in the presence of zaprinast (1 μM) as a positive control, or compound CI-18 or compound CI-26 at the concentrations shown in FIG. Stimulation was conducted to examine β-hexosaminidase activity (%) as an indicator of the degree of degranulation by cells. The results are shown in FIG. For comparison, FIG. 2 shows the results of performing the same treatment as above on RBL-2H3 cells (mock) not expressing rat GPR35.
In FIG. 2, error bars indicate standard errors (n = 3), and it is judged that there is a significant difference when * p <0.05 and ** p <0.01. Statistical processing was performed by one-way analysis of variance and Dunnett's test.
　図２に示すように、ラットＧＰＲ３５を発現しているＲＢＬ－２Ｈ３細胞では、ＣＩ－１８又はＣＩ－２６の存在下でβ－ヘキソサミニダーゼ活性が用量依存的に有意に低下した。この結果は、ＣＩ－１８又はＣＩ－２６はＩｇＥを介する抗原刺激による脱顆粒応答を抑制し、抗アレルギー作用を示すことを示唆している。
  As shown in FIG. 2, in RBL-2H3 cells expressing rat GPR35, β-hexosaminidase activity was significantly reduced in the presence of CI-18 or CI-26 in a dose-dependent manner. This result suggests that CI-18 or CI-26 suppresses the antigen-induced degranulation response mediated by IgE, and exhibits an antiallergic action.
＜ラット腹腔マスト細胞を用いた評価＞
　ラット腹腔マスト細胞を用いてＩｇＥを介する抗原刺激による脱顆粒応答に対する化合物の影響を検討した。 <Evaluation using rat peritoneal mast cells>
Rat peritoneal mast cells were used to investigate the effect of compounds on IgE-mediated antigen-induced degranulation responses.
　Ｗｉｓｔａｒラット（雄、７週齢）から採取したラット腹腔細胞を、密度勾配遠心法により分画し、９０～９５％の純度の精製マスト細胞を得た。得られた細胞を、抗ＤＮＰ　ＩｇＥ抗体（ｃｌｏｎｅ　ＳＰＥ－７）（１０μｇ／ｍｌ）で３７℃３時間感作した。その後、２回洗浄操作を行って遊離ＩｇＥ抗体を除いた。次いで、リゾホスファチジルセリン（２μＭ）およびジニトロフェノール結合ヒト血清アルブミン（ＤＮＰ－ＨＳＡ）（１００ｎｇ／ｍｌ）で刺激をして、脱顆粒応答を誘導した。
　あわせて、上記と同様の操作において、ザプリナスト（１μＭ）あるいは表３に示す濃度の化合物ＣＩ－１６、１８、２６又は６３を、ＤＮＰ－ＨＡＳと同時に添加した。脱顆粒応答の程度は、β－ヘキソサミニダーゼ活性（％）を指標に測定した。結果を表３に示す。表３において、ＳＤは標準偏差（ｎ＝３）を示す。 Rat peritoneal cells collected from Wistar rats (male, 7 weeks old) were fractionated by density gradient centrifugation to obtain purified mast cells of 90-95% purity. The resulting cells were sensitized to anti-DNP IgE antibody (clone SPE-7) (10 μg / ml) at 37 ° C. for 3 hours. Thereafter, washing was performed twice to remove free IgE antibodies. Degranulation responses were then induced by stimulation with lysophosphatidylserine (2 μM) and dinitrophenol conjugated human serum albumin (DNP-HSA) (100 ng / ml).
In addition, in the same operation as described above, zaprinast (1 μM) or compound CI-16, 18, 26 or 63 at the concentration shown in Table 3 was added simultaneously with DNP-HAS. The degree of degranulation response was measured using β-hexosaminidase activity (%) as an index. The results are shown in Table 3. In Table 3, SD indicates a standard deviation (n = 3).
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
　表３に示すように、ＣＩ－１６、１８、２６、６３の存在下ではβ－ヘキソサミニダーゼ活性が用量依存的に有意に低下した。この結果は、ＣＩ－１６、１８、２６、６３はＩｇＥを介する抗原刺激による脱顆粒応答を抑制し、抗アレルギー作用を示すことを示唆している。 As shown in Table 3, β-hexosaminidase activity was significantly reduced in the presence of CI-16, 18, 26, 63 in a dose-dependent manner. This result suggests that CI-16, 18, 26, 63 suppress the IgE-mediated antigen-induced degranulation response and exhibits an antiallergic action.
＜製剤例１＞
　合成したＣＩ－１６を用いて、常法により次の組成からなる錠剤を調製した。
　ＣＩ－１６　　　　　　　　　　　　１００ｍｇ
　乳糖　　　　　　　　　　　　　　　６０ｍｇ
　馬鈴薯でんぷん　　　　　　　　　　３０ｍｇ
　ポリビニルアルコール　　　　　　　２ｍｇ
　ステアリン酸マグネシウム　　　　　１ｍｇ
　タール色素　　　　　　　　　　　　微量 Formulation Example 1
Using the synthesized CI-16, a tablet having the following composition was prepared by a conventional method.
CI-16 100 mg
Lactose 60 mg
Potato starch 30 mg
Polyvinyl alcohol 2 mg
Magnesium stearate 1 mg
Tar pigment trace amount
＜製剤例２＞
　合成したＣＩ－１６を用いて、常法により次の組成からなる散剤を調製した。
　ＣＩ－１６　　　　　　　　　　　　１５０ｍｇ
　乳糖　　　　　　　　　　　　　　　２８０ｍｇ Formulation Example 2
Using the synthesized CI-16, a powder having the following composition was prepared by a conventional method.
CI-16 150 mg
Lactose 280 mg
＜製剤例３＞
　合成したＣＩ－１６を用いて、常法により次の組成からなるシロップ剤を調製した。
　ＣＩ－１６　　　　　　　　　　　　１００ｍｇ
　精製白糖　　　　　　　　　　　　　４０ｍｇ
　ｐ－ヒドロキシ安息香酸エチル　　　４０ｍｇ
　ｐ－ヒドロキシ安息香酸プロピル　　１０ｍｇ
　ストロベリーフレーバー　　　　　　０．１ｃｃ
　以上の材料に水を加えて全量１００ｃｃとする。 Formulation Example 3
A syrup having the following composition was prepared by a conventional method using CI-16 synthesized.
CI-16 100 mg
Refined white sugar 40 mg
Ethyl p-hydroxybenzoate 40 mg
Propyl p-hydroxybenzoate 10 mg
Strawberry flavor 0.1cc
Add water to the above materials to make a total volume of 100 cc.
　日本国特許出願第２０１７－１７４７９９号及び第２０１８－１４６９６１号の開示は、その全体が参照により本明細書に取り込まれる。
　本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に援用されて取り込まれる。 The disclosures of Japanese Patent Application Nos. 2017-174799 and 2018-146961 are incorporated herein by reference in their entirety.
All documents, patent applications, and technical standards described herein are as specific and individually as individual documents, patent applications, and technical standards are incorporated by reference. Hereby incorporated by reference.

Claims (27)

  1. 　下記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000001
    ［一般式（Ｉ）において、ＸはＯ又はＮＨを表し、Ｒ１は置換もしくは非置換アリール基又は置換もしくは非置換芳香族複素環基を表し、Ｒ２は置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、置換もしくは非置換芳香族複素環アルキル基、ＯＲ４（Ｒ４は水素原子、置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、又は置換もしくは非置換芳香族複素環アルキル基である）、ＮＲ５Ｒ６（Ｒ５及びＲ６はそれぞれ独立にＲ４と同義であり、一緒になって環を形成してもよい）、ＮＲ７ＣＯＲ８（Ｒ７及びＲ８はそれぞれ独立にＲ４と同義である）、ＮＲ９ＳＯ２Ｒ１０（Ｒ９及びＲ１０はそれぞれ独立にＲ４と同義である）、Ｓ（Ｏ）ｎＲ１１（ｎは０、１もしくは２であり、Ｒ１１はＲ４と同義である）、ＣＯＲ１２（Ｒ１２はＲ４と同義である）、ＣＯＯＲ１３（Ｒ１３はＲ４と同義である）、ＯＣＯＲ１４（Ｒ１４はＲ４と同義である）、ＣＯＮＲ１５Ｒ１６（Ｒ１５及びＲ１６はそれぞれ独立にＲ４と同義である）、ＳＯ２ＮＲ１７Ｒ１８（Ｒ１７及びＲ１８はそれぞれ独立にＲ４と同義である）、ＯＣＨ２ＣＯＯＲ１９（Ｒ１９はＲ４と同義である）、ＯＳＯ２Ｒ２０（Ｒ２０はＲ４と同義である）、ＳＲ２１（Ｒ２１はＲ４と同義である）、ニトロ基、シアノ基又はハロゲン原子を表し、Ｒ３はＣＯＯＲ２２（Ｒ２２はＲ４と同義である）を表す。Ｒ２に付されたｎはＲ２の個数を表し、０～３の整数である。］     Heterocyclic compounds represented by the following general formula (I) or pharmacologically acceptable salts of the above-mentioned heterocyclic compounds.
    Figure JPOXMLDOC01-appb-C000001
    [In general formula (I), X represents O or NH, R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted Substituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or substituted Substituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 5 R 6 (R 5 and R 6 have the same meanings as R 4 each independently, NR 7 COR 8 (R 7 and R 8 each independently have the same meaning as R 4 ), NR 9 SO 2 R 10 (R 9 and R 10 each independently may form a ring) the same meaning as R 4), S (O) n R 11 (n is 0, 1 or 2, R 11 has the same meaning as R 4), COR 12 (R 12 has the same meaning as R 4 ), COOR 13 (R 13 is the same as R 4 ), OCOR 14 (R 14 is the same as R 4 ), CONR 15 R 16 (R 15 and R 16 are each independently the same as R 4 ) ), SO 2 NR 17 R 18 (R 1 And R 18 is synonymous with R 4 each independently), OCH 2 COOR 19 (R 19 has the same meaning as R 4), OSO 2 R 20 (R 20 has the same meaning as R 4), SR 21 ( R 21 represents the same as R 4 ), a nitro group, a cyano group or a halogen atom, and R 3 represents COOR 22 (R 22 has the same meaning as R 4 ). N attached to R 2 represents the number of R 2, is an integer of 0-3. ]
  2. 　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－１）で表される、請求項１に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000002
    ［一般式（Ｉ－１）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］     The heterocyclic compound according to claim 1 or the pharmacological compound according to claim 1, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-1) Acceptable salt.
    Figure JPOXMLDOC01-appb-C000002
    [In the general formula (I-1), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
  3. 　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－２）で表される、請求項１に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000003
    ［一般式（Ｉ－２）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］     The heterocyclic compound according to claim 1 or the pharmacological compound according to claim 1, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-2) Acceptable salt.
    Figure JPOXMLDOC01-appb-C000003
    [In the general formula (I-2), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
  4. 　ＸがＯである、請求項１～請求項３のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt of the heterocyclic compound, wherein X is O.
  5. 　Ｒ２がＮＲ５Ｒ６又はＮＲ７ＣＯＲ８である、請求項１～請求項４のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt of the heterocyclic compound, wherein R 2 is NR 5 R 6 or NR 7 COR 8 .
  6. 　Ｒ１が置換基を有していないか、置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を置換基として有する、請求項１～請求項５のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 R 1 has no substituent, a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group) , OR (R is a hydrogen atom, a substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R is each independently a hydrogen atom or substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted alkyl group) , SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent The heterocyclic compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt of the heterocyclic compound.
  7. 　Ｒ３がＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）である、請求項１～請求項６のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to any one of claims 1 to 6, or a pharmacologically acceptable compound of the heterocyclic compound, wherein R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group). Salt.
  8. 　Ｒ２がＮＨ２又はＮＨＣＯＲ８である、請求項１～請求項７のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound or the pharmacologically acceptable salt of the heterocyclic compound according to any one of claims 1 to 7, wherein R 2 is NH 2 or NHCOR 8 .
  9. 　Ｒ２がＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）である、請求項１～請求項８のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt of the heterocyclic compound, wherein R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group).
  10. 　ＧＰＲ３５作動薬としての活性を有する、請求項１～請求項９のいずれか１項に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to any one of claims 1 to 9, which has activity as a GPR35 agonist, or a pharmacologically acceptable salt of the heterocyclic compound.
  11. 　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の少なくとも一方に対する活性を有する、請求項１０に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to claim 10 or a pharmacologically acceptable salt of the heterocyclic compound according to claim 10, which has activity against at least one of human GPR35 and non-human animal GPR35.
  12. 　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の両方に対する活性を有する、請求項１０又は請求項１１に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound according to claim 10 or 11, or a pharmacologically acceptable salt of the heterocyclic compound, which has activity against both human GPR35 and non-human animal GPR35.
  13. 　前記ヒト以外の動物がげっ歯類である、請求項１１又は請求項１２に記載の複素環化合物又は前記複素環化合物の薬理学的に許容される塩。 The heterocyclic compound or the pharmacologically acceptable salt of the heterocyclic compound according to claim 11 or 12, wherein the non-human animal is a rodent.
  14. 　下記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物の薬理学的に許容される塩である、ＧＰＲ３５作動薬。
    Figure JPOXMLDOC01-appb-C000004
    ［一般式（Ｉ）において、ＸはＯ又はＮＨを表し、Ｒ１は置換もしくは非置換アリール基又は置換もしくは非置換芳香族複素環基を表し、Ｒ２は置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、置換もしくは非置換芳香族複素環アルキル基、ＯＲ４（Ｒ４は水素原子、置換もしくは非置換アルキル基、置換もしくは非置換シクロアルキル基、置換もしくは非置換アルケニル基、置換もしくは非置換アルキニル基、置換もしくは非置換脂環式複素環基、置換もしくは非置換アリール基、置換もしくは非置換アラルキル基、置換もしくは非置換芳香族複素環基、又は置換もしくは非置換芳香族複素環アルキル基である）、ＮＲ５Ｒ６（Ｒ５及びＲ６はそれぞれ独立にＲ４と同義であり、一緒になって環を形成してもよい）、ＮＲ７ＣＯＲ８（Ｒ７及びＲ８はそれぞれ独立にＲ４と同義である）、ＮＲ９ＳＯ２Ｒ１０（Ｒ９及びＲ１０はそれぞれ独立にＲ４と同義である）、Ｓ（Ｏ）ｎＲ１１（ｎは０、１もしくは２であり、Ｒ１１はＲ４と同義である）、ＣＯＲ１２（Ｒ１２はＲ４と同義である）、ＣＯＯＲ１３（Ｒ１３はＲ４と同義である）、ＯＣＯＲ１４（Ｒ１４はＲ４と同義である）、ＣＯＮＲ１５Ｒ１６（Ｒ１５及びＲ１６はそれぞれ独立にＲ４と同義である）、ＳＯ２ＮＲ１７Ｒ１８（Ｒ１７及びＲ１８はそれぞれ独立にＲ４と同義である）、ＯＣＨ２ＣＯＯＲ１９（Ｒ１９はＲ４と同義である）、ＯＳＯ２Ｒ２０（Ｒ２０はＲ４と同義である）、ＳＲ２１（Ｒ２１はＲ４と同義である）、ニトロ基、シアノ基又はハロゲン原子を表し、Ｒ３はＣＯＯＲ２２（Ｒ２２はＲ４と同義である）を表す。Ｒ２に付されたｎはＲ２の個数を表し、０～３の整数である。］     A GPR35 agonist which is a heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt of the heterocyclic compound.
    Figure JPOXMLDOC01-appb-C000004
    [In general formula (I), X represents O or NH, R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R 2 represents a substituted or unsubstituted alkyl group, substituted or substituted Non-substituted cycloalkyl group, substituted or non-substituted alkenyl group, substituted or non-substituted alkynyl group, substituted or non-substituted alicyclic heterocyclic group, substituted or non-substituted aryl group, substituted or non-substituted aralkyl group, substituted or non-substituted aromatic group Group heterocyclic group, substituted or unsubstituted heteroaromatic alkyl group, OR 4 (R 4 is a hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted Substituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or substituted Substituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 5 R 6 (R 5 and R 6 have the same meanings as R 4 each independently, NR 7 COR 8 (R 7 and R 8 each independently have the same meaning as R 4 ), NR 9 SO 2 R 10 (R 9 and R 10 each independently may form a ring) the same meaning as R 4), S (O) n R 11 (n is 0, 1 or 2, R 11 has the same meaning as R 4), COR 12 (R 12 has the same meaning as R 4 ), COOR 13 (R 13 is the same as R 4 ), OCOR 14 (R 14 is the same as R 4 ), CONR 15 R 16 (R 15 and R 16 are each independently the same as R 4 ) ), SO 2 NR 17 R 18 (R 1 And R 18 is synonymous with R 4 each independently), OCH 2 COOR 19 (R 19 has the same meaning as R 4), OSO 2 R 20 (R 20 has the same meaning as R 4), SR 21 ( R 21 represents the same as R 4 ), a nitro group, a cyano group or a halogen atom, and R 3 represents COOR 22 (R 22 has the same meaning as R 4 ). N attached to R 2 represents the number of R 2, is an integer of 0-3. ]
  15. 　前記一般式（Ｉ）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－１）で表される、請求項１４に記載のＧＰＲ３５作動薬。
    Figure JPOXMLDOC01-appb-C000005
    ［一般式（Ｉ－１）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］     The GPR35 agonist according to claim 14, wherein the heterocyclic compound represented by the general formula (I) or the heterocyclic compound is represented by the following general formula (I-1).
    Figure JPOXMLDOC01-appb-C000005
    [In the general formula (I-1), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
  16. 　前記一般式（Ｉ－１）で表される複素環化合物又は前記複素環化合物は下記一般式（Ｉ－２）で表される、請求項１４に記載のＧＰＲ３５作動薬。
    Figure JPOXMLDOC01-appb-C000006
    ［一般式（Ｉ－２）において、Ｒ１、Ｒ２、Ｒ３、Ｘ及びｎは一般式（Ｉ）におけるＲ１、Ｒ２、Ｒ３、Ｘ及びｎと同義である。］     The GPR35 agonist according to claim 14, wherein the heterocyclic compound represented by the general formula (I-1) or the heterocyclic compound is represented by the following general formula (I-2).
    Figure JPOXMLDOC01-appb-C000006
    [In the general formula (I-2), R 1 , R 2, R 3, X and n have the same meanings as R 1, R 2, R 3 , X and n in the general formula (I). ]
  17. 　ＸがＯである、請求項１４～請求項１６のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 16, wherein X is O.
  18. 　Ｒ２がＮＲ５Ｒ６又はＮＲ７ＣＯＲ８である、請求項１４～請求項１７のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 17, wherein R 2 is NR 5 R 6 or NR 7 COR 8 .
  19. 　Ｒ１が置換基を有していないか、置換もしくは非置換アルキル基、ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＣＨ２ＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＯＲ（Ｒは水素原子、置換もしくは非置換アルキル基）、ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＣＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ＣＯＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＯ２Ｒ（Ｒは置換もしくは非置換アルキル基）、ＳＯ２ＮＲＲ（Ｒはそれぞれ独立に水素原子又は置換もしくは非置換アルキル基）、ＳＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）、ニトロ基、シアノ基又はハロゲン原子を置換基として有する、請求項１４～請求項１８のいずれか１項に記載のＧＰＲ３５作動薬。 R 1 has no substituent, a substituted or unsubstituted alkyl group, COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), OCH 2 COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group) , OR (R is a hydrogen atom, a substituted or unsubstituted alkyl group), NRR (R is each independently a hydrogen atom or a substituted or unsubstituted alkyl group), COR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), CONRR (R is each independently a hydrogen atom or substituted or unsubstituted alkyl group), SO 2 R (R is a substituted or unsubstituted alkyl group), SO 2 NRR (R is each independently a hydrogen atom or substituted or unsubstituted alkyl group) , SR (R is a hydrogen atom or a substituted or unsubstituted alkyl group), a nitro group, a cyano group or a halogen atom as a substituent The GPR35 agonist according to any one of claims 14 to 18, wherein
  20. 　Ｒ３がＣＯＯＲ（Ｒは水素原子又は置換もしくは非置換アルキル基）である、請求項１４～請求項１９のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 19, wherein R 3 is COOR (R is a hydrogen atom or a substituted or unsubstituted alkyl group).
  21. 　Ｒ２がＮＨ２又はＮＨＣＯＲ８である、請求項１４～請求項２０のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 20, wherein R 2 is NH 2 or NHCOR 8 .
  22. 　Ｒ２がＮＨＣＯＡｒ（Ａｒは置換もしくは非置換アリール基）である、請求項１４～請求項２１のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 21, wherein R 2 is NHCOAr (Ar is a substituted or unsubstituted aryl group).
  23. 　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の少なくとも一方に対する活性を有する、請求項１４～請求項２２のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 22, which has activity against at least one of human GPR35 and non-human animal GPR35.
  24. 　ヒトのＧＰＲ３５と、ヒト以外の動物のＧＰＲ３５の両方に対する活性を有する、請求項１４～請求項２３のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 23, which has activity against both human GPR35 and non-human animal GPR35.
  25. 　前記ヒト以外の動物がげっ歯類である、請求項２３又は請求項２４に記載のＧＰＲ３５作動薬。 25. The GPR35 agonist according to claim 23 or 24, wherein the non-human animal is a rodent.
  26. 　ＧＰＲ３５が関与する症状又は疾患の治療に用いるための、請求項１４～請求項２５のいずれか１項に記載のＧＰＲ３５作動薬。 The GPR35 agonist according to any one of claims 14 to 25 for use in the treatment of a condition or disease involving GPR35.
  27. 　請求項１～請求項１３のいずれか１項に記載の複素環化合物もしくは前記複素環化合物の薬理学的に許容される塩、又は請求項１４～請求項２６のいずれか１項に記載のＧＰＲ３５作動薬を有効成分として含む、医薬組成物。 The heterocyclic compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt of the heterocyclic compound, or GPR 35 according to any one of claims 14 to 26 Pharmaceutical composition containing an agonist as an active ingredient.
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